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1 Evidence-based practice guideline: Disease-modifying Therapies for Multiple Sclerosis
2 Report of the Guideline Development, Dissemination, and Implementation Subcommittee
3 (GDDI) of the American Academy of Neurology
4 Alexander Rae-Grant, MD, FRCP(C)1; Gregory Day, MD, MSc, FRCPC2; Ruth Ann Marrie,
6 MD, PhD3; Alejandro Rabinstein, MD, FAAN4; Bruce Cree, MD, PhD, MCR5; Gary Gronseth,
7 MD, FAAN6; Michael Haboubi, DO7; June Halper, MSN, APN-C, MSCN, FAAN8; Jonathan P.
8 Hosey, MD, FAAN9; David E. Jones, MD10; Annette Langer-Gould, MD, PhD11; Robert Lisak,
9 FRCP (UK), FAAN, FANA12; Daniel Pelletier, MD13; Sonja Potrebic, MD, PhD, FAAN14;
10 Cynthia Sitcov15; Rick Sommers16; Julie Stachowiak, PhD17; Thomas S.D. Getchius18; Shannon
11 A. Merillat, MLIS19; Tamara Pringsheim, MD20
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5 12 1. Cleveland Clinic, Cleveland, OH
14 2. Knight Alzheimer Disease Research Center, Washington University in St. Louis, Saint
Louis, MO
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13 16 3. University of Manitoba, Winnipeg, Manitoba
17 4. Mayo Clinic, Rochester, MN
18 5. Multiple Sclerosis Center, University of California, San Francisco, CA
19 6. Kansas University Medical Center, Kansas City, KS
20 7. University of Louisville, Louisville, KY
21 8. Consortium of Multiple Sclerosis Centers, Hackensack, NJ
22 9. St. Luke’s University Health Network, Bethlehem, Pa
23 10. University of Virginia, Charlottesville, VA
1 Confidential draft: not for distribution, dissemination, or publication
1 11. Kaiser Permanente Southern California, Pasadena, CA
2 12. Consortium of Multiple Sclerosis Centers, Hackensack, NJ; Wayne State University,
Detroit, MI
3 13. University of Southern California, Los Angeles, CA
5 14. Kaiser Permanente Southern California, Los Angeles, CA
6 15. National Multiple Sclerosis Society, Arlington, VA
7 16. National Multiple Sclerosis Society, New York, NY
8 17. National Multiple Sclerosis Society, Santa Fe, NM
9 18. American Academy of Neurology, Minneapolis, MN
10 19. American Academy of Neurology, Minneapolis, MN
11 20. University of Calgary, Calgary, Alberta
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4 12 Acknowledgement
14 The authors would like to acknowledge the North American Research Committee on Multiple
15 Sclerosis (NARCOMS) Registry for their assistance in administering an outcomes survey, the
16 results of which were included in this guideline. NARCOMS is supported in part by the
17 Consortium of MS Centers (CMSC) and its Foundation.
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13 18 19 Address correspondence and reprint requests to
20 American Academy of Neurology:
21 [email protected]
22 Title character count: 115
23 Abstract word count: [xxx]
2 Confidential draft: not for distribution, dissemination, or publication
1 Manuscript word count: [XXXXX]
2 STUDY FUNDING
This practice guideline protocol was developed with financial support from the American
Academy of Neurology. Authors who serve as AAN subcommittee members or methodologists
(A.R.-G., A.R., G.S.D., M.H., A.L.G., S.P., T.P.) were reimbursed by the AAN for expenses
related to travel to subcommittee meetings where drafts of manuscripts were reviewed. All
authors on the panel were reimbursed by the AAN for expenses related to travel to two in-person
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meetings.
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3 DISCLOSURE
5 Alexander Rae-Grant is a local PI for one multiple sclerosis (MS) treatment study in progressive
6 MS with Novartis and Biogen IDEC, for which he does not receive any intellectual property,
7 time, or financial reimbursement; receives royalties from two textbooks he has published, one on
8 neurology and one on MS; and organizes and receives honoraria for ground rounds and
9 neurology review courses.
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4 10 11 Alejandro Rabinstein serves as an associate editor for the Neurocritical Care journal; receives
12 publishing royalties from Elsevier, Oxford, and UptoDate; and has served as an external safety
13 monitor for the trial ALIAS, and as a member of the event adjudication team for the PREVAIL
14 trial. His institution receives financial compensation from DJO Global.
15 3 Confidential draft: not for distribution, dissemination, or publication
1 Bruce Cree has received compensation for consulting from Abbvie, Biogen IDEC, EMD Serono,
2 MedImmune, Novartis, Genzyme/Sanofi Aventis, and Teva Neurosciences; has received
3 research support from Acorda, Avanir, Biogen IDEC, EMD Serono, Hoffman La Roche,
4 MedImmune, and Teva Neurosciences; has given expert testimony and prepared an affidavit for
5 medical malpractice cases (1 or 2 per year) within his area of expertise; and has acted as
6 consultant in a legal proceeding for Biogen IDEC and Acorda.
7 Gregory Day serves as the clinical director of the Anti-NMDA Receptor Encephalitis
9 Foundation, Inc. Canada (the Foundation is supported by private donor contributions) but does
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8 not receive financial reimbursement for his appointment or service; received the Future Leader in
11 Dementia award in October 2013 (including travel support to a Canadian conference for
12 dementia), sponsored by Pfizer, Canada; has received research support from the Weston Brain
13 Foundation, as a recipient of the Eugene M Johnson Jr. Weston Brain Institute Postdoctoral
14 Fellowship in Dementia Research; and holds stock in ANI Pharmaceuticals.
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15 16 Michael Haboubi has received travel reimbursement and honoraria for grand rounds
17 presentations in Madisonville, Kentucky.
18 19 June Halper has no relevant disclosures to report.
20 21 Jonathan P. Hosey has no relevant disclosures to report.
22 4 Confidential draft: not for distribution, dissemination, or publication
1 David E. Jones authored an MS Coalition consensus paper on disease-modifying therapies
2 (DMTs) in MS and served as co-chair of the advocacy committee of the Consortium of Multiple
3 Sclerosis Centers (CMSC), but did not receive financial compensation for either service; receives
4 institutional and personal compensation for consulting with Biogen IDEC, Genzyme, and
5 Novartis Pharmaceuticals; receives travel reimbursement from Biogen IDEC, Genzyme, CMSC,
6 and Multiple Sclerosis Association of America (MSAA) for travel to meetings; has received
7 honoraria for projects with the CMSC and MSAA; is employed by the University of Virginia;
8 and has given expert testimony on a malpractice case involving a patient with neurosarcoidosis.
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9 Annette Langer-Gould is involved in the National Multiple Sclerosis Society’s (NMSS) MS and
11 Pregnancy Study, and the MS Prevalence Working Group, but does not receive financial
12 compensation for her involvement; has received travel reimbursement from the Mayo Clinic,
13 Arizona, where she spoke as an invited speaker; from the Institute of Medicine, Washington, DC,
14 for participating on a study panel; and from the National Institute for Neurological Disorders and
15 Stroke (NINDS), to participate in a study section; receives research support from Biogen IDEC
16 for her service as a local PI for two clinical trials, from Hoffman LaRoche for her service as a
17 local PI for a clinical trial, and from the NINDS as R01 grant funding.
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10 18 19 Robert Lisak serves as the President of the CMSC and as a member of the Board of the DMC
20 Foundation; has served on scientific advisory boards for Syntimmune and Mallinckrodt; has
21 received funding for travel from the CMSC, the NMSS, the GBS/CIDP Foundation, and the
22 International Syntimmune for travel to consultants meetings; has served as a journal editor for
23 Clinical and Experimental Neuroimmunology and for Clinical Neuropharmacology; has received
5 Confidential draft: not for distribution, dissemination, or publication
1 publishing royalties from Willey for International Neurology, A Clinical Approach; has received
2 honoraria from Syntimmune, Mallinckrodt, and Teva Pharmaceuticals; has served on a speakers
3 bureau for Teva Pharmaceuticals for non-drug-related talks; has received research support from
4 Mallinckrodt for investigator-initiated wet bench studies, and from Teva, Biogen IDEC,
5 Novartis, Avanir, and Acorda for serving as a site investigator in multicenter trials; has received
6 financial compensation from the NMSS; has given expert testimony, prepared an affidavit, and
7 acted as witness for Teva Pharmaceuticals; and has acted as a witness for Acorda.
8 Ruth Ann Marrie has served as site principal investigator for Sanofi-Aventis clinical trials;
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9 receives research grants from nonprofit organizations, including CIHR, NMSS, MS Society of
11 Canada, MS Scientific Research Foundation, CMSC, Research Manitoba, and Rx & D Health
12 Research Foundation; and serves on the editorial board of Neurology.
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10 13 Daniel Pelletier has served on scientific advisory boards for Biogen-IDEC, Genzyme, Hoffman
15 LaRoche, Acorda, Novartis, and EMD-Serono; has received research support for Biogen-IDEC,
16 Genzyme, Hoffman LaRoche, and the NIH NINDS; and has received honoraria for providing
17 consulting services at scientific advisory board meetings from Biogen-IDEC, Genzyme,
18 Hoffman LaRoche, Acorda, Novartis, and EMD-Serono.
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14 19 20 Sonja Potrebic receives travel reimbursement from the AAN for the RITE work group and
21 Registry Committee meetings.
22 23 Rick Sommers reports no relevant disclosures.
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1 2 Cynthia Sitcov reports no relevant disclosures.
3 4 Julie Stachowiak reports no relevant disclosures.
5 Thomas S.D. Getchius has received financial compensation for travel for speaking at the
7 University of Louisville mTBI conference; has been serving as the vice-chair of the Council of
8 Medical Specialty Societies Clinical Practice Guideline Component Group from November 2013
9 to present, and has received research support from the CDC as a grant for muscular dystrophy
guideline development, dissemination, and implementation.
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6 11 12 Shannon A. Merillat reports no relevant disclosures.
13 Tamara Pringsheim has received research support from Shire Canada Inc., and the Canadian
15 Institute for Health Research.
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14 16 17 ABSTRACT
18 Maximum of 250 words; should summarize the guideline as follows:
19 Objective: Summary of clinical focus
20 Methods: Description of process
21 Results: Status, quality, and content of evidence
22 Recommendations: Summary of recommendations
23 7 Confidential draft: not for distribution, dissemination, or publication
INTRODUCTION
2 Multiple sclerosis (MS) affects approximately 400,000 people in the United States and 2.3
3 million patients worldwide (Browne 2014). Annual direct costs are estimated to be $24,000
4 higher for people living with MS, than those without MS (Campbell 2014). In many patients MS
5 is ultimately disabling, although the course varies markedly (Confavreaux 2006). Since 1993,
6 multiple disease-modifying therapies (DMTs) have been approved in the United States for the
7 treatment of relapsing forms of MS; most of these therapies are approved for use in other
8 industrialized nations. In addition, many other medications have been used off-label for disease
9 modification of MS. All of these medications may have adverse effects, which may vary from
bothersome to life-threatening.
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1 11 Controversies persist concerning who should receive these medications (e.g., with respect to
13 disease course and disease activity). It is sometimes unclear when or whether therapy should be
14 initiated, and whether there are sufficient data to comment on the comparative efficacy of agents
15 (Bruck 2013, Wingerchuk 2014). In addition, changes in the diagnostic criteria for MS in 2010
16 (Polman 2011), as well as modification of the classification scheme for MS subtypes in 2014
17 (Lublin 2014), have complicated the extension of efficacy data from clinical trials. Before
18 recommending a specific therapy, the clinician must navigate these complexities while carefully
19 balancing the potential for therapeutic benefits of a medication with patient preferences,
20 monitoring recommendations, and drug- and individual-specific risk factors. The recent
21 proliferation of new DMTs with differing mechanisms of action, risk profiles and monitoring
22 requirements has advanced this discussion to the forefront of clinical care, increasing its
23 relevance to clinicians and patients. AAN members and leadership have articulated a strong need
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1 for an updated guideline in this topic area. Given these complexities, an up-to-date guideline
2 focusing on these medications is critical to delivering optimal care to patients with MS.
3 The prior 2002 AAN clinical practice guideline on DMTs in MS (Goodin 2002) systematically
5 reviewed injectable medications approved for use in patients with MS at that time, including
6 interferon-beta 1b (Interferon Beta 1b SQ alternate day; Betaseron), interferon beta1a IM
7 (Interferon beta 1a intramuscular weekly; Avonex), interferon beta 1a SQ (Interferon beta 1a SQ
8 three times a week; Rebif) and glatiramer acetate (Copaxone). Medications commonly prescribed
9 off-label for the treatment of MS were not reviewed (e.g., azathioprine, cyclophosphamide,
mycofenolate mofetil) (Goodin 2002).
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4 11 The treatment landscape has changed considerably over the past 14 years, with more than 16
13 medications currently approved and widely prescribed for the treatment of MS in the United
14 States, and other agents nearing commercial approval (e.g., ocreluzimab). Recognizing these
15 remarkable therapeutic advances and persistent knowledge gaps, an updated systematic review
16 and practice guideline was prioritized by the AAN GDDI and AAN leadership in 2015. The
17 general membership of the American Academy of Neurology and other clinicians involved in
18 care of people with MS are the target users of this guideline. In addition, this guideline may be
19 informative to patients and their families, clinical and institutional leaders, and administrators.
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12 20 21 The updated guideline reviews indications for the use of DMT; counseling prior to and during
22 use of DMTs; patient preferences regarding DMT use; stopping DMTs; and indications for use in
23 different types of MS (relapsing remitting MS [RRMS], secondary progressive MS [SPMS],
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1 primary progressive MS [PPMS]). We reviewed adverse effects related to DMT use including
2 those affecting tolerability and less common but important risks and adverse effects. When
3 available, data concerning patient preference and patient-prioritized outcomes for treatment were
4 expressly analyzed. In addition, we solicited opinions concerning outcome measures of
5 importance from guideline panelists and patients with MS (via the NARCOMS registry) using a
6 formalized process. Perceived health benefits, adverse effects, and risks were formally
7 considered when developing recommendations.
8 The clinical questions for the guideline were developed by the panel and disseminated for public
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9 review in our guideline protocol. No substantive changes were made based on public review.
11 After review of the available evidence, adequate evidence was available to address the following
12 questions:
13 1.
14 annualized relapse rates?
15 2.
16 disease activity as measured by new T2 lesion burden or atrophy measures?
17 3.
18 progression as measured by in-study disease progression measures?
19 4.
20 different DMT superior to continuing present DMT in terms of relapse rate and MRI T2 or
21 gadolinium lesion activity?
22 5. In people with progressive MS, are DMTs superior to placebo or other DMTs as measured by
23 relapse rate or in-study disease progression?
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In people with RRMS, are DMTs superior to placebo or other DMTs as measured by
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In people with RRMS, are DMTs superior to placebo or other DMTs in reducing MRI new
In people with RRMS, are DMTs superior to placebo or other DMTs in preventing disease
In people with RRMS who experience disease activity while on a DMT, is changing to a
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1 6. What are the adverse effects of DMTs in patients with MS compared with placebo (adverse
2 event related discontinuation, and serious or life threatening adverse events)?
3 7. In people with clinically isolated syndromes, are DMTs superior to placebo in decreasing the
4 risk of conversion to clinically definite MS?
5 DESCRIPTION OF THE ANALYTIC PROCESS
7 In May 2015, a multidisciplinary panel consisting of 12 AAN physician members, 2
8 representative members from the Consortium of Multiple Sclerosis Centers (CMSC), and 3
9 patient representatives were recruited to develop this guideline. Two AAN staff representatives
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6 were also appointed to the panel. The physicians include content experts (B.C., D.E.J., D.P.,
11 R.A.M., J.H.); a methodology expert (T.P.); Guideline Development, Dissemination, and
12 Implementation Subcommittee (GDDI) members (A.R., A.R.G., G.S.P., A.L.G.); and CMSC
13 representatives (J.H., R.L.). The patient representatives (J.S., R.S., C.S.) are 3 adults with an MS
14 diagnosis. All panel members were required to submit online conflict of interest (COI) forms and
15 copies of their curriculum vitae (CV). The panel leadership, consisting of the lead author
16 (A.R.G.), the AAN methodologist (T.P.), and the AAN staff persons (T.G., S.M.), reviewed the
17 COI forms and CVs for financial and intellectual COI. These documents were specifically
18 screened to exclude individuals with a clear financial conflict as well as those whose professional
19 and intellectual bias might diminish the perceived credibility of the review. In accordance with
20 AAN policy, the lead author (A.R.G.) has no COI. Four of the 20 authors were determined to
21 have COI, which were judged to be not significant enough to preclude them from authorship
22 (D.E.J., B.C., D.P., R.L.). All authors determined to have COI were not permitted to review or
23 rate the evidence. These individuals were utilized in an advisory capacity to help validate key
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1 questions, assess the scope of the literature search, and identify seminal articles to validate the
2 literature search, and participated in the recommendation development process. AAN GDDI
3 leadership provided final approval of the author panel. This panel was solely responsible for
4 decisions concerning the design, analysis and reporting of the proposed systematic review, which
5 was then submitted for approval to the AAN GDDI.
6 This evidence-based guideline follows the methodologies outlined in the 2011 edition of the
8 AAN’s guideline development process manual. We summarize the process here and provide a
9 detailed description in the appendices referenced below. This process is compliant with Institute
10 of Medicine recommendations for guideline development (Graham 2011). Over the course of its
11 development, the public and experts had an opportunity to review the draft protocol during a 30-
12 day public comment period, during which the document was posted on the AAN website. During
13 this period, AAN staff sent invitations to review and comment on the guideline to key stake-
14 holders, including all AAN section members, and pertinent external physician and patient
15 organizations, including the National Multiple Sclerosis Society, the Consortium for MS Centers,
16 and (others to be added). The guideline was reviewed by the GDDI subcommittee before and
17 after the public comment period.
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7 18 19 Panel members developed the clinical questions and the data extraction template. The guideline
20 panel defined DMTs as medications that aim to affect the clinical course of MS by decreasing
21 relapses and/or slowing disease progression. We limited our search for relevant literature to
22 medications that have been approved by the US Food and Drug Administration (FDA), Health
23 Canada or the European Medicines Agency, or medications historically used for disease
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modification in MS but which were not licensed for this purpose. When disputes arose
2 concerning whether a medication should be included, the panel erred on the side of inclusion
3 (e.g., corticosteroids for disease modification and cladribine). In addition, agents which
4 potentially would receive licensure within the time frame of the guideline process were included
5 (e.g., daclizumab, approved by FDA May 2016; and ocrelizumab). Using this strategy, 20
6 medications were identified and included in this review: methotrexate, cyclophosphamide,
7 pulsed corticosteroids for disease modification, interferon-beta (four types; interferon beta 1b SQ
8 alt day, interferon beta 1a IM SQ, pegylated interferon SQ q alt week, interferon beta 1a SQ
9 TIW), glatiramer acetate, natalizumab, azathioprine, teriflunomide, mycophenolate mofetil,
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1 rituximab, daclizumab, mitoxantrone, alemtuzumab, fingolimod, dimethyl fumarate, intravenous
11 immunoglobulin for disease modification, and cladribine. To find relevant studies, the project
12 methodologist (T.P.) searched the Cochrane Library for Cochrane Systematic Reviews, including
13 any of the above mentioned medications for disease modification in individuals with MS. All
14 Cochrane reviews were evaluated by a second reviewer and graded using the AMSTAR tool—a
15 rating instrument of systematic review quality (ref to be added). Cochrane reviews were updated
16 by repeating the outlined search strategies in MEDLINE and CENTRAL and/or EMBASE from
17 the date last searched in the review to the present (XXXX). When there was a DMT for which no
18 previous Cochrane review had been published, we performed a de novo systematic review
19 following the 2011 AAN guideline development process manual (Neurology 2011). The search
20 was restricted to peer reviewed English-language articles on human subjects. A secondary search
21 of references of all Cochrane reviews and polling of all panel members was conducted until
22 March 2016 to identify any articles missed in the initial search. For efficacy outcomes, we
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1 considered data from randomized controlled trials. For harms, we considered data from
2 randomized controlled trials and cohort studies, case reports or case series.
3 Two non-conflicted panel members rated the class of evidence for each article according to the
5 AAN scheme for classification of therapeutic articles. Disagreements were resolved by a third
6 panel member. Outcome data from included studies were extracted by the guideline
7 methodologist and verified by a second panel member. Data for different disease types (RRMS,
8 SPMS, PPMS) were analyzed separately where possible. Studies comparing different DMTs
9 were included in this analysis. Prior to data analysis the panel completed an anonymous survey
10 on what would be considered a minimal clinically meaningful differences for various measures
11 of DMT efficacy and adverse effects to use in the analytic portion of the guideline. For relapses,
12 a relative risk reduction of ≥5% was considered clinically important, and a relative risk reduction
13 of ≤2% was considered clinically unimportant. For disability progression, a relative risk
14 reduction of ≥2% was considered clinically important, and a relative risk reduction of ≤1% was
15 considered clinically unimportant. For adverse event related discontinuation, a risk difference of
16 ≥10% was considered clinically important, and a risk difference of ≤5% was considered
17 clinically unimportant. For serious or life threatening adverse events, a risk difference of ≥0.1%
18 was considered clinically important, and a risk difference of ≤0.01% was considered clinically
19 unimportant.
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4 20 21 A modified GRADE process was utilized to develop conclusions (Guyatt 2011). In this process
22 the evidence is analyzed based on a variety of parameters of risk of bias (multiple types),
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1 consistency, directness, precision, and publication bias. Using this process, class of evidence can
2 be modified up or down transparently (Guyatt 2011).
3 The panel formulated practice recommendations on the basis of the strength of evidence and
5 other factors, including axiomatic principles of care, the magnitude of anticipated health benefits
6 relative to harms, financial burden, availability of interventions, and patient preferences. The
7 panel assigned levels of obligation (A, B, C, U, R) to the recommendations using a modified
8 Delphi process. Considerations for future research and recommendations were also developed
9 during the process of this guideline development.
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10 11 This guideline will be reassessed over time for currency and need for updating according to the
12 published AAN Guideline Development, Dissemination and Implementation process (Neurology
13 2011).
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14 RESULTS OF PHYSICIAN AND PATIENT SURVEY ON DESIRED OUTCOMES
16 Although studies have independently considered how MS experts [1, 2] and patients [3-8] with
17 MS weigh factors in therapeutic decision-making, few studies have investigated how closely
18 aligned prescriber- and patient-priorities are throughout this process. As AAN guidelines are
19 developed primarily to improve the ability of physicians to meet patient needs, we sought to
20 compare how outcomes potentially affected by DMTs were rank-ordered by panel experts (N =
21 18) and patients with MS (N = 2156). Data from 5 outcomes of interest were consistently
22 reported in high-quality (Class I or II) studies of medications for patients with RRMS: relapse
23 rate, disability progression, discontinuation of treatment due to adverse events, neuroimaging
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changes and serious adverse events (threatening life or organ). Three additional outcomes of
2 interest were identified through review of studies focused on patient-specified outcome measures
3 [3, 7, 8], including the effect of treatment on cognition, MS symptoms (e.g., fatigue, pain,
4 urinary incontinence), and quality of life measures. MS experts and patients with MS were asked
5 to rank all outcomes “in order of importance to you when choosing a MS treatment.” The MS
6 Guideline Development guideline panel was electronically surveyed using Google Surveys
7 (December 18, 2015 to January 11, 2016). Patients with MS participating in the North American
8 Research Committee on Multiple Sclerosis (NARCOMS) registry were invited to participate via
9 email. MS patient responses were accrued for a 7-day period (January 5–11, 2016). Survey
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1 questions (Supplement 1) were developed in consultation with members of the MS guideline
11 development and NARCOMS executive committees.
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10 12 All 18 members of the MS Guideline Development panel (100% response rate) and 2156 of 5487
14 actively engaged NARCOMS registry members (39.3% response rate) responded to the survey
15 request. The percentage of respondents designating an outcome as first-, second- or third-highest
16 priority is shown in Figure X. There was good agreement between MS experts and patients in the
17 rank-ordering of outcome measures of greatest importance to therapeutic decision making. The
18 ability of MS DMTs to reduce disability progression and relapse rate were identified as the two
19 most important factors when choosing a MS treatment. The potential for serious adverse events
20 associated with a treatment was the third most important factor when selecting a MS DMT.
21 Physicians were more likely than patients to rank relapse rate as a top priority (Fisher’s exact
22 test, two-tailed: p = 0.02). No significant differences were observed between respondents
23 concerning other outcomes (Fisher’s exact test, two-tailed: p > 0.05). Of interest, a cumulative
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1 total of 20% of MS experts and 18% of patients with MS identified selection of therapies most
2 likely to lead to improvements in quality of life measures. MS symptoms and preservation of
3 cognition was their top priority. Data concerning these measures are not consistently reported in
4 Class I or II studies of MS DMTs, which identifies a potentially important shortcoming in the
5 literature concerning meaningful outcomes that may be addressed through future studies.
6 ANALYSIS OF EVIDENCE
8 A total of 20 Cochrane systematic reviews were identified and used in the evidence review
9 process. These systematic reviews included 65 randomized controlled trials, which were
10 included in our evidence synthesis. For the update of the Cochrane reviews and de novo
11 systematic reviews, the combined searches yielded 3123 abstracts. Each abstract was reviewed
12 for relevance by at least 2 panel members. Of these, 235 were deemed relevant. The
13 corresponding articles were obtained for full-text review by 2 panelists working independently.
14 61 additional articles were identified for data extraction.
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15 16 All trials included individuals with MS ≥18 years of age. The maximum age of participants
17 varied across trials, but it was generally between 50 to 60 years. The majority of studies were 2
18 years in length (range between six months and three years). Trials occurred in multiple countries
19 worldwide.
20 21 Therapeutic question: In people with RRMS, are DMTs superior to placebo or other DMTs
22 as measured by annualized relapse rates?
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1 The efficacy of DMTs for preventing relapses was assessed in most trials by measuring the
2 proportion of patients with relapses compared to placebo over 2 years. Annualized relapse rates
3 (ARR) were derived from this information. Results are reported by drug, in alphabetical order.
4 Alemtuzumab
6 One class I (CARE-MS 1) and one class 2 (CAMMS223) study evaluated the proportion of
7 patients with RRMS with at least one relapse at two years with alemtuzumab treatment compared
8 to interferon beta 1a SQ three times a week. Meta-analysis of data from 914 participants
9 revealed reveals a risk ratio of 0.43 (0.29, 0.61), favoring alemtuzumab. Meta-analysis of data
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5 from the same two studies revealed a raw mean difference in annualized relapse rate of 0.26
11 (0.22, 0.29), favoring alemtuzumab.
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10 Conclusions
14 For individuals with RRMS, alemtuzumab is more effective than interferon beta 1a SQ 3 times a
15 week in reducing the risk of relapse at 2 years (high confidence, 1 Class 1 study, 1 Class 2 study;
16 confidence upgraded due to magnitude of effect). For individuals with RRMS, alemtuzumab is
17 more effective than interferon beta 1a SQ 3 times a week in reducing the ARR (high confidence,
18 1 Class 1 study, 1 Class 2 study; confidence upgraded due to magnitude of effect).
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13 19 20 21 Azathioprine
22 One class II study (Goodkin 1991) evaluated the proportion of individuals with at least 1 relapse
23 at 2 years with azathioprine vs placebo. This study found a risk ratio of 0.74 (0.50, 1.07),
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1 favoring treatment. The same study reported the ARR after 2 years of treatment; the raw mean
2 difference was 0.49 (0.07, 0.91), favoring treatment.
3 There are 2 Class II studies (Massacesi 2014; Etemadifar 2007) comparing azathioprine to beta
5 interferons in 244 individuals with RRMS for the ARR. Meta-analysis of data from these studies
6 shows a rate ratio of 0.64 (0.44, 0.92), favoring azathioprine. One of these Class II studies
7 (Etemadifar 2007) also evaluated the proportion of individuals with RRMS with relapses at 1
8 year. The RR was 0.75 (0.55, 0.99), favoring azathioprine.
9 Conclusions
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4 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
11 azathioprine compared to placebo in reducing the risk of relapse over 24 months (very low
12 confidence, 1 Class II study; confidence in evidence downgraded because of imprecision).
13 Azathioprine is probably more effective than placebo in reducing the mean number of relapses
14 over 2 years (moderate confidence, 1 Class II study; confidence upgraded due to magnitude of
15 effect). Azathioprine is more effective than beta interferons in reducing the ARR (high
16 confidence, 2 Class II studies; confidence upgraded due to magnitude of effect). Azathioprine is
17 probably more effective than beta interferon in reducing the risk of relapse over 12 months
18 (moderate confidence, 1 Class II study; confidence upgraded due to magnitude of effect).
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10 19 20 Cladribine
21 Two Class II studies (Romine 1999, Giovannoni 2010) evaluated cladribine vs placebo in 1376
22 individuals with RRMS, with 1 study (Giovannoni 2010) evaluating 2 different doses of oral
23 cladribine, and the other (Romine 1999) evaluating subcutaneous cladribine. The raw mean
19 Confidential draft: not for distribution, dissemination, or publication
1 difference in the ARR was 0.19 (0.14, 0.24). The proportion of patients with at least 1 relapse at
2 2 years was studied in 1 Class II study of 1326 individuals treated with oral cladribine 3.5 mg/kg
3 or 5.2 mg/kg. The risk ratio was 0.53 (0.45, 0.63) in individuals treated with either dose of
4 cladribine relative to placebo.
5 Conclusions
7 For individuals with RRMS, cladribine is more effective than placebo in reducing the ARR (high
8 confidence, 2 Class II studies; confidence upgraded due to magnitude of effect). Cladribine is
9 probably more effective than placebo in reducing the risk of relapse over 2 years (moderate
confidence, 1 Class II study; confidence upgraded due to magnitude of effect).
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6 Corticosteroids
13 One Class IV study of 81 individuals with RRMS (Zivadinov 2001) evaluated the effect of
14 methylprednisone 1 g/d for 5 days every 4 months vs placebo on the risk of relapse at 2 years,
15 and the ARR. The risk ratio for at least 1 relapse at two years was 1.16 (0.851, 1.591); the raw
16 mean difference in the annualized relapse rate was 0.0 (-0.238, 0.238).
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12 17 18 Two Class II studies (Sorensen 2009, Ravnborg 2010) evaluated monthly pulsed
19 methylprednisolone added to interferon-beta treatment compared to placebo added to interferon
20 treatment in 471 individuals with RRMS. The risk ratio for at least 1 relapse at 2 years was 0.33
21 (0.20, 0.54) based on data from the Sorensen study, and the risk ratio for at least 1 relapse at 3
22 years was 0.78 (0.62, 0.98) based on data from the Ravnborg study. The raw mean difference in
23 the ARR based on data from both studies was 0.24 (0.02, 0.47).
20 Confidential draft: not for distribution, dissemination, or publication
1 Conclusions
3 For individuals with RRMS, there is insufficient evidence to determine the efficacy of pulsed
4 corticosteroids alone compared to placebo in reducing the risk of relapse over 2 years or the
5 ARR (very low confidence, 1 Class IV study). Monthly pulsed corticosteroids added to
6 interferon-beta is probably more effective than placebo added to interferon in reducing the risk of
7 relapse over 2 years and 3 years (moderate confidence, 1 Class II study, confidence upgraded
8 due to magnitude of effect). Monthly pulsed corticosteroids added to interferon-beta is probably
9 more effective than placebo added to interferon-beta in reducing the ARR (moderate confidence,
2 Class II studies).
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2 Cyclophosphamide
13 One Class III study (Killian 1988) evaluated cyclophosphamide vs placebo in 14 individuals
14 with RRMS. The risk ratio for at least 1 relapse at 1 year was 0.67 (0.25, 1.44). The raw mean
15 difference between cyclophosphamide and placebo for the AAR was 1.80 (0.56, 3.04).
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12 16 17 Conclusions
18 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
19 cyclophosphamide compared to placebo in reducing the risk of relapse over 12 months (very low
20 confidence, 1 Class III study). Cyclophosphamide is possibly more effective than placebo in
21 reducing the ARR (low confidence, 1 Class III study; confidence upgraded due to magnitude of
22 effect).
23 21 Confidential draft: not for distribution, dissemination, or publication
1 Daclizumab High Yield Process (HYP)
2 One Class I study (Gold 2013) evaluated the effect of daclizumab HYP vs placebo in 397
3 individuals with RRMS. The risk ratio for relapse at 1 year was 0.54 (0.38, 0.75), and the RMD
4 in the ARR was 0.25 (0.13, 0.37). One Class II (Kappos 2015) study compared daclizumab HYP
5 to interferon beta 1a in 1841 individuals with RRMS over 3 years. The risk ratio for at least 1
6 relapse at 3 years was 0.67 (0.60, 0.75), and the RMD in the ARR was 0.17 (0.12, 0.22), favoring
7 daclizumab.
8 Conclusions
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9 For individuals with RRMS, daclizumab is more effective than placebo in decreasing the risk of
11 at least 1 relapse at 1 year (high confidence, 1 class I study, confidence in evidence upgraded due
12 to magnitude of effect). Daclizumab is more effective than placebo in decreasing the ARR (high
13 confidence, 1 Class I study, confidence in evidence upgraded due to magnitude of effect).
14 Daclizumab is probably more effective than interferon beta 1a in decreasing the risk of at least 1
15 relapse at 3 years (moderate confidence, 1 Class II study; confidence in evidence upgraded due
16 to magnitude of effect). Daclizumab is probably more effective than interferon beta 1a in
17 decreasing the ARR at 3 years (moderate confidence, 1 Class II study; confidence in evidence
18 upgraded due to magnitude of effect).
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10 19 20 Dimethyl Fumarate
21 One Class I (Fox 2012) and 1 Class II (Gold 2012) study evaluated the efficacy of dimethyl
22 fumarate vs placebo on relapses in 1540 individuals with RRMS. The risk ratio for the
22 Confidential draft: not for distribution, dissemination, or publication
1 proportion of individuals with at least 1 relapse at 2 years with dimethyl fumarate compared to
2 placebo was 0.64 (0.54, 0.77), and the raw mean difference in the ARR was 0.19 (0.13, 0.25).
3 Conclusions
5 In individuals with RRMS, dimethyl fumarate is more effective than placebo in decreasing the
6 risk of at least 1 relapse at 2 years (high confidence, 1 Cclass I and 1 Class II study; confidence
7 in evidence upgraded due to magnitude of effect). Dimethyl fumarate is more effective than
8 placebo in decreasing the ARR (high confidence, 1 Class I and 1 Class II study; confidence in
9 evidence upgraded due to magnitude of effect).
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4 Fingolimod
12 One Class I (Kappos 2010) and 1 Class II (Calabresi 2014) study compared fingolimod to
13 placebo for the risk of relapse at 2 years in 1556 individuals with RRMS. The risk ratio for the
14 proportion of individuals with at least 1 relapse at 2 years was 0.57 (0.50, 0.65), favoring
15 fingolimod. Two Class I studies (Kappos 2010, Saida 2012) and 1 Class II (Calabresi 2014)
16 study compared fingolimod to placebo for the ARR in 1670 individuals with RRMS. The raw
17 mean difference between fingolimod and placebo was 0.21 (0.16, 0.26), favoring fingolimod.
18 One Class I study (Cohen 2010) compared fingolimod to interferon beta 1a in 860 individuals
19 with RRMS. The risk ratio for at least 1 relapse at 12 months was 0.58 (0.46, 0.75), and the
20 RMD in the ARR was 0.17 (0.08, 0.26), favoring fingolimod.
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11 21 22 Conclusions
23 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with RRMS, fingolimod is more effective than placebo in reducing the risk of
2 relapse over 2 years (high confidence, 1 Class I and 1 Class 2 study; confidence upgraded due to
3 magnitude of effect). Fingolimod is more effective than placebo in reducing the ARR (high
4 confidence, 2 Class I studies and 1 Class 2 study). Fingolimod is more effective than interferon
5 beta 1a in reducing the risk of relapse at 1 year (high confidence, 1 Class I study; confidence in
6 evidence upgraded due to magnitude of effect). Fingolimod is more effective than interferon beta
7 1a in reducing the ARR (high confidence, 1 Class I study; confidence in evidence upgraded due
8 to magnitude of effect).
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9 Glatiramer Acetate
11 Two Class I studies (Fox 2012, Khan 2013) and 1 Class II (Johnson 1995) study evaluated the
12 ARR with glatiramer compared to placebo in 2368 individuals with RRMS. The RMD was 0.18
13 (0.09, 0.28), favoring glatiramer. There is 1 Class I study (Fox 2012) and 2 Class II (Bornstein
14 1987, Johnson 1995) studies in 1012 individuals with RRMS evaluating the proportion of
15 individuals with at least 1 relapse at 2 years. The risk ratio was 0.82 (0.69, 0.97), favoring
16 glatiramer acetate. One Class II study (Mikol 2008) compared glatiramer to Interferon beta 1a
17 SQ 3 times a week in 764 individuals with RRMS. There was no difference between the
18 proportion of patients with at least 1 relapse at 2 years, with a risk ratio of 0.93 (0.77, 1.14). Two
19 Class II studies (Cavadid 2009, O'Connor 2009) compared glatiramer to Interferon Beta 1b SQ
20 alternate day (250 micrograms) in 1420 individuals with RRMS. There was no difference
21 between the proportion of patients with at least 1 relapse at 2 years, with a risk ratio of 1.19
22 (0.75, 1.90).
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10 23 24 Confidential draft: not for distribution, dissemination, or publication
Conclusions
2 For individuals with RRMS, glatiramer is more effective than placebo in reducing the ARR (high
3 confidence, 2 Class I and 1 Class II studies). Glatiramer is probably more effective than placebo
4 in reducing the risk of relapse at 2 years (moderate confidence, 1 Class I and 2 Class II studies).
5 Interferon beta 1a SQ 3 times a week is possibly no more effective than glatiramer in reducing
6 the risk of at least 1 relapse at 2 years (low confidence, 1 Class II study). Interferon Beta 1b SQ
7 alternate day is possibly no more effective than glatiramer in reducing the risk of at least 1
8 relapse at 2 years (low confidence, 2 Class II studies; confidence in evidence downgraded due to
9 imprecision).
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10 Immunoglobulins
12 Two Class I (Fazekas 1997, Fazekas 2008) and 2 Class II (Achiron 1998, Lewanska 2002)
13 studies compared immunoglobulins to placebo in 460 individuals with RRMS. Meta-analysis of
14 study results revealed no difference between treatments, with a RMD of 0.37 (-0.21, 0.94) in the
15 ARR. One Class I (Fazekas 1997) and 1 Class II (Achiron 1998) study reported the proportion of
16 190 individuals with at least 1 relapse at 2 years. The risk ratio was 0.74 (0.61, 0.87), favoring
17 immunoglobulins.
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11 18 19 Conclusions
20 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
21 immunoglobulins compared to placebo in reducing the ARR (very low confidence, 2 Class I
22 study and 2 Class II studies; confidence in evidence downgraded due to imprecision).
23 Immunoglobulins are more effective than placebo in reducing the risk of at least 1 relapse
25 Confidential draft: not for distribution, dissemination, or publication
1 over2two years (high confidence, 1 Class I study and 1 Class II study; confidence in evidence
2 upgraded due to magnitude of effect).
3 Interferon beta 1a intramuscular weekly
5 One Class 1 (Vollmer 2014) and 1 Class 2 (Jacobs 1996) study evaluated the proportion of
6 individuals with RRMS with at least 1 relapse at 2 years compared to placebo. Meta-analysis of
7 data from 1198 individuals revealed a risk ratio of 0.79 (0.68, 0.92), favoring treatment. One
8 Class I study (Vollmer 2014) found that interferon beta 1a intramuscular weekly was more
9 effective than placebo in reducing the ARR, with a RMD1 of 0.08 (0.01, 0.15).
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10 Conclusions
12 For individuals with RRMS, interferon beta 1a intramuscular weekly is more effective than
13 placebo in reducing the risk of relapse over 24 months (high confidence, 1 Class I study, 1 Class
14 II study; confidence upgraded due to magnitude of effect). Interferon beta 1a intramuscular
15 weekly is probably more effective than placebo in reducing the ARR (moderate confidence, 1
16 Class I study).
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11 17 18 Interferon beta 1a SQ three times a week
19 One Class I study (PRISMS 1998) compared Interferon beta 1a SQ 3 times a week to placebo in
20 560 individuals with RRMS. The risk of relapse at 2 years was significantly lower with
21 Interferon beta 1a SQ 3 times a week, with a risk ratio of 0.84 (0.77, 0.92). One Class II study
22 (Panitch 2002) compared Interferon beta 1a SQ 3 times a week to Interferon beta 1a
1
The raw mean difference is used when all studies use the same outcome measure to assess an outcome. The raw mean difference is the mean difference between the treatment groups for the specified outcome. 26 Confidential draft: not for distribution, dissemination, or publication
1 intramuscular weekly in 677 individuals with RRMS. The risk of relapse at one year was
2 significantly lower with Interferon beta 1a SQ 3 times a week compared to Interferon beta 1a
3 intramuscular weekly, with a risk ratio of 0.84 (0.72, 0.99).
4 Conclusions
6 For individuals with RRMS, Interferon beta 1a SQ 3 times a week is more effective than placebo
7 in reducing the risk of relapse at 2 years (high confidence, 1 Class I study; confidence in
8 evidence upgraded due to magnitude of effect). Interferon beta 1a SQ 3 times a week is probably
9 more effective than Interferon beta 1a intramuscular weekly in reducing the risk of relapse at 1
year (moderate confidence, 1 Class II study).
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5 11 Interferon Beta 1b SQ alternate day
13 One Class II study (Group 1993) including 227 individuals with RRMS evaluated the effect of
14 Interferon Beta 1b SQ alternate day vs placebo on relapses. This study found a risk ratio of 0.82
15 (0.70, 0.95) for the proportion of individuals with at least 1 relapse at 2 years, and a RMD of
16 0.43 (0.24, 0.62) in the relapse rate over 2 years.
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12 17 18 Conclusions
19 For individuals with RRMS, Interferon Beta 1b SQ alternate day is probably more effective than
20 placebo in reducing the risk of relapse over 2 years (moderate confidence, 1 Class II study;
21 confidence upgraded due to magnitude of effect). Interferon Beta 1b SQ alternate day is probably
22 more effective than placebo in reducing the relapse rate over 2 years (moderate confidence, 1
23 Class II study; confidence upgraded due to magnitude of effect).
27 Confidential draft: not for distribution, dissemination, or publication
1 2 Methotrexate
3 One Class III study (Currier 1993) compared methotrexate to placebo in 20 individuals with
4 RRMS. There was no significant difference in the risk of relapse over 18 months, with a risk
5 ratio of 0.35 (0.10, 1.04). One Class II study (ref to be added) compared methotrexate to
6 interferon beta 1a in 80 individuals with RRMS. The difference between treatments in the
7 number of relapses over 12 months was not statistically significant, although the RMD of 0.39 (-
8 0.01, 0.79) favored interferon beta 1a over methotrexate.
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9 Conclusions
11 In individuals with RRMS, there is insufficient evidence to determine the efficacy of
12 methotrexate compared to placebo in decreasing the proportion of patients who relapsed over 18
13 months (very low confidence, 1 Class III study). There is insufficient evidence to determine the
14 efficacy of methotrexate compared to interferon beta 1a in decreasing the number of relapses
15 over 12 months (very low confidence, 1 Class III study).
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10 16 17 Mitoxantrone
18 One Class I study (Millefiorini 1997) compared mitoxantrone to placebo in 51 individuals with
19 RRMS. The risk ratio for the proportion of individuals with a relapse over 24 months was 0.47
20 (0.27, 0.77), favoring mitoxantrone.
21 22 Conclusion
28 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with RRMS, mitoxantrone is more effective than placebo in decreasing the risk
2 of relapse at 2 years (high confidence, 1 Class I study; confidence in evidence upgraded due to
3 magnitude of effect).
4 Mycophenolate Mofetil
6 Two Class II studies (Etemadifar 2010, Remington 2010) compared mycophenolate mofetil plus
7 interferon beta 1a to placebo plus interferon beta 1a in 50 individuals with RRMS. No significant
8 difference was observed between treatments in the risk of relapse at 1 year, with a risk ratio of
9 0.63 (0.18, 2.23). One Class III study (Frohman 2010) compared mycophenolate mofetil to
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5 interferon beta 1a in 35 individuals with RRMS. There was no significant difference in the risk
11 of relapse at 6 months, with a risk ratio of 1.18 (0.22, 6.16).
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10 Conclusions
14 For individuals with RRMS, mycophenolate plus interferon beta 1a is possibly no more effective
15 than placebo plus interferon beta 1a in decreasing the risk of relapse at 1 year (low confidence, 2
16 Class II studies; confidence in evidence downgraded due to imprecision). There is insufficient
17 evidence to determine the efficacy of mycophenolate mofetil compared to interferon beta 1a in
18 decreasing the risk of relapse at 6 months (very low confidence, 1 Class III study).
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13 19 20 Natalizumab
21 One Class I study (Polman 2006) compared natalizumab to placebo in 942 individuals with
22 RRMS. The risk of at least 1 relapse at 2 years was significantly lower with natalizumab than
29 Confidential draft: not for distribution, dissemination, or publication
1 placebo, with a risk ratio of 0.56 (0.49, 0.64). The annualized relapse rate was significantly lower
2 with natalizumab, with a RMD of 0.41 (0.31, 0.51).
3 4 Conclusion
5 For individuals with RRMS, natalizumab is more effective than placebo in reducing the risk of
6 relapse at 2 years, and reducing the ARR (high confidence, 1 Class I study; confidence in
7 evidence upgraded due to magnitude of effect).
8 Pegylated Interferon
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9 One Class I study (Calabresi 2014) compared pegylated interferon 125 mcg every 2 weeks to
11 placebo in 1012 individuals with RRMS. The risk of at least 1 relapse at 1 year was significantly
12 lower with pegylated interferon, with a risk ratio of 0.62 (0.49, 0.78). The ARR was significantly
13 lower with pegylated interferon, with a RMD of 0.11 (0.01, 0.21).
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10 Conclusion
16 For individuals with RRMS, pegylated interferon is more effective than placebo in reducing the
17 risk of relapse and the ARR at 1 year (high confidence, 1 Class I study; confidence in evidence
18 upgraded due to magnitude of effect).
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15 19 20 Rituximab
21 One Class II study compared rituximab to placebo in 104 individuals with RRMS (Hauser 2008).
22 The risk of relapse was significantly lower with rituximab compared to placebo, with a risk ratio
30 Confidential draft: not for distribution, dissemination, or publication
1 of 0.51 (0.28, 0.94). The ARR at 1 year was not significantly different between treatments with a
2 RMD 0.30 (-0.07, 0.67).
3 Conclusions
5 For individuals with RRMS, rituximab is probably more effective than placebo in decreasing the
6 risk of relapse at 1 year (moderate confidence, 1 Class II study; confidence in evidence upgraded
7 due to magnitude of effect). There is insufficient evidence to determine the efficacy of rituximab
8 compared to placebo in decreasing the ARR at 1 year (very low confidence, 1 Class II study;
9 confidence in evidence downgraded due to imprecision).
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10 Teriflunomide
12 One Class II study (O'Connor 2011) compared teriflunomide to placebo in 1088 individuals with
13 RRMS. The risk of at least one relapse at 2 years was significantly lower with teriflunomide,
14 with a risk ratio of 0.88 (0.79, 0.98). Three Class II studies (O'Connor 2006, O'Connor 2011,
15 Confavreux 2014) compared teriflunomide to placebo in 1597 individuals with RRMS. The ARR
16 was significantly lower with teriflunomide compared to placebo, with a RMD of 0.18 (0.11,
17 0.25).
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11 18 19 Conclusions
20 For individuals with RRMS, teriflunomide is probably more effective than placebo in decreasing
21 the risk of relapse at 2 years (moderate confidence, 1 Class II study; confidence in evidence
22 upgraded due to magnitude of effect). Teriflunomide is more effective than placebo in decreasing
31 Confidential draft: not for distribution, dissemination, or publication
1 the ARR (high confidence, 3 Class II studies; confidence in evidence upgraded due to magnitude
2 of effect).
3 Therapeutic question: In people with RRMS, are DMTs superior to placebo or other DMTs
5 in reducing MRI new disease activity as measured by new T2 lesion burden or atrophy
6 measures?
7 Various measures of the effect of DMTs on MRI disease activity were performed, including
8 mean differences in volume or number of T2 lesions, the proportion of patients with new or
9 enlarging T2 lesions, or changes in whole brain volume compared to baseline.
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10 Alemtuzumab
12 One Class I study in 563 relapsing patients with MS (Cohen 2012) comparing alemtuzumab to
13 interferon beta 1a reported a decrease in T2 lesion volume from baseline to 2 years in, with a
14 standardized mean difference (SMD)2 of 0.18 (0.01, 0.36). The same study reported a lower
15 proportion of patients with new or enlarging T2 lesions at 2 years in those treated with
16 alemtuzumab compared to interferon beta 1a, with a risk ratio of 0.84 (0.71, 0.99). One Class II
17 study (Coles 2012) found no difference between alemtuzumab and interferon beta 1a concerning
18 the T2 lesion load from baseline to 3 years, with an SMD 0.10 (-0.20, 0.39). The same Class II
19 study (Coles 2012) found a smaller decrease in brain volume on T1 from baseline to 3 years with
20 alemtuzumab compared to interferon beta 1a, with an SMD of 0.37 (0.07, 0.67).
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11 21 2
The standardized mean difference is used as a summary statistic in meta‐analysis when the studies all assess the same outcome but measure it in a variety of ways. In this circumstance it is necessary to standardize the results of the studies to a uniform scale before they can be combined. The standardized mean difference expresses the size of the intervention effect in each study relative to the variability observed in that study. 32 Confidential draft: not for distribution, dissemination, or publication
Conclusions
2 For individuals with RRMS, alemtuzumab is probably more effective than interferon beta 1a in
3 decreasing the volume of T2 lesions from baseline to 2 years (moderate confidence, 1 Class I
4 study). Alemtuzumab is probably more effective than interferon beta 1a in reducing the risk of
5 new or enlarging T2 lesions at 2 years (moderate confidence, 1 Class I study). There is
6 insufficient evidence to determine the efficacy of alemtuzumab compared to interferon beta 1a in
7 decreasing the T2 lesion load from baseline to 3 years (very low confidence, 1 Class II study;
8 confidence in evidence downgraded due to imprecision). Alemtuzumab is probably more
9 effective than interferon beta 1a in decreasing the change in brain volume on T1 from baseline to
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1 3 years (moderate confidence, 1 Class II study, confidence in evidence upgraded due to
11 magnitude of effect).
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10 Azathioprine
14 One Class II study comparing azathioprine to beta interferons (Massacesi 2014) evaluated the
15 proportion of individuals with RRMS with no new T2 lesions at 2 years. There was no
16 significant difference between treatments, with a RR of 1.21 (0.81, 1.82).
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13 17 18 Conclusion
19 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
20 azathioprine compared to beta interferon in reducing the risk of new T2 lesions at 2 years (very
21 low confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
22 23 Cladribine
33 Confidential draft: not for distribution, dissemination, or publication
1 One Class II study (Giovannoni 2010) evaluated the effect of 2 different doses of oral cladribine
2 (3.5 mg vs 5.25 mg) in 1326 individuals with RRMS on the proportion of patients with at least 1
3 active T2 lesion at 2 years. This study demonstrated a risk ratio of 0.529 (0.478, 0.587) with
4 either dose of cladribine compared to placebo.
5 Conclusion
7 For patients with RRMS, cladribine is probably more effective than placebo in reducing the risk
8 of at least 1 active T2 lesion at 2 years (moderate confidence, 1 Class II study; confidence in the
9 evidence upgraded due to magnitude of effect).
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6 Corticosteroids
12 One Class II study (Zivadinov 2001) compared pulsed corticosteroids to placebo in 81
13 individuals with RRMS on MRI T2 lesion volume and brain parenchymal volume at 5 years.
14 This study demonstrated a SMD of 0.203 (-0.234, 0.640) for T2 lesion volume and a SMD of
15 0.622 (0.175, 1.068) for brain parenchymal volume at 5 years.
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11 16 17 Conclusions
18 For patients with RRMS, there is insufficient evidence to determine the efficacy of pulsed
19 corticosteroids compared to placebo in reducing T2 lesion volume at 5 years (very low
20 confidence, 1 Class II study, confidence in evidence downgraded due to imprecision). Pulsed
21 corticosteroids are probably more effective than placebo in reducing the loss of parenchymal
22 volume at 5 years (moderate confidence, 1 Class II study, confidence upgraded due to magnitude
23 of effect).
34 Confidential draft: not for distribution, dissemination, or publication
1 2 Daclizumab HYP
3 One Class I study (Gold 2013) evaluated the effect of daclizumab HYP vs placebo on the mean
4 number of new or newly enlarging lesions at 1 year in 397 individuals with RRMS. This study
5 found a SMD of 0.94 (0.74, 1.15) favoring daclizumab HYP. One Class II study (Kappos 2015)
6 compared daclizumab HYP to interferon beta 1a in 1841 individuals with RRMS. The SMD in
7 the mean number of new or newly enlarging T2 hyperintense lesions over 2 years was 0.42
8 (0.33, 0.52), favoring daclizumab HYP.
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9 Conclusions
11 For individuals with RRMS, daclizumab HYP is more effective than placebo in preventing new
12 or newly enlarging T2 lesions at 1 year (high confidence, 1 Class I study; confidence in evidence
13 upgraded due to magnitude of effect). Daclizumab HYP is probably more effective than
14 interferon beta 1a in preventing new or newly enlarging T2 lesions at 2 years (moderate
15 confidence, 1 Class II study, confidence in evidence upgraded due to magnitude of effect).
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10 16 17 Dimethyl Fumarate
18 One Class I (Fox 2012) and 1 Class II (Gold 2012) study compared the effect of dimethyl
19 fumarate to placebo on the mean number of new or enlarging T2 lesions at 2 years in 1097
20 individuals with RRMS. The SMD was 0.49 (0.29, 0.69), favoring dimethyl fumarate.
21 22 Conclusion
35 Confidential draft: not for distribution, dissemination, or publication
1 In individuals with RRMS, dimethyl fumarate is more effective than placebo in decreasing the
2 number of new or enlarging T2 lesions at 2 years (high confidence, 1 Class I and 1 Class II
3 study; confidence in evidence upgraded due to magnitude of effect).
4 Fingolimod
6 One Class I (Kappos 2010) and 1 Class II (Calabresi 2014) study compared the proportion of
7 individuals with new or enlarging T2 lesions at 2 years with fingolimod vs placebo in 1224
8 persons with RRMS. The risk ratio was 0.65 (0.59, 0.71), favoring fingolimod. One Class I study
9 (Cohen 2010) in 733 individuals with RRMS compared fingolimod to interferon beta 1a. The
10 risk ratio for the proportion of individuals with new or enlarged T2 lesions at 12 months was
11 0.83 (0.72, 0.96).
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5 12 Conclusions
14 In individuals with RRMS, fingolimod is more effective than placebo in reducing the risk of new
15 or enlarging T2 lesions at 2 years (high confidence, 1 Class I and 1 Class II study; confidence in
16 evidence upgraded due to magnitude of effect). Fingolimod is probably more effective than
17 interferon beta 1a in reducing the risk of new or enlarging T2 lesions over 1 year (moderate
18 confidence, 1 Class I study).
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13 19 20 Glatiramer
21 One Class I study (Fox 2012) compared the number of new or enlarging T2 lesions at 2 years in
22 292 individuals with RRMS receiving glatiramer vs placebo. The SMD between treatments was
23 0.46 (0.23, 0.69), favoring glatiramer. One Class II study (Mikol 2008) compared the proportion
36 Confidential draft: not for distribution, dissemination, or publication
1 of patients with active T2 lesions at 2 years with glatiramer vs interferon beta 1a SQ 3 times a
2 week in 460 individuals with RRMS. There was no difference between treatments, with a risk
3 ratio of 0.95 (0.82, 1.11).
4 Conclusions
6 For individuals with RRMS, glatiramer is more effective than placebo in decreasing the number
7 of new or enlarging T2 lesions at 2 years (high confidence, 1 Class I study; confidence in
8 evidence upgraded due to magnitude of effect). Interferon beta 1a SQ 3 times a week is possibly
9 no more effective than glatiramer in decreasing the risk of active T2 lesions at 2 years (low
confidence, 1 Class II study).
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5 11 Interferon beta 1a intramuscular weekly
13 One Class I study (Vollmer 2014) evaluated the mean change in brain volume from baseline to 2
14 years and the cumulative number of new/enlarged T2 lesions at months 12 and 24 with interferon
15 beta 1a intramuscular weekly compared to placebo. No significant difference in brain volume
16 was detected (SMD 0.003 [-0.128, 0.134]); however, the cumulative number of new or enlarged
17 T2 lesions was lower in the interferon beta 1a intramuscular weekly group (SMD 0.37, 95% CI
18 0.23, 0.50).
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12 19 20 Conclusions
21 For individuals with RRMS, there is insufficient evidence to determine the efficacy of interferon
22 beta 1a intramuscular weekly compared to placebo in reducing the change in brain volume at 2
23 years (very low confidence, 1 Class I study; confidence in evidence downgraded due to
37 Confidential draft: not for distribution, dissemination, or publication
1 imprecision). Interferon beta 1a intramuscular weekly is more effective than placebo in reducing
2 the cumulative number of new or enlarged T2 lesions at months 12 and 24 (high confidence, 1
3 Class 1 study; confidence in evidence upgraded due to magnitude of effect).
4 Interferon beta 1a SQ 3 times a week
6 One Class I study (PRISMS 1998) evaluated new T2 activity over 2 years in 366 individuals
7 with RRMS treated with interferon beta 1a SQ 3 times a week compared to placebo. The risk
8 ratio for new T2 activity was 0.75 (0.67, 0.83), favoring interferon beta 1a SQ 3 times a week. 1
9 Class II study (Panitch 2002) compared interferon beta 1a SQ 3 times a week to interferon beta
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5 1a intramuscular weekly in 677 individuals with RRMS. The proportion of individuals with new
11 or enlarging T2 lesions at 1 year was significantly lower with interferon beta 1a SQ 3 times a
12 week, with a risk ratio of 0.62 (0.50, 0.76).
13 AF
10 Conclusions
15 For individuals with RRMS, interferon beta 1a SQ 3 times a week is more effective than placebo
16 in reducing the risk of new or enlarging T2 lesions at 2 years (high confidence, 1 Class I study;
17 confidence in evidence upgraded due to magnitude of effect). Interferon beta 1a SQ 3 times a
18 week is probably more effective than interferon beta 1a intramuscular weekly in reducing the
19 risk of new or enlarging T2 lesions at 1 year (moderate confidence, 1 Class II study; confidence
20 in evidence upgraded due to magnitude of effect).
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14 21 22 Mitoxantrone
38 Confidential draft: not for distribution, dissemination, or publication
1 One Class I study (Millefiorini 1997) of mitoxantrone vs placebo evaluated the number of new
2 lesions on T2 from baseline to 2 years in 42 individuals with RRMS. The SMD between
3 treatments was 0.64 (0.02, 1.26), favoring mitoxantrone.
4 5 Conclusion
6 In individuals with RRMS, mitoxantrone is more effective than placebo in decreasing the
7 number of new lesions on T2 at 2 years (high confidence, 1 Class I study; confidence in evidence
8 upgraded due to magnitude of effect).
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9 Mycophenolate Mofetil
11 One Class II study (Remington 2010) compared mycophenolate mofetil plus interferon beta 1a to
12 placebo plus interferon beta 1a in 24 individuals with RRMS. There was no significant
13 difference in T2 lesion volume percent change or brain volume percent change at 1 year between
14 treatments. The SMD for T2 lesion volume percent change was 0.52 (-0.29, 1.34) and for brain
15 volume percent change was 0.72 (-0.11, 1.55). One Class II study (add ref) compared
16 mycophenolate mofetil to interferon beta 1a in the mean number of new T2 lesions at 6 months
17 in 35 individuals with RRMS. There was no significant difference between treatments, with an
18 SMD of 0.38 (-0.29, 1.06).
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10 19 20 Conclusions
21 In individuals with RRMS, there is insufficient evidence to determine the efficacy of
22 mycophenolate mofetil plus interferon beta 1a compared to placebo plus interferon beta 1a in
23 decreasing the percentage of T2 lesion volume change or brain volume change at 1 year (very
39 Confidential draft: not for distribution, dissemination, or publication
1 low confidence, 1 Class II study; confidence in evidence downgraded due to imprecision). There
2 is insufficient evidence to determine the efficacy of mycophenolate mofetil compared to
3 interferon beta 1a in decreasing the mean number of new T2 lesions at 6 months (very low
4 confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
5 Natalizumab
7 One Cass I study (Polman 2006) compared natalizumab to placebo in 942 individuals with
8 RRMS. The risk of having at least 1 new or enlarging T2 lesion at 1 year was significantly lower
9 with natalizumab than placebo, with a risk ratio of 0.51 (0.45, 0.57). The MRI T2 lesion load at 2
10 years was significantly less with natalizumab than with placebo with a SMD of 0.28 (0.14, 0.42);
11 individuals treated with natalizumab had a mean decrease in lesion load, whereas individuals
12 treated with placebo had a mean increase in lesion load.
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6 13 Conclusion
15 In individuals with RRMS, natalizumab is more effective than placebo in reducing the risk of at
16 least 1 new or enlarging T2 lesion at 1 year and in reducing the MRI T2 lesion load at 2 years
17 (high confidence, 1 Class I study; confidence in evidence upgraded due to magnitude of effect).
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14 18 19 Pegylated Interferon
20 One Class I study (Calabresi 2014) compared pegylated interferon 125 mcg every 2 weeks to
21 placebo in 1012 individuals with RRMS. The number of new or newly enlarging T2 lesions at 1
22 year was significantly reduced with pegylated interferon, with a SMD of 0.60 (0.48, 0.73).
23 40 Confidential draft: not for distribution, dissemination, or publication
1 Conclusion
2 For individuals with RRMS, pegylated interferon is more effective than placebo in reducing the
3 number of new or newly enlarging T2 lesions at 1 year (high confidence, 1 Class I study,
4 confidence in evidence upgraded due to magnitude of effect).
5 Rituximab
7 One Class II study (Hauser 2008) compared rituximab to placebo in 104 individuals with RRMS.
8 The mean decrease in volume of lesions on T2 MRI from baseline to week 36 was significantly
9 greater with rituximab compared to placebo, with a SMD of 0.48 (0.07, 0.90).
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10 Conclusion
12 For individuals with RRMS, rituximab is probably more effective than placebo in decreasing the
13 volume of T2 lesions from baseline to week 36 (moderate confidence, 1 Class II study,
14 confidence in evidence upgraded due to magnitude of effect).
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15 16 Teriflunomide
17 One Class II study (O'Connor 2011) compared teriflunomide 14 mg to placebo in 721
18 individuals with RRMS. Teriflunomide was more effective than placebo in decreasing the
19 volume of MRI T2 lesions at 2 years than placebo, with a SMD of 0.19 (0.05, 0.34).
20 21 Conclusion
41 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with RRMS, teriflunomide is probably more effective than placebo in decreasing
2 the volume of MRI T2 lesions at 2 years (moderate quality, 1 Class II study; confidence in
3 evidence upgraded due to magnitude of effect).
4 Therapeutic question: In people with RRMS, are DMTs superior to placebo or other DMTs
6 in preventing disease progression as measured by in-study disease progression measures?
7 The most consistently reported measure for in-study disability progression was the proportion of
8 patients with disability progression, defined as an increase in the Expanded Disability Status
9 Scale (EDSS) of 1 point in those with a baseline EDSS less than or equal to 5.0, or an increase of
10 0.5 points in those with a baseline EDSS greater than or equal to 5.5, sustained for 3 or 6 months,
11 which was detected over a 2-year study period.
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5 Alemtuzumab
14 One Class 1 (Cohen 2012) and 1 Class II (Coles 2012) study evaluated the proportion of patients
15 with disability progression sustained for 6 months over 2 years with alemtuzumab compared to
16 interferon beta 1a, including a total of 914 patients. Meta-analysis of data demonstrated a risk
17 ratio of 0.44 (0.28, 0.70), favoring alemtuzumab.
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13 18 19 Conclusion
20 For individuals with RRMS, alemtuzumab is more effective than interferon beta 1a in reducing
21 the risk of disability progression over 2 years (high confidence, 1 Class I and 1 Class II study;
22 confidence upgraded due to magnitude of effect).
23 42 Confidential draft: not for distribution, dissemination, or publication
1 Azathioprine
2 One Class II study (add reference) evaluated the proportion of individuals with disability
3 progression sustained for at least 2 months with azathioprine vs placebo, reporting a risk ratio of
4 0.58 (0.23, 1.46), favoring azathioprine.
5 Conclusion
7 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
8 azathioprine compared to placebo in reducing the risk of disability progression over 24 months
9 (very low confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
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10 Cladribine
12 One Class II study (Giovannoni 2010) evaluated the proportion of patients with a 3 month
13 sustained change in EDSS at 2 years with 2 doses of oral cladribine in 1326 individuals with
14 RRMS. Relative to placebo, the risk ratio for either dose of cladribine was 0.72 (0.56, 0.91),
15 favoring cladribine.
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11 16 17 Conclusion
18 For individuals with RRMS, cladribine is probably more effective than placebo in reducing the
19 risk of disability progression over 2 years (moderate confidence, 1 Class II study; confidence in
20 evidence upgraded due to magnitude of effect).
21 22 Corticosteroids
43 Confidential draft: not for distribution, dissemination, or publication
1 One Class IV study (Zivadinov 2001) compared every 4 months pulsed intravenous
2 corticosteroids (methylprednisolone 1 g for 5 days with oral prednisone taper) to placebo for
3 disability progression (sustained changed in EDSS for 4 months) at 2 years in 81 individuals
4 with RRMS. The risk ratio was 0.14 (0.04, 0.49), favoring pulsed corticosteroids. One Class II
5 study (Ravnborg 2010) evaluated the proportion of patients with disability progression sustained
6 for 6 months with pulsed corticosteroid added to interferon compared to placebo added to
7 interferon in 341 individuals with RRMS over 3 years. The risk ratio was 0.93 (0.66, 1.33),
8 favoring pulsed corticosteroids.
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9 Conclusions
11 For individuals with RRMS, pulsed corticosteroids are possibly more effective than placebo in
12 reducing the risk of disability progression at 2 years (low confidence, 1 Class IV study;
13 confidence in evidence upgraded due to magnitude of effect). Pulsed corticosteroids added to
14 interferon are possibly no more effective than placebo added to interferon in reducing the risk of
15 disability progression over 3 years (low confidence, 1 Class II study).
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10 16 17 Daclizumab HYP
18 One Class I study (Gold 2013) evaluated the proportion of individuals with disease progression
19 sustained for 3 months with daclizumab HYP compared to placebo after 1 year in 397
20 individuals with RRMS. The risk ratio was 0.43 (0.22, 0.84), favoring daclizumab HYP. One
21 Class II study (Kappos 2015) compared daclizumab HYP to interferon beta 1a in 1841
22 individuals with RRMS. The risk ratio for disability progression sustained for 3 months over 3
23 years was 0.80 (0.66, 0.98), favoring daclizumab HYP.
44 Confidential draft: not for distribution, dissemination, or publication
1 2 Conclusion
3 In individuals with RRMS, daclizumab HYP is more effective than placebo in decreasing the
4 risk of disability progression at 1 year (high confidence, 1 Class I study; confidence in evidence
5 upgraded due to magnitude of effect). Daclizumab HYP is probably more effective than
6 interferon beta 1a in decreasing the risk of disability progression at 3 years (moderate
7 confidence, 1 Class II study; confidence in evidence upgraded due to magnitude of effect).
8 Dimethyl Fumarate
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9 One Class I (Fox 2012) and 1 Class II (Gold 2012) study evaluated dimethyl fumarate vs placebo
11 in 1539 individuals with RRMS. The risk ratio for disability progression sustained for 3 months
12 over 2 years was 0.65 (0.53, 0.81), favoring dimethyl fumarate.
13 AF
10 Conclusion.
15 In individuals with RRMS, dimethyl fumarate is more effective than placebo in decreasing the
16 risk of disability progression over 2 years (high confidence, 1 Class I and 1 Class II study;
17 confidence in evidence upgraded due to magnitude of effect).
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14 18 19 Fingolimod
20 One Class I (Kappos 2010) and 1 Class II (Calabresi 2014) study compared fingolimod to
21 placebo in 1556 individuals with RRMS. The risk ratio for disability progression sustained for 3
22 months over 2 years was 0.81 (0.68, 0.96), favoring fingolimod. One Class I study (Cohen 2010)
45 Confidential draft: not for distribution, dissemination, or publication
1 compared fingolimod to interferon beta 1a in 860 individuals with RRMS. The risk ratio for
2 disability progression sustained for 3 months over 1 year was 0.74 (0.45, 1.21).
3 Conclusion
5 In individuals with RRMS, fingolimod is more effective than placebo in reducing the risk of
6 disability progression over 2 years (high confidence, 1 Class I and 1 Class II study; confidence in
7 evidence upgraded due to magnitude of effect). Fingolimod is possibly no more effective than
8 interferon beta 1a in reducing the risk of disability progression over 1 year (low confidence, 1
9 Class I study; confidence in evidence downgraded due to imprecision).
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10 Glatiramer Acetate
12 One Class I (Fox 2012) and 2 Class II (Bornstein 1987, Johnson 1995) studies compared
13 glatiramer acetate to placebo in 1024 individuals with RRMS. The risk ratio for the proportion of
14 individuals with disease progression sustained for at least 3 months over 2 years was 0.76 (0.53,
15 1.08). One Class II study (O'Connor 2009) compared glatiramer to interferon beta 1b SQ
16 alternate day (250 mg) in 1345 individuals with RRMS. A greater proportion of individuals
17 taking interferon beta 1b SQ alternate day had confirmed disease progression compared to those
18 taking glatiramer, with a risk ratio of 1.32 (1.08, 1.64).
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11 19 20 Conclusion
21 For individuals with RRMS, glatiramer is possibly no more effective than placebo in reducing
22 the risk of disability progression over 2 years (low confidence, 1 Class I and 2 Class II studies;
23 confidence in evidence downgraded due to imprecision). Interferon beta-1b SQ alternate day is
46 Confidential draft: not for distribution, dissemination, or publication
1 probably less effective than glatiramer in decreasing the risk of disease progression over 2 years
2 (moderate confidence, 1 Class II study; confidence in evidence upgraded due to magnitude of
3 effect).
4 Immunoglobulins
6 One Class I (Fazekas 1997) and 1 Class II (Achiron 1998) study compared immunoglobulins to
7 placebo, measuring the risk of disability progression over 2 years in 190 people with RRMS.
8 There was no difference between immunoglobulins and placebo, with a risk ratio of 0.70 (0.39,
9 1.24).
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10 Conclusion
12 For individuals with RRMS, there is insufficient evidence to determine the efficacy of
13 immunoglobulins compared to placebo in reducing the risk of disability progression at 2 years
14 (very low confidence, 1 Class I and 1 Class II study; confidence in evidence downgraded due to
15 imprecision).
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11 16 17 Interferon beta 1a intramuscular weekly
18 One Class I (Vollmer 2014) and 1 Class II (Jacobs 1996) study evaluated the proportion of
19 individuals with disability progression sustained for 3 or 6 months over the 2-year study period
20 and included a total of 1198 patients. Meta-analysis of data demonstrated a risk ratio of 0.71
21 (0.52, 0.97), favoring interferon beta 1a intramuscular weekly.
22 23 Conclusion
47 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with RRMS, interferon beta 1a intramuscular weekly is more effective than
2 placebo in reducing the risk of disability progression over 24 months (high confidence, 1 Class I
3 and 1 Class II study; confidence upgraded due to magnitude of effect).
4 5 Interferon beta 1b SQ alternate day
6 One Class II study (Group 1993) evaluated the proportion of individuals with RRMS with
7 disability progression sustained for 3 months in a 3–year study of interferon beta 1b SQ alternate
8 day vs placebo. This study demonstrated a risk ratio of 0.73 (0.47, 1.14).
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9 Conclusion
11 For individuals with RRMS, interferon beta 1b SQ alternate day is possibly no more effective
12 than placebo in reducing the risk of disability progression over 36 months (low confidence, 1
13 Class II study; confidence in evidence downgraded due to imprecision).
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14 Interferon beta 1a SQ 3 times a week
16 One Class I study (PRISMS 1998) compared interferon beta 1a SQ 3 times a week to placebo in
17 560 individuals with RRMS. The proportion of individuals with disability progression sustained
18 for 3 months was significantly lower with interferon beta 1a SQ 3 times a week compared to
19 placebo, with a risk ratio of 0.77 (0.61, 0.96).
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15 20 21 Conclusion
48 Confidential draft: not for distribution, dissemination, or publication
1 For patients with RRMS, interferon beta 1a SQ 3 times a week is more effective than placebo in
2 reducing the risk of disability progression over 2 years (high confidence, 1 Class I study;
3 confidence in evidence upgraded due to magnitude of effect).
4 5 Methotrexate
6 One Class III study (Currier 1993) compared methotrexate to placebo in 20 individuals with
7 RRMS. There was no significant difference between treatments in the risk of disability
8 progression over 18 months, with a risk ratio of 0.73 (0.24, 2.00).
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9 Conclusion
11 There is insufficient evidence to determine the efficacy of methotrexate compared to placebo in
12 the risk of disability progression over 18 months (very low confidence, 1 Class III study).
13 AF
10 Mitoxantrone
15 One Class I study (Millefiorini 1997) compared mitoxantrone to placebo in 51 individuals with
16 RRMS. The risk ratio for disability progression from baseline to endpoint at 2 years was 0.20
17 (0.05, 0.73), favoring mitoxantrone.
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14 18 19 Conclusion
20 For patients with RRMS, mitoxantrone is more effective than placebo in decreasing the risk of
21 disability progression at 2 years (high confidence, 1 Class I study, confidence in evidence
22 upgraded due to magnitude of effect).
23 49 Confidential draft: not for distribution, dissemination, or publication
1 Natalizumab
2 One Class I study (Polman 2006) compared natalizumab to placebo in 942 individuals with
3 RRMS. The risk of disability progression sustained for 12 weeks over 2 years was significantly
4 lower with natalizumab, with a risk ratio of 0.64 (0.52, 0.80).
5 Conclusion
7 For patients with RRMS, natalizumab is more effective than placebo in decreasing the risk of
8 disability progression at 2 years (high confidence, 1 Class I study, confidence in evidence
9 upgraded due to magnitude of effect).
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6 Pegylated Interferon
12 One Class I study (Calabresi 2014) compared pegylated interferon 250 mcg every 2 weeks to
13 placebo in 1012 individuals with RRMS. The risk ratio for disease progression sustained for 3
14 months over 1 year was 0.61 (0.40, 0.93).
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15 16 Conclusion:
17 For patients with RRMS, pegylated interferon is more effective than placebo in decreasing the
18 risk of disability progression at 1 year (high confidence, 1 Class I study, confidence in evidence
19 upgraded due to magnitude of effect).
20 21 Teriflunomide
50 Confidential draft: not for distribution, dissemination, or publication
1 Two Class II studies (O'Connor 2011, Confavreux 2014) compared teriflunomide 14 mg to
2 placebo in 1479 individuals with RRMS. Teriflunomide was associated with a lower risk of
3 disability progression sustained for 12 weeks than placebo, with a risk ratio of 0.76 (0.62, 0.93).
4 5 Conclusion
6 In individuals with RRMS, teriflunomide 14 mg is more effective than placebo in reducing the
7 risk of disability progression over 2 years (high confidence, 2 Class II studies; confidence in
8 evidence upgraded due to magnitude of effect).
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9 Therapeutic question: In people with RRMS who experience disease activity while on a
11 DMT, is changing to a different DMT superior to continuing present DMT in terms of
12 relapse rate and MRI T2 activity?
13 Alemtuzumab
14 One Class I study (Coles 2012) compared alemtuzumab to interferon beta 1a in individuals with
15 RRMS who experienced a relapse in the past year while taking interferon (any formulation) or
16 glatiramer. Alemtuzumab was more effective than interferon beta 1a in reducing the risk of
17 relapse at 2 years (risk ratio 0.59, 95%CI 0.51, 0.69), reducing the ARR (RMD 0.26, 95% CI
18 0.13, 0.39), reducing the proportion of patients with disability progression over 2 years (RR 0.38,
19 95% CI 0.28, 0.50), and decreasing the proportion of individuals with new or enlarging T2
20 hyperintense lesions at 24 months (RR 0.68, 95%CI 0.58, 0.78).
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10 21 22 Conclusion
51 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with RRMS who experienced a relapse on interferon or glatiramer, alemtuzumab
2 is more effective than interferon beta 1a in reducing the reducing the ARR, reducing the risk of
3 relapse, disability progression, and risk of new or enlarging T2 lesions over 2 years (high
4 confidence, 1 Class 1 study; confidence upgraded due to magnitude of effect).
5 Natalizumab
7 One Class I study (Rudick 2006) compared interferon beta 1a plus natalizumab (“natalizumab
8 add-on therapy”) to interferon beta 1a plus placebo in 1171 individuals with RRMS who
9 experienced at least one relapse in the past 12 months on interferon. Natalizumab add-on therapy
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6 was more effective than adding placebo for all clinical outcome measures, with a risk ratio for
11 relapse at 2 years of 0.62 (0.55, 0.70), a RMD in ARR of 0.41 (0.36, 0.59), and a risk ratio of
12 0.80 (0.69, 0.93) for disability progression sustained for 12 weeks over 2 years. Natalizumab
13 add-on therapy was also more effective than adding placebo for all MRI outcomes, including the
14 risk of having at least 1 new or enlarging T2 lesion at 1 year with a risk ratio of 0.51 (0.44, 0.59).
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15 16 One Class II study (Goodman 2009) compared glatiramer plus natalizumab to glatiramer plus
17 placebo in 110 individuals with RRMS who relapsed at least once in the past 12 months on
18 glatiramer. There was no difference between natalizumab add-on therapy and placebo in the
19 number of individuals who relapsed over 6 months, with a risk ratio of 0.80 (0.42, 1.52).
20 Natalizumab add-on therapy was more effective than placebo in decreasing the mean number of
21 new or enlarging T2 lesions at 6 months, with a SMD of 0.48 (0.10, 0.86).
22 23 Conclusions
52 Confidential draft: not for distribution, dissemination, or publication
In individuals with RRMS who experienced one or more relapses in the past 12 months on
2 interferon, adding natalizumab is more effective than adding placebo in decreasing the risk of
3 relapse over 2 years, decreasing the ARR, decreasing the risk of disability progression over 2
4 years, and decreasing the risk of new or enlarging T2 lesions at 1 year (high confidence, 1 Class I
5 study; confidence in evidence upgraded due to magnitude of effect). In individuals with RRMS
6 who experienced one or more relapses in the past 12 months on glatiramer, there is insufficient
7 evidence to determine the efficacy of natalizumab added to glatiramer compared to placebo
8 added to glatiramer in decreasing the risk of relapse at 6 months (very low confidence, 1 Class II
9 study; confidence in evidence downgraded due to imprecision). Natalizumab added to glatiramer
10 is probably more effective than placebo added to glatiramer in decreasing the cumulative number
11 of new or enlarging T2 lesions at 6 months (moderate quality evidence, 1 Class II study;
12 confidence in evidence upgraded due to magnitude of effect).
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1 13 Therapeutic question: In people with progressive MS, are DMTs superior to placebo or
15 other DMTs as measured by relapse rate or in-study disease progression?
16 Azathioprine
17 One Class II study (Ellison 1989) compared azathioprine to placebo in 64 people with
18 progressive forms of MS. This study demonstrated a risk ratio of 0.53 (0.25, 1.10) for relapses at
19 2 years, and a RMD of 0.31 (0.01, 0.61) in the number of relapses at 2 years. The study also
20 evaluated the proportion of individuals with disability progression from baseline to endpoint over
21 3 years and demonstrated a risk ratio of 0.64 (0.32, 1.25), favoring azathioprine.
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14 22 23 Conclusions
53 Confidential draft: not for distribution, dissemination, or publication
1 For patients with progressive forms of MS, there is insufficient evidence to determine the
2 efficacy of azathioprine compared to placebo in reducing the risk of relapse over 2 years (very
3 low confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
4 Azathioprine is probably more effective than placebo in reducing the mean number of relapses
5 over 2 years (moderate confidence, 1 Class II study; confidence in evidence upgraded due to
6 magnitude of effect). There is insufficient evidence to determine the efficacy of azathioprine
7 compared to placebo in reducing the risk of disability progression over 3 years (very low
8 confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
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9 Cladribine
11 One Class II study (Rice 2000) evaluated the proportion of patients with disability progression at
12 1 year in 111 individuals with SPMS treated with subcutaneous cladribine compared to placebo.
13 The risk ratio was 0.78 (0.44, 1.42).
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10 Conclusion
16 For individuals with SPMS, cladribine is possibly no more effective than placebo in reducing the
17 risk of disability progression at 1 year (low confidence, 1 Class II study).
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15 18 19 Corticosteroids
20 One Class II study compared high-dose corticosteroids (bimonthly pulses of 500 mg IV for 3
21 days) to low-dose corticosteroids (bimonthly pulses of 10 mg IV for 3 days) in 108 individuals
22 with SPMS (Goodkin, Kinkel et al. 1998). The risk ratio for the proportion of individuals with
54 Confidential draft: not for distribution, dissemination, or publication
1 relapses at 2 years was 0.33 (0.08, 1.44). The risk ratio for the proportion of patients with
2 worsening of disability from baseline to endpoint was 1.50 (0.29, 7.54).
3 Conclusion:
5 In individuals with SPMS, high-dose pulsed steroids are possibly no more effective than low-
6 dose pulsed corticosteroids in reducing the proportion of individuals with relapses at 2 years (low
7 confidence, 1 Class II study). High-dose pulsed steroids are possibly no more effective than low-
8 dose pulsed corticosteroids in reducing the proportion of individuals with SPMS with disability
9 progression at 2 years (low confidence, 1 Class II study).
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10 Cyclophosphamide
12 Two Class II studies (CCMSG 1991, Likosky 1991) evaluated the proportion of 97 individuals
13 with progressive forms of MS with disability progression over 2 years. The risk ratio for
14 disability progression was 1.37 (0.88, 2.13).
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15 16 Conclusion
17 For individuals with progressive forms of MS, there is insufficient evidence to determine the
18 efficacy of cyclophosphamide compared to placebo in reducing the risk of disability progression
19 over 2 years (very low confidence, 2 Class II studies; confidence in evidence downgraded due to
20 imprecision).
21 22 Glatiramer Acetate
55 Confidential draft: not for distribution, dissemination, or publication
1 One Class II study (Bornstein 1991) compared glatiramer to placebo in 106 individuals with
2 progressive forms of MS. The risk ratio for the proportion of individuals with confirmed
3 disability progression sustained for 3 months over 2 years was 0.69 (0.33, 1.46). One Class II
4 study (Wolinsky, Narayana et al. 2007) compared glatiramer to placebo in 943 individuals with
5 PPMS. The risk ratio for confirmed disability progression sustained for 3 months over 2 years
6 was 0.99 (0.86, 1.14).
7 Conclusion
9 For patients with progressive forms of MS, glatiramer is possibly no more effective than placebo
10 in reducing the risk of disability progression over 2 years (low confidence, 1 Class II study). For
11 patients with PPMS, glatiramer is possibly no more effective than placebo in reducing the risk of
12 disability progression over 2 years (low confidence, 1 Class II study).
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8 Immunoglobulins
15 There are 2 Class II studies (Hommes 2004, Pohlau 2007) comparing immunoglobulins to
16 placebo in 515 individuals with progressive MS. There was no difference between
17 immunoglobulins and placebo in the risk of at least 1 relapse at 2 years, with a risk ratio of 0.96
18 (0.79, 1.16), or in the risk of disability progression over 2 years, with a risk ratio of 0.96 (0.74,
19 1.25).
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14 20 21 Conclusion
56 Confidential draft: not for distribution, dissemination, or publication
1 For individuals with progressive MS, there is insufficient evidence to determine the efficacy of
2 immunoglobulins compared to placebo in reducing the risk of relapse or disability progression
3 over 2 years (very low confidence, 2 Class II studies).
4 Interferon beta 1a intramuscular weekly
6 One Class II study (Cohen 2002) evaluated the efficacy of interferon beta 1a intramuscular
7 weekly for relapse prevention and clinical disease progression in 436 individuals with SPMS.
8 Individuals treated with interferon beta 1a intramuscular weekly had a lower risk of relapse at 2
9 years, with a risk ratio of 0.72 (0.54, 0.95). The proportion of individuals with disability
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5 progression sustained for three months was not different between interferon beta 1a
11 intramuscular weekly and placebo, with a risk ratio of 0.85 (0.64, 1.12). One Class I study (Leary
12 2003) in 50 individuals with PPMS found that the proportion of individuals with disability
13 progression sustained for 3 months was not different between interferon beta 1a intramuscular
14 weekly and placebo, with a risk ratio of 1.19 (0.78, 1.21).
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15 16 Conclusion
17 For individuals with SPMS, interferon beta 1a intramuscular weekly is probably more effective
18 than placebo in reducing the risk of relapse over 2 years (moderate confidence, 1 Class II study;
19 confidence upgraded due to magnitude of effect). For individuals with SPMS, interferon beta 1a
20 intramuscular weekly is possibly no more effective than placebo in reducing the risk of disability
21 progression over 24 months (low confidence, 1 Class II study). For individuals with PPMS,
22 interferon beta 1a intramuscular weekly is possibly no more effective than placebo in reducing
23 the risk of disability progression over 2 years (low confidence, 1 Class I study).
57 Confidential draft: not for distribution, dissemination, or publication
1 Interferon beta 1a SQ 3 times a week
3 There is 1 Class I study (SPECTRIMS 2001) comparing interferon beta 1a SQ 22 mcg or 44 mcg
4 3 times a week to placebo in 618 individuals with SPMS. Both doses of interferon beta 1a SQ 3
5 times a week were more effective than placebo in decreasing the mean number of exacerbations
6 per year. The RMD between interferon beta 1a SQ 3 times a week of 22 mcg and placebo was
7 0.21 (0.14, 0.28), and the RMD between interferon beta 1a SQ 3 times a week of 44 mcg and
8 placebo was 0.21 (0.15, 0.27), favoring interferon beta 1a SQ 3 times a week. The same study
9 also evaluated the risk of disability progression sustained for 3 months over 2 years. There was
10 no difference between either dose of interferon beta 1a SQ 3 times a week and placebo, with a
11 risk ratio of 0.93 (0.79, 1.10).
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2 Conclusion
14 In individuals with SPMS, interferon beta 1a SQ 3 times a week is more effective than placebo in
15 decreasing the mean number of exacerbations per year (high confidence, 1 Class I study;
16 confidence in evidence upgraded due to magnitude of effect). Interferon beta 1a SQ 3 times a
17 week is possibly no more effective than placebo in reducing the risk of disability progression
18 over 2 years (low confidence, 1 Class I study; confidence in evidence downgraded due to
19 imprecision).
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13 20 21 Interferon Beta 1b SQ alternate day
22 Two Class II studies evaluated the efficacy of interferon beta 1b SQ alternate day compared to
23 placebo on the risk of relapse, ARR and disability progression in 1333 individuals with SPMS
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1 (Kappos 1998, NASG 2004). The risk ratio for at least 1 relapse over 3 years was 0.84 (0.75,
2 0.93), and the RMD in ARR was 0.16 (0.02, 0.29), favoring interferon beta 1b SQ alternate day.
3 The risk ratio for the proportion of patients with disability progression over 3 years was 0.85
4 (0.71, 1.02), favoring interferon beta 1b SQ alternate day. One Class II study compared
5 interferon beta 1b SQ alternate day vs placebo in 73 individuals with PPMS (Montalban 2009).
6 The risk ratio for the proportion of patients with disability progression sustained for 3 months
7 over a 2 year period was 0.69 (0.32, 1.43).
8 Conclusion
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9 For patients with SPMS, interferon beta 1b SQ alternate day is more effective than placebo in
11 reducing the risk of relapse over 3 years (high confidence, 2 Class II studies; confidence
12 upgraded due to magnitude of effect). Interferon beta 1b SQ alternate day is more effective than
13 placebo in reducing the ARR (high confidence, 2 Class II studies, confidence upgraded due to
14 magnitude of effect). Interferon beta 1b SQ alternate day is possibly no more effective than
15 placebo in reducing the risk of disability progression over 36 months (low confidence, 2 Class II
16 studies; confidence in evidence downgrade due to imprecision). For patients with PPMS,
17 interferon beta 1b SQ alternate day is possibly no more effective than placebo in reducing the
18 risk of disability progression over 2 years (low confidence, 1 Class II study).
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10 19 20 Methotrexate
21 There is 1 Class II study (Goodkin 1995) comparing methotrexate to placebo in 60 individuals
22 with chronic progressive MS. The risk of relapse over 2 years was not significant between
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1 treatments, with a risk ratio of 1.12 (0.41, 3.13). The risk of disability progression sustained for 2
2 months over 2 years was not significant between treatments, with a risk ratio of 0.81 (0.47, 1.38).
3 4 Conclusion
5 For individuals with chronic progressive MS, there is insufficient evidence to determine the
6 efficacy of methotrexate compared to placebo in reducing the risk of relapse or disability
7 progression over 2 years (very low confidence, 1 Class II study; confidence in evidence
8 downgraded due to imprecision).
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9 Mitoxantrone
11 There is 1 Class II study (Hartung 2002) comparing mitoxantrone (12 mg/m2 and 5 mg/m2) to
12 placebo in 124 individuals with worsening RRMS and SPMS. The risk of relapse over 2 years
13 was lower with mitoxantrone, with a risk ratio of 0.68 (0.48, 0.94). The risk ratio for disability
14 progression from baseline to endpoint over 2 years was 0.33 (0.13, 0.82), also favoring
15 mitoxantrone.
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10 16 17 Conclusion
18 For individuals with worsening RRMS and SPMS, mitoxantrone is probably more effective than
19 placebo in decreasing the risk of relapse and disability progression over 2 years (moderate
20 confidence, 1 Class II study; confidence in evidence upgraded due to magnitude of effect).
21 22 Rituximab
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1 There is 1 Class II study of rituximab vs placebo in 439 individuals with PPMS (Hawker 2009).
2 There was no difference between treatments in the proportion of individuals with confirmed
3 disease progression sustained for 3 months after 2 years of treatment, with a risk ratio of 0.78
4 (0.60, 1.02).
5 6 Conclusion
7 In individuals with PPMS, rituximab is possibly no more effective than placebo in decreasing the
8 risk of disease progression over 2 years (low confidence, 1 Class II study).
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9 Therapeutic question: What are the adverse effects of DMTs in patients with MS compared
11 with placebo (adverse event related discontinuation, and serious or life threatening adverse
12 events)?
13 Alemtuzumab
14 Meta-analysis of the 2 Class 1 (Cohen 2012, Coles 2012) and 1 Class 2 (Investigators, Coles et
15 al. 2008) studies found a risk difference of -3.8% (-6.4, -1.3) for adverse event related
16 discontinuation, with more individuals in the interferon beta 1a treatment group discontinuing
17 due to adverse events than the alemtuzumab group. There was no significant difference in the
18 risk of cancer, death, liver toxicity, serious infection, immune thrombocytopenic purpura
19 between treated groups across 24–month follow-up. There was a higher risk of “thyroid-
20 associated” events (e.g., hyperthyroidism, hypothyroidism, thyroiditis, goiter and thyroid cyst) in
21 individuals treated with alemtuzumab compared to interferon beta 1a, with a risk difference of
22 13.9% (9.3, 18.6).
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1 Conclusions
2 Alemtuzumab possibly has a lower risk than interferon beta 1a of adverse event related
3 discontinuation at 24 months (low confidence, 2 Class I and 1 Class II studies). There is
4 insufficient evidence to determine the difference between alemtuzumab and interferon beta 1a in
5 the risk of cancer, death, liver toxicity, serious infection, and immune thrombocytopenic purpura
6 (very low confidence, 2 Class I and 1 Class II studies; confidence in evidence downgraded due to
7 imprecision). Alemtuzumab has a higher risk than interferon beta 1a of a thyroid-associated
8 event (high confidence, 2 Class II and 1 Class II studies).
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9 Azathioprine
11 One Class II study (Goodkin 1991) of 52 individuals with RRMS found a risk difference of
12 16.69% (-2.26, 34.69) between azathioprine and placebo for the proportion of individuals with
13 adverse event related discontinuation.
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10 Conclusion
16 For individuals with RRMS, there is insufficient evidence to determine the risk difference
17 between azathioprine and placebo for adverse event related discontinuation at 24 months (very
18 low confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
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15 19 20 Cladribine
21 One Cass II study (Giovannoni 2010) of 1326 individual with RRMS found a risk difference of
22 0.43% (-1.20, 1.67) between cladribine and placebo for the proportion of individuals who
23 discontinued due to adverse events at 2 years. The same study found a risk difference of 1.13%
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1 (0.12, 2.07) for neoplasms and a risk difference of 24.86% (21.55, 28.00) for lymphocytopenia.
2 Neoplasms in the cladribine group included uterine leiomyomas, melanoma, cervical carcinoma,
3 carcinoma of pancreas, ovarian carcinoma; no tumors were seen in the placebo group.
4 Conclusions
6 For individuals with RRMS, cladribine is possibly not different from placebo in the risk of
7 adverse event related discontinuation at 2 years (low confidence, 1 Class II study). Cladribine
8 possibly has a higher risk of neoplasms than placebo (low confidence, 1 Class II study).
9 Cladribine probably has a higher risk of lymphocytopenia than placebo (moderate confidence, 1
Class II study, confidence in evidence upgraded due to large effect size).
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5 Corticosteroids
13 One Class II study (Sorensen 2009) evaluated the number of individuals with RRMS
14 discontinuing treatment due to adverse effects with pulsed corticosteroids plus interferon vs
15 placebo plus interferon over 2 years. The risk difference was 24.15% (12.18, 36.13), with more
16 individuals receiving corticosteroids discontinuing treatment due to adverse effects. Data from
17 the same study found a risk difference between pulsed corticosteroid plus interferon and placebo
18 plus interferon of 14.82% (1.39, 27.74) for psychiatric symptoms. Data from 2 Class II studies
19 (Sorensen 2009, Ravnborg, Sorensen et al. 2010) found a risk difference of 21.9% (15.5, 28.3)
20 for sleep disturbances with corticosteroids plus interferon vs placebo plus interferon.
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12 21 22 Conclusion
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1 For individuals with RRMS, pulsed corticosteroids plus interferon probably increases the risk of
2 adverse event related discontinuation at 2 years compared to placebo plus interferon (moderate
3 confidence, 1 Class II study, confidence in evidence upgraded due to magnitude of effect).
4 Pulsed corticosteroids plus interferon possibly increases the risk of psychiatric symptoms
5 compared to placebo plus interferon (low confidence, 1 Class II study). Pulsed corticosteroids
6 plus interferon has a higher risk of sleep disturbances compared to placebo plus interferon (high
7 confidence, 2 Class II studies; confidence upgraded due to magnitude of effect).
8 Cyclophosphamide
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9 One Class III study (Killian 1988) of cyclophosphamide vs placebo evaluated the risk of adverse
11 event related discontinuation at 1 year in 14 patients with RRMS. The risk difference was -
12 12.5% (-47.09, 27.86).
13 AF
10 Conclusion
15 For individuals with RRMS, there is insufficient evidence to determine the risk difference
16 between cyclophosphamide and placebo for adverse event related discontinuation at 1 year (very
17 low confidence, 1 Class III study).
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14 18 19 Daclizumab HYP
20 One Class I study (Gold 2013) of daclizumab HYP vs placebo evaluated the risk difference in
21 serious infections over 1 year. The risk difference was 2.88% (0.47, 6.15), with more individuals
22 with daclizumab HYP experiencing serious infections. The same study evaluated the risk
23 difference for elevation of ALT or AST beyond 5 times the normal upper limit and found a risk
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1 difference of 3.84% (0.82, 7.55) with daclizumab HYP. One Class II study (Kappos 2015)
2 compared daclizumab HYP to interferon beta 1a over 3 years. The risk difference for adverse
3 event related discontinuation was 3.3% (0.001, 6.46), with more individuals in daclizumab HYP
4 than interferon discontinuing treatment.
5 Conclusions
7 For individuals with RRMS, daclizumab HYP has a higher risk of serious infection and
8 pronounced AST/ALT elevation than placebo (high confidence, 1 Class I study; confidence in
9 evidence upgraded due to magnitude of effect). Daclizumab HYP possibly importantly increases
10 the risk of adverse event related discontinuation compared to interferon (low confidence, 1 Class
11 II study).
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6 Dimethyl Fumarate
14 One Class I (Fox 2012) and 1 Class II (Gold 2012) study evaluated the number of patients who
15 discontinued dimethyl fumarate vs placebo for adverse effects (excluding relapses) at 2 years in
16 1540 individuals with RRMS. The risk difference was 6.8% (2.8, 10.7). Data from the same 2
17 studies found a risk difference for serious infections at 2 years of 0.8% (-0.7, 2.2).
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13 18 19 Conclusion
20 For individuals with RRMS, dimethyl fumarate possibly importantly increases the risk of
21 adverse event related discontinuation compared to placebo (low confidence, 1 Class I and 1
22 Class II study). There is insufficient evidence to determine the risk difference between dimethyl
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1 fumarate and placebo for serious infections (very low confidence, 1 Class I and 1 Class II study;
2 confidence in evidence downgraded due to imprecision).
3 Fingolimod
5 There is 1 Class I (Kappos 2010) and 1 Class II (Calabresi 2014) study comparing fingolimod to
6 placebo in 1556 individuals with RRMS. The risk difference for adverse event related
7 discontinuation at 2 years was 3.6% (-4.4, 11.5). The risk difference for lower respiratory tract or
8 lung infection was 3.0% (0.2, 5.9), and the risk difference for having an ALT 5 times normal was
9 1.1% (0.94, 3.33). The risk difference for death was -0.4% (-1.73, 0.48) and neoplasms was
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4 1.23% (-1.23, 4.1). There is 1 Class I study (Cohen 2010) comparing fingolimod to interferon
11 beta 1a in 860 individuals with RRMS. The risk difference for adverse event related
12 discontinuation at 1 year was 1.88% (-0.99, 4.84), and was 1.63% for neoplasms (0.22, 3.41).
13 AF
10 Conclusion
15 In individuals with RRMS, fingolimod is possibly no different from placebo in the risk of
16 adverse event related discontinuation at 2 years (low confidence, 1 Class I and 1 Class II study;
17 confidence in evidence downgraded due to imprecision). Fingolimod increases the risk of lower
18 respiratory tract or lung infection compared to placebo (high confidence, 1 class I and 1 Class II
19 study; confidence in evidence upgraded due to magnitude of effect). Fingolimod possibly
20 increases the risk of having an ALT five times normal compared to placebo (low confidence, 1
21 Class II study). There is insufficient evidence to determine the risk difference between
22 fingolimod and placebo for death and neoplasms (very low confidence, 1 Cass II study;
23 confidence in evidence downgraded due to imprecision). Fingolimod is probably not different
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1 from interferon beta 1a in the risk of adverse event related discontinuation at 1 year (moderate
2 confidence, 1 class I study). Fingolimod has a higher risk than interferon beta 1a of neoplasm
3 (high confidence, 1 Class I study, confidence in evidence upgraded due to magnitude of effect).
4 Glatiramer
6 There are 1 Class I (Fox 2012) and 2 Class II (Bornstein 1987, Johnson 1995) studies comparing
7 glatiramer to placebo for adverse event related discontinuation over 2 years in 1015 individuals
8 with RRMS. The difference in treatment discontinuation was not significant, with a risk
9 difference of 2.2% (-1.4, 5.8). There is 1 Class II study of 756 individuals with RRMS
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5 comparing adverse event related discontinuation with glatiramer vs Interferon beta 1a SQ 3 times
11 a week (Mikol 2008). There was no significant difference between treatments in discontinuation,
12 with a risk difference of 0.97% (-2.39, 4.35). There is 1 Class II study of 1333 individuals with
13 RRMS comparing injection site reactions and influenza-like illness with glatiramer vs interferon
14 beta 1b SQ alternate day (250 ug) (O'Connor 2009). The risk of injection site reactions was
15 higher with glatiramer than interferon beta 1b SQ alternate day, with a risk difference of 10.12%
16 (4.44, 15.67). The risk of influenza-like illness was higher with interferon beta 1b SQ alternate
17 day that glatiramer, with a risk difference of 34.81% (30.74, 38.53).
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10 18 19 Conclusions
20 For individuals with RRMS, glatiramer is probably not different from placebo in the risk of
21 adverse event related discontinuation at 2 years (moderate confidence, 1 Class I and 2 Class II
22 studies). Glatiramer is possibly not different from interferon beta 1a SQ 3 times a week in the
23 risk of adverse event related discontinuation (low confidence, 1 Class II study). Interferon beta
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1 1b SQ alternate day possibly importantly has a lower risk of injection site reactions than
2 glatiramer (low confidence, 1 Class II study). Interferon beta 1b SQ alternate day has a higher
3 risk of influenza-like illness than glatiramer (moderate confidence, 1 Class II study; confidence
4 in evidence upgraded due to magnitude of effect).
5 Immunoglobulins
7 There is 1 Class I study (Fazekas 1997) evaluating the risk of adverse event related
8 discontinuation at 24 months with immunoglobulin vs placebo in 150 individuals with RRMS.
9 The risk difference was 2.67% (-3.74, 9.86).
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6 Conclusion
12 In individuals with RRMS, immunoglobulins are probably no different from placebo in the risk
13 of adverse event related discontinuation at 2 years (moderate confidence, 1 Class I study).
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11 14 Interferon beta 1a intramuscular weekly
16 Meta-analysis of the 1 Class I (Vollmer 2014) and one class 2 (Jacobs 1996) studies found that
17 interferon beta 1a intramuscular weekly was not associated with a higher risk of adverse event
18 related discontinuation than placebo at 2 years, with a risk difference of 3.0% (-1.4, 7.4).
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15 19 20 Conclusion
21 For individuals with RRMS, Interferon beta 1a intramuscular weekly is probably not different
22 from placebo in the risk of adverse event related discontinuation (moderate confidence, 1 Class I
23 and 1 Class II study).
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1 Interferon beta 1a SQ 3 times a week
3 There is 1 Class I study (PRISMS 1998) comparing interferon beta 1a SQ 3 times a week to
4 placebo in 560 individuals with RRMS. The risk difference in adverse event related
5 discontinuation at 2 years was 2.95% (-0.21, 5.58). There is 1 Class I study (SPECTRIMS 2001)
6 comparing interferon beta 1a SQ 3 times a week to placebo in 619 individuals with SPMS. The
7 risk difference in adverse event related discontinuation over 3 years was 5.55% (1.69, 8.88).
8 There is 1 Class II study (Panitch 2002) comparing interferon beta 1a SQ 3 times a week to
9 interferon beta 1a intramuscular weekly in 677 individuals with RRMS. The risk difference in
10 adverse event related discontinuation over 1 year was 0.28% (-3.27, 3.83). The risk of injection
11 site reactions was higher with interferon beta 1a SQ 3 times a week than interferon beta 1a
12 intramuscular weekly, with a risk difference of 15.31% (9.67, 20.90).
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2 Conclusion
15 In patients with RRMS, interferon beta 1a SQ 3 times a week is possibly no different from
16 placebo in the risk of adverse event related discontinuation at 2 years (low confidence, 1 Class I
17 study; confidence in evidence downgraded due to imprecision). In patients with SPMS,
18 interferon beta 1a SQ 3 times a week possibly importantly increases the risk of adverse event
19 related discontinuation over 3 years (low confidence, 1 Class I study). In patients with RRMS,
20 interferon beta 1a SQ 3 times a week is possibly no different from interferon beta 1a
21 intramuscular weekly in the risk of adverse event related discontinuation at 1 year (low
22 confidence, 1 Class II study). In patients with RRMS, interferon beta 1a SQ 3 times a week
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1 possibly importantly increases the risk of injection site reaction compared to interferon beta 1a
2 intramuscular weekly (low confidence, 1 Class II study).
3 Interferon Beta 1b SQ alternate day
5 One Class II study (Group 1993) of 227 individuals with RRMS found a risk difference of 7.25%
6 (2.11, 13.43) between interferon Beta 1b SQ alternate day and placebo for the proportion of
7 individuals with adverse event related discontinuation. One Class II study of 718 individuals
8 with SPMS found a risk difference of 8.42% (4.47, 12.56) between interferon beta 1b SQ
9 alternate day and placebo for the proportion of individuals with adverse event related
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4 discontinuation (Kappos 1998). The risk of injection site reactions was higher in all studies of
11 individuals with RRMS, SPMS and PPMS, with a risk difference of 63.66% (53.41, 71.64),
12 38.09% (31.1, 44.52) and 77.78% (59.34, 88.28) respectively.
13 AF
10 Conclusion
15 In patients with RRMS and SPMS, interferon beta 1b SQ alternate day possibly importantly
16 increases the risk of adverse event related discontinuation (low confidence, 1 Class II study for
17 each MS subtype). In patients with RRMS, SPMS, and PPMS, interferon beta 1b SQ alternate
18 day probably has a higher risk of injection site reactions than placebo (moderate confidence, 1
19 Class II study for each MS subtype; confidence in evidence upgraded due to magnitude of
20 effect).
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14 21 22 Mitoxantrone
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1 There is 1 class II study (Hartung 2002) assessing the risk of adverse effects with mitoxantrone
2 compared to placebo over 2 years in 126 individuals with relapsing progressive MS.
3 Mitoxantrone use was associated with a higher risk of amenorrhea (risk difference 28.00%;
4 10.40, 47.58), nausea and vomiting (risk difference 55.49%; 38.97, 67.52), alopecia (risk
5 difference, 30.04%; 12.65, 45.01), urinary tract infections (19.76%; 5.21, 33.52), and leukopenia
6 (19.35%; 9.62, 30.85).
7 Conclusion
9 In individuals with relapsing progressive MS, mitoxantrone probably importantly increases the
10 risk of amenorrhea, nausea and vomiting, and alopecia (moderate confidence, 1 Class II study,
11 confidence in evidence upgraded due to magnitude of effect). Mitoxantrone possibly importantly
12 increases the risk of urinary tract infections and leukopenia (low confidence, 1 Class II study).
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8 Natalizumab
15 There is 1 Class I study (Polman 2006) comparing natalizumab to placebo in 942 individuals
16 with RRMS. There was no difference between natalizumab and placebo in the risk of adverse
17 event related discontinuation, with a risk difference of 3.2% (-0.6, 6.5). No significant risk
18 difference was reported in neoplasms (0.5%; -1.1, 1.6), or death (0.3%; -0.9, 1.2).
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14 19 20 Conclusion
21 In individuals with RRMS, natalizumab is possibly no different from placebo in the risk of
22 adverse event related discontinuation over 2 years (low confidence, 1 Class I study). There is
23 insufficient evidence to determine the difference between natalizumab and placebo in the risk of
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1 neoplasm or death (very low confidence, 1 Class I study; confidence in evidence downgraded
2 due to imprecision).
3 Pegylated Interferon
5 There is 1 Class I study (Calabresi 2014) comparing pegylated interferon 125 mcg every 2 weeks
6 to placebo in 1012 individuals with RRMS. The risk difference in adverse event related
7 discontinuation at 1 year was 3.48% (1.35, 5.82). The risk difference for severe adverse events,
8 defined as symptoms that cause severe discomfort, incapacitation, or a significant effect on daily
9 life was 6.98% (2.69, 11.25).
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4 AF
10 Conclusions
12 In patients with RRMS, pegylated interferon possibly importantly increases the risk of adverse
13 event related discontinuation at 1 year (low confidence, 1 Class I study). In patients with RRMS,
14 pegylated interferon importantly increases the risk of severe adverse events (high confidence, 1
15 Class I study, confidence in evidence upgraded due to magnitude of effect).
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11 16 17 Rituximab
18 There is 1 Class II study comparing rituximab to placebo in 104 individuals with RRMS (Hauser,
19 Waubant et al. 2008). The risk difference in adverse event related discontinuation from the study
20 was -1.37% (-14.57, 7.35) and for an infection-associated serious adverse event was 2.82% (-
21 15.88, 5.37).
22 23 Conclusion
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1 In individuals with RRMS, there is insufficient evidence to determine the risk difference between
2 rituximab and placebo for adverse event related withdrawal and infection associated serious
3 adverse events (very low confidence, 1 Class II study; confidence in evidence downgraded due
4 to imprecision).
5 Teriflunomide
7 There is 1 Class II study (O'Connor 2011) comparing teriflunomide to placebo in 1088
8 individuals with RRMS for adverse event related discontinuation. The risk difference in adverse
9 event related discontinuation over 2 years was 2.36% (-1.47, 5.75). There is 1 Class II study
10 (Confavreux 2014) comparing teriflunomide to placebo in 1165 individuals with RRMS for
11 serious infections. The risk difference for serious infections was 0.35% (-2.07, 2.29).
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6 Conclusion
14 For individuals with RRMS, teriflunomide is possibly no different from placebo in the risk of
15 adverse event related discontinuation (low confidence, 1 Class II study). There is insufficient
16 evidence that teriflunomide is different from placebo in the risk of serious infections (very low
17 confidence, 1 Class II study; confidence in evidence downgraded due to imprecision).
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13 18 19 Therapeutic Question: In people with clinically isolated syndromes (CIS), are DMTs
20 superior to placebo in decreasing the risk of conversion to clinically definite MS (CDMS)?
21 Cladribine
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1 There is 1 Class II study (Leist 2014) comparing oral cladribine 5.25 mg/kg to placebo in 410
2 individuals with CIS. The risk of conversion to CDMS over 2 years was significantly lower with
3 cladribine, with a risk ratio of 0.43 (0.29, 0.62).
4 5 Conclusion
6 For individuals with CIS, cladribine is probably more effective than placebo in reducing the
7 proportion of patients converting to CDMS over 3 years (moderate confidence, 1 Class II study;
8 confidence in evidence upgraded due to magnitude of effect).
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9 Glatiramer
11 There is 1 Class I study (Comi, Martinelli et al. 2009) comparing glatiramer to placebo in 481
12 individuals with CIS. The risk of conversion to CDMS over 3 years was significantly lower with
13 glatiramer, with a risk ratio of 0.58 (0.44, 0.75).
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10 Conclusion
16 For individuals with CIS, glatiramer is more effective than placebo in reducing the proportion of
17 patients converting to CDMS over 3 years (high confidence, 1 Class I study; confidence in
18 evidence upgraded due to magnitude of effect).
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15 19 20 Immunoglobulins
21 There is 1 Class II study (Achiron, Kishner et al. 2004) comparing IVIG to placebo in 90
22 individuals with CIS. The risk of conversion to CDMS over 1 year was significantly lower with
23 IVIG, with a risk ratio of 0.50 (0.28, 0.88).
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1 2 Conclusion
3 For individuals with CIS, immunoglobulin is probably more effective than placebo in reducing
4 the proportion of patients converting to CDMS over 1 year (moderate confidence, 1 Class II
5 study; confidence in evidence upgraded due to magnitude of effect).
6 Interferon beta 1a intramuscular weekly
8 There is 1 Class II study (Jacobs, Beck et al. 2000) comparing interferon beta 1a intramuscular
9 weekly to placebo in 383 individuals with CIS. The risk of conversion to CDMS over 3 years
10 was significantly lower with interferon beta 1a intramuscular weekly, with a risk ratio of 0.71
11 (0.56, 0.89).
12 AF
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7 Conclusion
14 For individuals with CIS, interferon beta 1a intramuscular weekly is probably more effective
15 than placebo in reducing the proportion of patients converting to CDMS over 3 years (moderate
16 confidence, 1 Class II study; confidence in evidence upgraded due to magnitude of effect).
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13 17 18 Interferon beta 1a SQ 3 times a week
19 There is 1 Class I study (Comi, Filippi et al. 2001) comparing interferon beta 1a SQ 44 mcg 3
20 times per week to placebo in 342 individuals with CIS. The risk of conversion to CDMS over 2
21 years was significantly lower with interferon beta 1a SQ 3 times a week, with a risk ratio of 0.55
22 (0.38, 0.78).
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1 Conclusion
2 For individuals with CIS, interferon beta 1a SQ 3 times a week is more effective than placebo in
3 reducing the proportion of patients converting to CDMS over 2 years (high confidence, 1 Class I
4 study; confidence in evidence upgraded due to magnitude of effect).
5 Interferon Beta 1b SQ alternate day
7 There is 1 Class II study (Kappos, Polman et al. 2006) comparing interferon beta 1b SQ alternate
8 day to placebo in 468 individuals with CIS. The risk of conversion to CDMS over 2 years was
9 significantly lower with interferon beta 1b SQ alternate day, with a risk ratio of 0.59 (0.46, 0.76).
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6 AF
10 Conclusion:
12 For individuals with CIS, interferon beta 1b SQ alternate day is probably more effective than
13 placebo in reducing the proportion of patients converting to CDMS over 2 years (moderate
14 confidence, 1 Class II study; confidence in evidence upgraded due to magnitude of effect).
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15 16 Teriflunomide
17 There is 1 Class II study comparing teriflunomide 14 mg to placebo in 411 individuals with CIS
18 (Miller 2014). The risk of conversion to CDMS over 2 years was significantly lower with
19 teriflunomide, with a risk ratio of 0.64 (0.44, 0.91).
20 21 Conclusion
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1 For individuals with CIS, teriflunomide is probably more effective than placebo in reducing the
2 proportion of patients converting to CDMS over 2 years (moderate confidence, 1 Class II study;
3 confidence in evidence upgraded due to magnitude of effect).
4 PRACTICE RECOMMENDATIONS
6 This section translates the conclusions into recommendations, or action statements. The
7 recommendations are statements that result from a modified Delphi process performed by the
8 panel members. The panel responds to key questions that capture key elements, including the
9 available evidence, strong evidence from closely related conditions, inferences from one or more
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5 of the other statements, and established principles of care. The recommendations are rated to
11 indicate their levels of strength (Level A, B, C, U, and R). Recommendations should not be
12 broader or narrower than the clinical question. Each recommendation or set of
13 recommendations is preceded by a clinical context section that delineates the justification for the
14 recommendations and their corresponding levels.
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15 16 Starting DMT Recommendations
17 Starting Recommendation 1
18 Rationale/Clinical Context: Receiving the diagnosis of multiple sclerosis (MS) is a stressful life
19 event (PRIN) (Schofield et al. 2003; Johnson 2003). People receiving major diagnoses may not
20 recall much of the information given to them at the time (Ptacek 1996). Providing information
21 about disease modifying therapy (DMT) at a follow-up interaction is likely to allow a better
22 understanding of these medications and their risks and benefits (PRIN).
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1 Statement 1
2 Clinicians should counsel patients just diagnosed with MS about specific treatment options with
3 DMT at a dedicated treatment visit.
4 5 Starting Recommendation 2
6 Rationale/Clinical Context: Respecting patient preferences is an important component of care for
7 chronic conditions (PRIN). Given the variety of DMTs available (EVID), evaluating patient
8 preferences may improve acceptance of and adherence to DMT (INFER).
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9 Statement 2a
11 Clinicians must ascertain and incorporate/review preferences in terms of safety, route of
12 administration, lifestyle, cost, efficacy, common side effects and tolerability in the choice of
13 DMT in patients with MS being considered for DMT.
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10 Statement 2b
16 Clinicians must engage in an ongoing dialogue regarding treatment decisions throughout the
17 course of the disease with patients with MS.
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15 18 19 Starting Recommendation 3
20 Rationale/Clinical Context: DMTs reduce but do not eliminate relapses and MRI activity
21 (EVID). Educating patients about realistic expectations regarding DMT effects is important
22 (PRIN) (Mohr 1996). Clinicians should inform patients that they may still need symptomatic
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1 treatment in addition to DMT (Henze, Rieckmann, Toyka, & Multiple Sclerosis Therapy
2 Consensus Group of the German Multiple Sclerosis 2006)(PRIN).
3 4 Statement 3
5 Clinicians should counsel that DMTs are prescribed to reduce relapses and new MRI lesion
6 activity. DMTs are not prescribed for symptom improvement in patients with MS.
7 Starting Recommendation 4
9 Rationale/Clinical Context: Given that DMT use requires commitment to ongoing therapy and an
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8 understanding of side effects (PRIN) (EVID), readiness to initiate DMT and factors causing
11 reluctance may have an impact on adherence to DMT use (INFER).
AF
10 12 Statement 4
14 Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance
15 in patients with MS who are candidates to initiate DMT.
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13 16 17 Starting Recommendation 5
18 Rationale/Clinical Context: In patients with MS, comorbid disease and adverse health behaviors
19 (e.g., depression and anxiety, vascular risk factors, physical inactivity, smoking) are associated
20 with worse outcomes (Marrie & Horwitz 2010; Tettey et al. 2016) (RELA). Similarly, addressing
21 depression prior to initiating DMT may improve decision making and adherence to DMT
22 (INFER). Concomitant medications may have important interactions with DMTs (R. H. Thomas
23 & Wakefield 2015) (RELA).
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1 2 Statement 5
3 Clinicians should counsel about comorbid disease and adverse health behaviors and potential
4 interactions of the DMT with concomitant medications when patients with MS initiate DMTs.
5 Starting Recommendation 6
7 Rationale/Clinical Context: Because DMT requires adherence to treatment to provide full
8 efficacy (INFER), and because that adherence to treatment may be an issue for patients with MS
9 (Katsarava et al. 2015; Irwin 2015) (RELA), discussing adherence issues prior to initiating DMT
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6 is good clinical practice (INFER). Efforts to increase adherence may improve outcomes
11 (INFER).
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10 12 Statement 6a
14 Clinicians should evaluate barriers to adherence to DMT in patients with MS.
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15 16 Statement 6b
17 Clinicians should counsel on the importance of adherence to DMT when patients with MS
18 initiate DMTs.
19 20 Starting Recommendation 7
21 Rationale/Clinical Context: Evidence from multiple Class I and II trials confirms that DMTs are
22 associated with a significant delay in second clinical relapse or new brain MRI lesions in patients
23 with a first demyelinating event (EVID). There is insufficient evidence concerning the
80 Confidential draft: not for distribution, dissemination, or publication
comparative efficacy of specific DMTs for this purpose. Decisions concerning selection of
2 specific DMTs for patients presenting with a first demyelinating event should abide by
3 prescribing principles espoused in other recommendations. Patients presenting with a first
4 demyelinating event and who do not meet the 2010 International Criteria for MS are commonly
5 encountered in clinical practice. Multiple prospective observational trials have consistently
6 confirmed that patients with a single clinical demyelinating event with two or more brain or
7 spinal cord lesions remain at increased risk of a future diagnosis of MS, with the highest risk
8 incurred within 5 years of the sentinel event (Miller, Barkhof, Montalban et al., 2005; Optic
9 2008) (RELA).
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1 AF
10 Statement 7
12 Clinicians may offer disease modifying therapy for patients with a single clinical demyelinating
13 event with two or more brain or spinal cord lesions that have imaging characteristics consistent
14 with MS.
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11 16 Starting Recommendation 8
17 Rationale/ Clinical context: In currently untreated patients with clinically isolated syndromes or
18 relapsing forms of MS who have not had relapses in two or more years and do not have active
19 new MRI lesion activity on a recent MRI, the benefit of initiating DMT has not been studied
20 (EVID). In such patients, the harm of initiating DMTs including side effects, major adverse
21 events, and burden of taking a long-term medication that may not be beneficial may outweigh the
22 potential benefit of reducing relapse rate (INFER).
23 81 Confidential draft: not for distribution, dissemination, or publication
1 Statement 8
2 Clinicians may recommend serial imaging and close follow-up rather than initiating DMT in
3 patients with CIS or relapsing forms of MS not on DMT who have not had relapses in the past 2
4 years and who do not have active new MRI lesion activity on a recent MRI.
5 Starting Recommendation 9
7 Rationale/Clinical Context: Multiple studies of disease modifying agents in patients with
8 relapsing forms of MS who have had recent relapses and or MRI activity (EVID) have shown
9 benefit of DMT in terms of reducing relapses and reducing MRI activity (EVID). This includes
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6 patients with a single clinical episode who meet 2010 International Criteria (EVID) (Comi,
11 DeStefano, Freedman et al. 2012; Miller, Wolinsky, Kappos et al. 2014).
AF
10 12 Statement 9
14 Clinicians should offer DMTs to patients with relapsing forms of MS with recent clinical
15 relapses or MRI activity.
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13 16 17 Starting Recommendation 10
18 Rationale/Clinical Context: Lack of adherence to treatment of chronic diseases is a wide-ranging
19 problem (RELA). The result of poor adherence is reduced effectiveness and increased healthcare
20 costs (RELA) (Singer, 2008; Brandes 2013; Girouard 2011; Oleen-Burkey 2011; Thomas,
21 Curkendall, Farr et al. 2016) (RELA). Regular interactions and assessments by clinicians
22 facilitate prompt identification and treatment of side effects, increased tolerability of the
23 medication, and safety monitoring (RELA) (Bender 2002; Mohr 1996; Treadaway 2009). Some
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1 MS DMTs have specific risk evaluation and mitigation strategies with recommendations for
2 follow-up frequency (RELA) (FDA, 2013, 2014, 2015b).
3 4 Statement 10a
5 Clinicians should monitor for medication adherence, side effects, tolerability, safety and
6 effectiveness of the therapy in patients with MS on DMTs.
7 Statement 10b
9 Clinicians should follow up either annually or according to medication-specific risk evaluation
and mitigation strategies (REMS) in patients with MS on DMTs.
AF
10 T
8 11 Starting Recommendation 11
13 Rationale/Clinical Context: DMT have potential risks in pregnant women (Bove et al. 2014)
14 (RELA) to varying degrees. Discussing pregnancy with patients with MS before initiating DMT
15 is good clinical practice (INFER). If patients with MS are planning pregnancy soon, DMT may
16 need to be deferred until after pregnancy (Coyle 2016) (RELA). In addition, since DMTs vary in
17 terms of pregnancy risks from Category B to Category X (Bove et al. 2014) (RELA), the choice
18 of DMT may depend on plans for pregnancy (INFER).
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12 19 20 Statement 11
21 Clinicians should monitor patient’s reproductive plans and counsel on reproductive risks and on
22 use of birth control while on a DMT in women of childbearing years with MS.
23 83 Confidential draft: not for distribution, dissemination, or publication
1 Starting Recommendation 12
2 Rationale/clinical context: Chemotherapy such as cyclophosphamide may affect male fertility
3 (Leroy et al. 2015) (RELA); thus, male patients starting cyclophosphamide should be counseled
4 about the risk of infertility. With teriflunomide treatment, there may be a risk of teratogenicity
5 from male sperm, which could extend for 2 years after treatment cessation if the patient is not
6 treated with chelation therapy (Cree 2013) (RELA).
7 Statement 12
9 Clinicians must counsel men with MS on their reproductive plans regarding treatment
implications before initiating teriflunomide or cyclophosphamide.
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8 11 Starting Recommendation 13
13 Rationale/clinical context: Post-approval, new evidence has shown a high risk of
14 cardiomyopathy, ovarian failure, male infertility, chromosomal aberrations and promyelocytic
15 leukemia (RELA) (Ellis, Boggild 2009; Ellis, Brown, Boggild 2014; Fleischer 2014; Le Page,
16 Leray, Edan, & French Mitoxantrone Safety Group 2011) associated with the use of
17 mitoxantrone. Other effective and lower risk medications, which we not available at the time of
18 FDA–approval for mitoxantrone (RELA), are available for use in MS.
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12 19 20 Statement 13
21 Clinicians should not prescribe mitoxantrone to patients for MS.
22 23 Starting Recommendation 14
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Rationale/Clinical Context: MS is a heterogeneous disease and is characterized by highly
2 variable degrees of disease activity in the relapsing phase as well as varying rates of worsening
3 during the progressive phases (Confavreux & Vukusic 2006; Lucchinetti et al. 2000; Lucchinetti
4 2000) (RELA). Definitions of very active MS vary and can include measures of relapsing
5 activity and MRI markers of disease activity such as numbers of contrast enhancing lesions
6 (Schmidt 2011) (RELA). Subgroup analyses from phase III pivotal trials of alemtuzumab,
7 fingolimod, and natalizumab showed a reduction in relapses and MRI measures in patients with
8 very active disease (EVID) (RELA) (Coles, Fox, Vladic et al. 2011; Devonshire, Havdrova,
9 Radue et al. 2012; Hutchinson 2009). Compared with interferon therapy, treatment with these
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1 therapies resulted in more favorable outcomes in the subgroup of patients with very active
11 disease (RELA) (Cohen, Barkhof, Comi et al. 2010; Cohen, Coles, Arnold et al. 2012; Coles,
12 Twyman, Arnold et al. 2012; Rudick 2006). However, the risks and benefits of each treatment
13 strategy need to be considered on a patient-by-patient basis (PRIN).
14 R
AF
10 Statement 14
16 Clinicians should prescribe alemtuzumab, fingolimod or natalizumab for patients with very
17 active MS.
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15 18 19 Starting Recommendation 15
20 Rationale/Clinical Context: DMTs should be available to all patients with relapsing forms of MS
21 (PRIN). Due to disparities in health care provision in different settings (RELA) (MSIF 2013,
22 Browne 2014), there may be situations where approved DMTs are not available to an individual.
23 In this situation, there may be support from the pharmaceutical industry or organizations, such as
85 Confidential draft: not for distribution, dissemination, or publication
1 the National Organization of Rare Diseases (NORD), county organizations, or government
2 organizations, to obtain DMTs. If this is not available, certain medications have a lower cost and
3 may become a choice for care. Azathioprine has mixed result and low confidence evidence to
4 support efficacy in relapsing forms of MS (EVID). Cladribine has evidence for benefit for the
5 both the oral and parental formulations but currently only the parenteral formulations are
6 available (EVID). Teriflunomide is the active metabolite of leflunomide (RELA) (Claussen
7 2012). Teriflunomide is approved for the treatment of relapsing forms of MS (EVID).
8 T
10 Statement 15a
Clinicians may direct patients with MS who are candidates for DMTs to support programs.
11 AF
9 Statement 15b
13 Clinicians should recommend one of the following DMTs (azathioprine, cladribine, minocycline,
14 leflunomide) for patients with relapsing forms of MS who do not have access to approved DMTs
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15 16 Starting Recommendation 16
17 Rationale/Clinical Context: Patients with a positive John Cunningham (JC) virus antibody have a
18 higher risk of developing progressive multifocal leukoencephalopathy (PML) while on
19 natalizumab, particularly after the second year on treatment or in patients who have had prior
20 immunosuppressive treatment (EVID). There are now other highly effective treatments that may
21 be used that have not been shown to have a similar risk of PML (EVID).
22 23 Statement 16
86 Confidential draft: not for distribution, dissemination, or publication
1 Clinicians should not initiate natalizumab treatment in patients with positive JC virus antibodies
2 in serum unless there are overwhelming reasons to do so.
3 Starting Recommendation 17
5 Rationale/Clinical Context: Rationale/Clinical Context: No currently approved DMTs have
6 demonstrated efficacy in PPMS (EVID). Interferon-beta, glatiramer acetate and rituximab are
7 possibly ineffective (EVID). The use of ineffective therapy may pose harms to the affected
8 individual, society and the health system (PRIN). Newer agents are being studied and ongoing
9 clinical trials may alter these findings (INFER).
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4 AF
10 11 Statement 17
12 For patients with PPMS clinicians should not initiate currently approved DMTs.
13 Switching DMT Recommendations (21 statements)
15 Switching Recommendation 1
16 Clinical Context. Ongoing disease activity, measured either by clinical relapses or new MRI
17 lesions (including unequivocally new T2 or new contrast-enhancing lesions), could lead to
18 physical or cognitive worsening over time (Fusniku et al.; Rocca et al.; Rio et al.; Prosperini et
19 al.) (RELA). Now that several DMTs are available and have demonstrated efficacy for the
20 prevention of clinical relapses and new MRI lesions (EVID), physicians and patients often face
21 the decision of switching from one DMT to another due to a perceived lack of efficacy. Such
22 lack of response to a DMT has been difficult to define, as most patients are not free of all disease
23 activity, and investigators have considered using the number of clinical attacks or new MRI
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14 87 Confidential draft: not for distribution, dissemination, or publication
1 lesions in the last 12 months (RELA) (Rio et al.; Prosperini et al.). DMTs take a variable amount
2 of time to become clinically active, and new lesion formation may occur after initiation but
3 before the time of full efficacy, confounding interpretation of follow-up MRIs (RELA) (Cohen,
4 Barkhof, Comi et al. 2010; Coles, Twyman, Arnold et al. 2012; Comi, Filippi, Wolinksy et al.
5 2001; Confavreaux 2014; Johnson, Brooks, Cohen et al. 1995; PRISMS 1998).
6 Statement 1a
8 Clinicians should periodically monitor MRI disease activity during the first 5 years from the
9 clinical onset of disease to detect the accumulation of new lesions in order to inform treatment
decisions in patients with MS on DMTs.
11 AF
10 T
7 Statement 1b
13 Clinicians should recognize that relapses or new MRI lesions may develop after initiation of a
14 DMT and before the treatment becomes effective in patients with MS on DMTs.
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12 D
15 16 Statement 1c
17 Clinicians should discuss switching from one DMT to another in patients who have been on a
18 DMT long enough to take full effect and are adherent to their therapy when a patient has
19 experienced one or more relapses, two or more unequivocally new MRI lesions, or increased
20 disability on examination, over a 1-year period on a DMT.
21 22 Switching Recommendation 2
88 Confidential draft: not for distribution, dissemination, or publication
1 Rationale/Clinical Context: None of the available DMTs are completely effective against
2 relapses and MRI activity (EVID). When a patient shows breakthrough disease (continued
3 relapses or MRI activity), trying a medication with a different mechanism or efficacy profile may
4 be beneficial (INFER). Although all possible clinical scenarios cannot be answered by drug
5 trials, current evidence supports higher efficacy of alemtuzumab, natalizumab, and fingolimod,
6 compared to previously approved self-injectable DMTs (EVID high). Tolerability and likelihood
7 of adherence are other factors that are important in decisions on switching DMTs (PRIN).
8 Physician judgment and patient preferences are critical in this process (PRIN).
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9 Statement 2
11 Clinicians may evaluate the amount of disease activity, adherence, adverse event profiles, and
12 mechanism of action of DMTs when switching DMTs in patients with breakthrough disease on
13 DMTs.
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10 R
14 Switching Recommendation 3
16 Rationale/Clinical Context: Multiple DMTs are available for MS (EVID). Switching therapies
17 may be appropriate in patients with MS who are experiencing side effects or complications with
18 a DMT (INFER). Adherence to injectable DMTs is often incomplete (Devonshire et al. 2011)
19 (RELA). Injection fatigue (physical or emotional) or injection-related pain or discomfort (EVID)
20 may be a common reason for poor adherence (INFER).
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15 21 22 Statement 3
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1 Clinicians should discuss a change to a non-injectable or less frequently injectable DMT in
2 patients who report pain with the injections or in those who report “injection fatigue” on
3 injectable DMTs.
4 5 Switching Recommendation 4
6 Rationale/Clinical Context: Adherence to a DMT may also be affected by medication adverse
7 effects (RELA) (Irwin 2015; Treadaway 2009). All DMTs have common adverse effects that
8 may affect adherence (refer to table) (EVID).
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9 Statement 4a
11 Clinicians should inquire about medication adverse effects with patients with MS who are taking
12 a DMT and attempt to manage these adverse effects, as appropriate.
13 AF
10 Statement 4b
15 Clinicians should discuss a medication switch with patients for whom these adverse effects
16 negatively influence adherence.
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14 17 18 Switching Recommendation 5
19 Rationale/Clinical Context: Persistent laboratory abnormalities such as elevated liver enzymes
20 and decreased white cell counts may prompt a discussion on switching DMT (refer to table)
21 (EVID).
22 23 Statement 5a
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1 Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as
2 outlined in the medication's package insert) in patients with MS who are on a DMT.
3 4 Statement 5b
5 Clinicians should discuss switching DMT or reducing dose or frequency (where there is data on
6 different doses [e.g., interferons, teriflunomide, azathioprine) when there are persistent
7 laboratory abnormalities.
9 Switching Recommendation 6
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8 Rationale/Clinical Context: PML is a serious safety concern (Clifford et al. 2010) (RELA) that
11 may affect compliance and necessitate consideration of a treatment switch (INFER). The risk of
12 PML is estimated at 4/1000 overall with natalizumab (Biogen 2016), however, the presence of
13 JCV antibodies, longer duration use, and prior immunosuppression increase the risk of PML with
14 natalizumab even further (RELA) (Clifford et al. 2010). There are rare reports of this infection
15 with the use of both fingolimod and dimethyl fumarate (RELA) (FDA 2015a) (Rosenkranz,
16 Novas, & Terborg, 2015) (Nieuwkamp et al. 2015).
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10 17 18 Statement 6a
19 Clinicians should counsel patients considering natalizumab, fingolimod, and dimethyl fumarate
20 about the risk of PML associated with these agents.
21 22 Statement 6b
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1 Clinicians should discuss switching to a DMT with a lower risk of PML in patients taking
2 natalizumab who are JC virus antibody positive or become JC virus antibody positive while on
3 therapy.
4 Switching Recommendation 7
6 Rationale/Clinical Context: Immunosuppressive medications may come with a risk of
7 opportunistic infection and malignancy, especially with prolonged use of the agent (EVID,
8 PRIN). These risks are often undefined with newer medication (INFER). Cases of cryptococcal
9 infections have been reported with the use of fingolimod (Huang 2015) (RELA). Herpes family
10 virus infections have been reported with fingolimod and natalizumab (Pelletier & Hafler 2012;
11 Ratchford, Costello, Reich & Calabresi 2012; Fine, Sorbello, Kortepeter & Scarazzini 2013)
12 (RELA). A potential increased risk of basal cell carcinoma was recently added to the product
13 label of fingolimod (RELA) (FDA 2016).
14 R
AF
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5 Statement 7a
16 Clinicians should counsel that new DMTs without long-term safety data have an undefined risk
17 of malignancy and infection in patients starting or using new DMTs.
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15 18 19 Statement 7b
20 If a patient with MS develops a malignancy while on a DMT, clinicians should promptly discuss
21 switching to an alternate DMT, especially for patients on azathioprine, methotrexate,
22 mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl
23 fumarate.
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1 2 Statement 7c
3 Patients with serious infections potentially linked to their DMT should switch DMTs (note this
4 does not pertain to management of PML in patients on DMT).
5 Switching Recommendation 8
7 Rationale/Clinical Context: Neutralizing antibodies may be produced against natalizumab and
8 have been associated with allergic reactions (Vennegoor et al. 2013; Krumbholz et al. 2007)
9 (RELA) (Vennegoor 2013; Krumbholz 2007). These antibodies may reduce the efficacy of the
drug (PRIN), especially if they are persistent.
11 AF
10 T
6 Statement 8a
13 Clinicians should check for natalizumab antibodies in patients who have infusion reactions prior
14 to subsequent infusions, or in patients who experience breakthrough disease on natalizumab.
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15 16 Statement 8b
17 Clinicians should switch DMTs in patients who have persistent natalizumab antibodies.
18 19 Switching Recommendation 9
20 Rationale/Clinical Context: Patients with MS taking natalizumab may discontinue natalizumab
21 because of fear of PML or for pregnancy planning (INFER). Discontinuation of natalizumab
22 increases the risk of MS relapse or MRI disease activity (RELA) within 6 months of
23 discontinuation (Prosperini 2015). Data assessing the appropriate choice of an alternate DMT
93 Confidential draft: not for distribution, dissemination, or publication
1 after natalizumab are limited. There is evidence that initiating fingolimod after 8 weeks reduces
2 new MRI lesions compared to initiation after 12 and 16 weeks, whereas initiating fingolimod
3 after 8 to 12 weeks increases the proportion of patients relapse-free compared to initiation after
4 16 weeks (RELA) (Comi 2015, Iaffaldano 2015, Kappos 2015).
5 6 Statement 9a
7 Physicians must counsel patients considering discontinuation of natalizumab that there is an
8 increased risk of MS relapse or MRI disease activity within 6 months of discontinuation.
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9 Statement 9b
11 Physicians and patients choosing to switch from natalizumab to fingolimod should initiate
12 treatment within 8 weeks after discontinuation of natalizumab (for reasons other than pregnancy
13 or pregnancy planning) to diminish the return of disease activity.
AF
10 R
14 Recommendation 10
16 Rationale/Clinical Context: Relapse risk is reduced during pregnancy and increases in the post-
17 partum period (RELA) (Finkelsztejn et al. 2011). Pregnancy exposure to DMTs have potential
18 risks to the fetus to varying degrees (RELA). The risks to the fetus vary from severe
19 malformations (category X) to no major increased risk of malformations, but unknown risks of
20 important early life outcomes such as infections, vaccination responses, asthma, and
21 neurocognitive disorders (category B). FDA approved medications are either Category B
22 (glatiramer acetate), Category C (interferons, dimethylfumarate, fingolimod, natalizumab),
23 Category D (mitoxantrone), or Category X (teriflunomide) (RELA). Discussing these potential
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15 94 Confidential draft: not for distribution, dissemination, or publication
1 risks and how best to minimize them is good clinical practice (PRIN). The majority of human
2 safety data for pregnancy exposure to DMTs is derived from accidental exposure early in
3 pregnancy. There is a paucity of safety information with second and third trimester exposure (Lu
4 et al. 2012) (RELA).
5 6 Statement 10a
7 Clinicians should counsel women to stop their DMT prior to conception.
8 Statement 10b
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9 Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the
11 risk of MS activity during pregnancy outweighs the risk of the specific DMT during pregnancy.
12 AF
10 Statement 10c
14 Clinicians should not initiate DMTs during pregnancy.
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15 16 Stopping DMT Recommendations
17 Stopping Recommendation 1
18 Rationale/Clinical Context: No randomized controlled trials have directly addressed the question
19 of whether, when or why to discontinue DMTs in an individual with RRMS who has no evidence
20 of relapses, disability progression and stable brain imaging (EVID). The natural history of
21 untreated RRMS is for relapses and disability accumulation to occur. Most individuals with
22 RRMS ultimately transition to SPMS if observed for long enough intervals although disease
23 course is highly variable (Weinshenker et al. 1989) (RELA). Patients who are stable on DMTs
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1 may question the continued value of using DMTs (INFER). If patients on DMTs stop these
2 medications, continued monitoring may show subclinical disease activity or relapse activity that
3 would indicate a possible need for resumption of treatment (INFER). Patients who are on DMTs
4 with no evidence of ongoing disease activity may be benefiting from their DMT with disease
5 suppression (INFER). There are presently no biological markers of medication efficacy that can
6 guide decision making in this area (EVID).
7 Statement 1a
9 In patients with relapsing remitting MS who are stable on DMT and wish to discontinue therapy,
10 clinicians should counsel patients regarding the uncertain risks of stopping therapy and the need
11 for ongoing follow-up and periodic re-evaluation of the decision to discontinue DMT.
12 AF
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8 Statement 1b
14 Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability
15 progression, stable imaging) on DMT should be allowed to continue on their current DMT.
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13 16 17 Stopping Recommendation 2
18 Rationale/Clinical Context: No randomized controlled trials have directly addressed the question
19 of whether or when to discontinue disease-modifying therapies in patients with SPMS (EVID).
20 Clinical trials have not evaluated the benefits of DMT in non-ambulatory individuals with SPMS
21 with respect to other clinically relevant domains including cognition and upper limb function
22 (EVID). Relapses are associated with more rapid disability progression in SPMS but tend to
23 occur in those at younger ages (< 55 years) (Paz Soldan et al. 2015; Tremlett, Zhao, Joseph,
96 Confidential draft: not for distribution, dissemination, or publication
1 Devonshire, & Neurologists 2008) (RELA). In patients with SPMS who are ambulatory with or
2 without assistance, interferon beta reduces the risk of relapse but does not delay disability
3 progression as measured by the EDSS—a measure that emphasizes ambulation (EVID). The
4 benefits of therapy should outweigh the risks (PRIN). The use of ineffective therapy may pose
5 harms to the affected individual, society and the health system (PRIN).
6 Statement 2a
8 Clinicians should advise discontinuation of DMT in patients with SPMS who do not have
9 ongoing relapses (or gadolinium enhancing lesions on MRI), and in addition who have not been
ambulatory (EDSS ≥7) for at least 2 years.
11 AF
10 T
7 Statement 2b
13 Clinicians should assess the likelihood of future relapse by assessing patient age and relapse
14 history (e.g., frequency, severity, time since most recent relapse or gadolinium enhancing lesion).
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15 16 Stopping Recommendation 3
17 Rationale/Clinical Context: No DMTs have demonstrated efficacy in PPMS (EVID). Interferon-
18 beta, glatiramer acetate and rituximab are possibly ineffective (EVID). As such, the issue of
19 discontinuing therapies should not be relevant to this subgroup (INFER), as they should not have
20 been initiated because the use of ineffective therapy may pose harms to the affected individual,
21 society and the health system (PRIN). Ongoing clinical trials may alter these findings.
22 23 Statement 3
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1 Clinicians should discuss discontinuation of currently approved DMTs in patients with PPMS
2 with no MRI disease activity currently receiving such treatments.
3 Stopping Recommendation 4
5 Rationale/Clinical Context: Patients with clinically isolated syndromes of demyelination as
6 defined in the international criteria of 2010 (Polman et al. 2011) may not progress to MS
7 (EVID). Patients with CIS who are on DMTs may at some point question the value of continuing
8 DMTs indefinitely (INFER). There remains a gap in knowledge about stopping DMTs in CIS
9 patients (INFER). Discussing the risks of continuing DMT vs the risks of their use being
unnecessary as part of ongoing treatment is good clinical practice (PRIN).
11 AF
10 T
4 Statement 4
13 Clinician should review the risk of continuing DMTs vs the risk of stopping DMT in patients
14 with CIS on DMTs.
15 16 RECOMMENDATIONS FOR FUTURE RESEARCH
17 This section presents the identified gaps in the literature. The challenge remains of choosing
18 which MS medication to use in which patient and when due to the limited real world efficacy
19 and safety data as reviewed herein. Below we present key gaps in the literature that if addressed,
20 would greatly improve informed decision-making.
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12 21 22 1. Comparative effectiveness and safety studies of MS DMTs in clinical practice that
23 examine outcomes important to patients, including long–term physical or cognitive
24 disability, preservation of cognition, MS symptoms, quality of life and efficacy on quality
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1 of life measures. It is particularly important to compare affordable to unaffordable
2 treatments, as many patients and insurance carriers in the USA can no longer afford to
3 purchase many of the FDA–approved MS DMTs
4 a.
Transparent reporting and comparison of the efficacy of MS DMTs among different
5 MS subpopulations including those who have had continued relapses and/or MRI
6 disease activity on previous MS DMTs, those with highly active disease by these
7 measures, those with clinically isolated syndrome and those in primarily progressive,
8 non-relapsing phase of the disease
b. Transparent reporting and comparison of long–term safety of MS DMTs among
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9 patients with comorbidities including diabetes, obesity, cardiovascular disease and
11 physical disability
AF
10 2. Research into biomarkers which can predict DMT efficacy in different patient
12 subpopulations. Identification of stronger surrogate clinical or biomarkers for long–term
14 physical or cognitive disability and quality of life
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13 3. More research on matching disease severity to specific DMT types and outcomes of such
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15 methodologies
16 4. More research on pregnancy and DMTs—particularly dissemination of information from
17 pregnancy registries
18 5. No randomized controlled trials have directly addressed the question of whether, when or
19 20 why to discontinue DMTs in an individual with RRMS who has no evidence of relapses,
21 disability progression and stable brain imaging. More studies are needed to inform in
22 which patients discontinuation of DMTs pose little to no harm.
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6.
1 In patients with SPMS, no randomized controlled trials have directly addressed the
question of whether or when to discontinue DMTs
2 7.
3 Clinical trials have not evaluated the benefits of DMT in non-ambulatory individuals
4 with SPMS with respect to other clinically relevant domains including cognition and
5 upper limb function
8.
6 Comparative efficacy of specific DMTs for treating persons with clinically isolated
syndrome is unknown
7 9.
Comparative efficacy of highly active DMTs is unknown
9 10. Optimal definition of highly active MS is lacking—uniform definition needed to enhance
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8 comparability between studies and to guide treatment decisions and prognostication
AF
10 11 11. What is the optimal definition of response when considering a switch in therapy?
12 12. Need for Class I/II evidence concerning the effect of MS-DMTs on outcomes deemed
important by MS experts and patients when selecting MS therapies; namely, efficacy of
14 drugs on quality of life, effect on preservation of cognition and effect on MS symptoms
15 (e.g., fatigue, urinary urgency, pain, etc.)
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13 13. Good data is lacking for the designation of therapies as “highly active” and the potential
16 to match therapies to individualized disease activity
17 18 14. More information is needed on what to do concerning pregnancy and MS (as our review
19 of the evidence has uncovered): when to stop? Are some agents safer than others? Might
20 some agents be safe enough to continue through conception / pregnancy in patients with
21 active disease?
22 15. Pregnancy and Lactation. Relapsing MS predominantly affects women of childbearing
23 age and unplanned pregnancies while on an MS DMT is common. To minimize risk to
100 Confidential draft: not for distribution, dissemination, or publication
1 the mother and child more studies are needed particularly of newer agents to address the
2 following:
a. Determine the safety of in utero or lactation exposure to DMTs, on both major birth
3 outcomes, neurocognitive development, infections and response to vaccines of the infant.
4 b. The risk of return of disease activity during pregnancy or the postpartum period on the
5 6 mother’s long term risk of disability and quality of life with pre-conception/early
7 pregnancy discontinuation of DMT or withholding treatments during lactation
9 Tables/Figures
Evidence tables. See appendices
11 Forest Plots. See appendices
12 Survey data figure
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10 T
8 13 14 Figure X: Outcomes of greatest importance to MS experts and patients with MS when selecting a
15 MS disease-modifying therapy. The percentage of physicians (N=18) and patients with MS
16 (N=2156) designating an outcome as first, second or third-highest priority when selecting a MS
17 disease-modifying therapy is depicted. Outcomes measures were similarly ranked by physicians
101 Confidential draft: not for distribution, dissemination, or publication
1 and patients. Within category differences were considered, with significant differences indicated
2 (*=p<0.05). MRI = brain magnetic resonance imaging; AE = adverse events; QoL = quality of
3 life
4 5 Side effect/major risk tables
6 Table 1: Considerations/populations which would suggest caution with specific FDA approved
7 MS therapies
8 Special Considerations/Populations
T
Medication
Interferons
AF
Leukopenia
(Betaseron®/Betaferon®/Extavia®,
Liver Disease
Avonex®, Rebif®)
Depression
Significant Spasticity
Cosmetic concerns (Skin induration)
Natalizumab (Tysabri®)
Liver Disease
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Glatiramer acetate (Copaxone®,Glatopa®)
History of Immunosuppression
JCV Seropositivity
Prolonged use >2 years
Fingolimod (Gilenya®)
Leukopenia
Liver Disease
Uveitis, Macular Edema
Diabetes
VZV Seronegativity
102 Confidential draft: not for distribution, dissemination, or publication
Atrioventricular Conduction Block
Medications that May Affect Cardiac
Conduction
Basal Cell Carcinoma
Teriflunomide (Aubagio®)
Liver Disease
Leukopenia
Hypertension
Short-term Plans for Pregnancy
Leukopenia
AF
Dimethyl Fumarate (Tecfidera®)
T
History of Tuberculosis
Alemtuzumab (Lemtrada®)
Thyroid disease
Daclizumab (Zinbryta®)
Hepatic disease
Autoimmune disease
Cardiac disease
Neutropenia <1,500 cells/mm3
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Mitoxantrone (Novantrone®)
VZV = varicella zoster virus.
1 2 3 4 103 Confidential draft: not for distribution, dissemination, or publication
1 Table 2: Risks of MS therapies and potential mitigation strategies.
Drug
Risks
Mitigation Strategies
Glatiramer
Skin reactions
Education, proper injection
technique
Acetate
Immediate post-injection
(Copaxone)
systemic reaction
Education to minimize unnecessary
testing/ED visits
Interferon beta
Flu-like symptoms
(Rebif, Betaseron,
Elevated liver enzymes
Avonex)
Leukopenia
Baseline and monitoring CBC
Headache
Baseline headache screen
Depression
Screen and monitor for depression
T
NSAIDs, hydration
Baseline and monitoring LFT
AF
R
Natalizumab
PML
D
2 (Tysabri)
Neutralizing antibodies as needed
JCV testing q6 months; For JCV+
pts, MRI q6m, screen for PML
symptoms, limit to 24 infusions,
avoid if prior immunosuppression
Allergic reaction
Increased risk with natalizumab
Ab+ or hx of anaphylaxis
Elevated liver enzymes
Baseline and monitoring LFT
Leukopenia
Baseline and monitoring CBC
104 Confidential draft: not for distribution, dissemination, or publication
Fingolimod
(Gilenya)
Cardiac events on 1st dose
Baseline EKG, first dose
Bradycardia, AV block
observation for 6 or 24 hours,
Cardiac arrest, arrhythmias
contraindicated for new or existing
cardiac disease or on
antiarrhythmic; cardiology consult if
abnormal EKG
Herpes infection
VZV serology screen; vaccination if
negative
Baseline and 3 month CBC
PML
None currently available
R
Lymphopenia
Contraindicated in pregnancy,
Liver dysfunction
Baseline and q6 month LFT;
Teratogenesis
D
(Aubagio)
Baseline and 3 month LFT
AF
Liver enzyme derangements
Teriflunomide
Baseline and 3 month OCT
T
Macular edema
ensure contraception
contraindicated for existing liver
disease
Reactivation of latent TB
Screen for TB (e.g. PPD)
Alopecia
Dimethyl
Lymphopenia
CBC at baseline, 3 mo, 6 mo
fumarate
Flushing
Education, non-enteric ASA
(Tecfidera)
GI symptoms
105 Confidential draft: not for distribution, dissemination, or publication
Take with food; symptomatic
PML
treatment; increased risk for pts with
GERD/gastritis
Lymphocyte monitoring every six
months
1 2 3 Alemtuzumab
Autoimmune events:
5 (Lemtrada)
Hyperthyroidism/Grave’s
Monthly CBC and CMP
T
4 AF
TSH every 3 months.
Immune thrombocytopenia
Platelets monthly
7 Immune glomerulonephritis
Renal function check
8 Skin cancer, lymphoproliferative
Skin check annually
9 disorders
R
6 11 D
10 ______________________________________________________________________________
12 13 Daclizumab
Hypersensitivity reactions
Prophylaxis prior to infusion
14 (Zinbryta)
Severe liver injury
Hepatic monitoring
Immune mediated disorders
Monitoring
Cardiomyopathy
Baseline EKG, history exam
15 16 17 18 Mitoxantone
106 Confidential draft: not for distribution, dissemination, or publication
1 (Novantrone)
LVEF assessment baseline and prior
2 to each dose, max dose lifetime
3 140mg/m2
Treatment related Leukemia
4 Monitoring
5 ______________________________________________________________________________
7 AV: Atrioventricular
8 CBC: Complete blood count
9 CMP: Complete metabolic profile
T
6 ED:Emergency Department
11 EKG: Electrocardiogram
12 GERD: Gastroesophageal reflux
13 JCV: John Cunningham Virus
14 LFT: Liver function tests
15 LVEF: left ventricular ejection fraction
16 NSAIDS: non-steroidal anti-inflammatory drugs
17 OCT: Ocular Coherence Tomography
18 PML: Progressive multifocal leukoencephalopathy
19 PPD: Purified protein derivative (PPD) skin test
20 TB: Tuberculosis
21 TSH: Thyroid stimulating hormone
22 VZV: Varicella zoster virus
23 Adapted from Onteneda et al, MSARD 2014
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10 107 Confidential draft: not for distribution, dissemination, or publication
DISCLAIMER
2 Practice guidelines, practice advisories, comprehensive systematic reviews, focused systematic
3 reviews and other guidance published by the American Academy of Neurology and its affiliates
4 are assessments of current scientific and clinical information provided as an educational service.
5 The information: 1) should not be considered inclusive of all proper treatments, methods of care,
6 or as a statement of the standard of care; 2) is not continually updated and may not reflect the
7 most recent evidence (new evidence may emerge between the time information is developed and
8 when it is published or read); 3) addresses only the question(s) specifically identified; 4) does not
9 mandate any particular course of medical care; and 5) is not intended to substitute for the
T
1 independent professional judgment of the treating provider, as the information does not account
11 for individual variation among patients. In all cases, the selected course of action should be
12 considered by the treating provider in the context of treating the individual patient. Use of the
13 information is voluntary. AAN provides this information on an “as is” basis, and makes no
14 warranty, expressed or implied, regarding the information. AAN specifically disclaims any
15 warranties of merchantability or fitness for a particular use or purpose. AAN assumes no
16 responsibility for any injury or damage to persons or property arising out of or related to any use
17 of this information or for any errors or omissions.
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10 18 19 CONFLICT OF INTEREST STATEMENT
20 The American Academy of Neurology is committed to producing independent, critical, and
21 truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the
22 potential for conflicts of interest to influence the recommendations of this CPG. To the extent
23 possible, the AAN keeps separate those who have a financial stake in the success or failure of the
108 Confidential draft: not for distribution, dissemination, or publication
products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms
2 were obtained from all authors and reviewed by an oversight committee prior to project
3 initiation. AAN limits the participation of authors with substantial conflicts of interest. The AAN
4 forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline
5 have been reviewed by at least three AAN committees, a network of neurologists, Neurology
6 peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of
7 Interest Policy can be viewed at www.aan.com. For complete information on this process, access
8 the 2011 AAN process manual, as amended
9 (https://www.aan.com/Guidelines/Home/Development).
Acknowledgments
11 AF
10 T
1 APPENDICES
13 Appendices will include GDDI member roster and mission statement, the complete search
14 strategy employed, the schemes for classification of evidence, rules for determining confidence
15 in evidence, the steps and rules for formulating recommendations, and the clinical contextual
16 profiles. This section can be populated by AAN staff and the methodologist assigned to the
17 project. All appendices are included in the complete manuscript, available as an online data
18 supplement to the main article.
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12 19 20 Starting DMT Recommendations 21 Statement 1 22 23 Clinicians should counsel patients just diagnosed with MS about specific treatment options with DMT at a dedicated treatment visit. 109 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
Mildly 10
3
Moderate
3 Yes
4 Yes
Always
10
4 Yes
Moderate
1
Small
9
B
4 Yes
T
C
10 Yes
Minimal
10
1
1
10 Yes
7 Yes
Usually
Large
Yes
Critically Important
9
1
Occasionally
10 Yes
Benefit >>> Harm
Modest
0
10 Yes
7
Very 0
R/U
10
Benefit >> Harm
1
1
Strength of recommendation
1 Consensus
< 50%
A
Statement 2a 3 4 5 Clinicians must ascertain and incorporate/review preferences in terms of safety, route of administration, lifestyle, cost, efficacy, common side effects and tolerability in the choice of DMT in patients with MS being considered for DMT. Domain
AF
2 Rating
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Rationale is logical
D
Axioms true
R
Evidence statements accurate
Strength of recommendation
6 Consensus
Benefit > Harm
0
1
Mildly 0
1
Moderate
0
6
Modest
1
Occasionally
0
3
Usually
1
Large
0
R/U
4
Very 4
Moderate
1
C
4
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
10
Critically Important
8
Minimal
11
Always
10
Small
10
Yes
Yes
Yes
Yes
Yes
A
7 Statement 2b 8 9 Clinicians must engage in an ongoing dialogue regarding treatment decisions throughout the course of the disease with patients with MS. 110 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
0
Mildly 1
Very 0
0
Moderate
5
Modest
1
0
Occasionally
0
3
Usually
0
Large
4
Moderate
0
0
R/U
C
3
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
14
Critically Important
10
Minimal
11
Always
11
Small
12
T
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
Statement 3 3 4 Clinicians should counsel that DMTs are prescribed to reduce relapses and new MRI lesion activity. DMTs are not prescribed for symptom improvement in patients with MS. Domain
AF
2 Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
R
Evidence statements accurate
10
100%
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
Axioms true
Strength of recommendation
5 Consensus
Benefit > Harm
0
0
Mildly 0
0
0
0
3
Usually
0
Large
0
R/U
7
Modest
Occasionally
3
Moderate
0
C
2
B
10 Yes
10 Yes
10 Yes
10 Yes
Benefit >>> Harm
0
Very Moderate
1
10
Benefit >> Harm
Yes
15 Yes
Critically Important
8 Yes
Minimal
11 Yes
Always
12 Yes
Small
13 Yes
A
6 7 Statement 4 8 9 Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance in patients with MS who are candidates to initiate DMT. 111 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 10
0
Moderate
6
Modest
1
1
Occasionally
4
Usually
0
Large
3
Moderate
0
0
Yes
10 Yes
10 Yes
10 Yes
3
B
14
Critically Important
9
Minimal
9
Always
12
Small
12
T
C
10 Yes
Benefit >>> Harm
0
Very 0
R/U
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
3 Statement 5 4 5 Clinicians should counsel about comorbid disease and adverse health behaviors and potential interactions of the DMT with concomitant medications when patients with MS initiate DMTs. AF
2 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Domain
Rating
< 50%
50% to < 80%
D
R
Rationale is logical
Strength of recommendation
6 Benefit > Harm
0
Mildly 7
Modest
0
Occasionally
6
Usually
1
Large
0
4
Moderate
0
C
10 Yes
10 Yes
10 Yes
10 Yes
Yes
High
Benefit >>> Harm
2
0
0
10
Very Moderate
0
10
Benefit >> Harm
0
0
R/U
80% to < 100%
Consensus
4
B
7 Statement 6a 8 Clinicians should evaluate barriers to adherence to DMT in patients with MS. 13
Critically Important
8
Minimal
9
Always
10
Small
11
A
Yes
Yes
Yes
Yes
Yes
112 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
0
Mildly 1
Very 0
0
Moderate
10
Modest
0
0
Occasionally
0
3
Usually
0
Large
5
Moderate
0
0
R/U
C
2
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
14
Critically Important
5
Minimal
12
Always
10
Small
13
T
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
Statement 6b 3 Clinicians should counsel on the importance of adherence to DMT when patients with MS initiate DMTs. AF
2 100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Domain
Rating
Rationale is logical
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
D
R
Axioms true
Strength of recommendation
4 Consensus
Benefit > Harm
0
0
Mildly 0
0
Moderate
0
10
Modest
0
Occasionally
0
3
Usually
0
Large
0
R/U
1
Very 5
Moderate
0
C
2
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
14
Critically Important
5
Minimal
12
Always
10
Small
13
Yes
Yes
Yes
Yes
Yes
A
5 6 Statement 7 7 8 Clinicians may offer disease modifying therapy for patients with a single clinical demyelinating event with two or more brain or spinal cord lesions that have imaging characteristics consistent with MS. 113 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 2 Yes
2 Yes
Minimal
1 Yes
Always
13
1 Yes
Moderate
9
Small
5
B
0 Yes
T
C
10 Yes
3
1
1
10 Yes
Critically Important
Usually
Large
10 Yes
12
10
Occasionally
10 Yes
Benefit >>> Harm
Modest
1
Yes
12
1
Moderate
R/U
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
< 50%
A
3 4 5 Statement 8 6 7 8 Clinicians may recommend serial imaging and close follow‐up rather than initiating DMT in patients with CIS or relapsing forms of MS not on DMT who have not had relapses in the past 2 years and who do not have active new MRI lesion activity on a recent MRI. R
Domain
AF
2 Consensus
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
N/A
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
N/A
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
Rationale is logical
Strength of recommendation
9 Rating
Benefit > Harm
1
2
Mildly 0
0
1
R/U
5
0
0
1 Yes
Always
7
Moderate
2
C
2 Yes
Minimal
Usually
Large
10
2 No
12
7
1
10 Yes
Critically Important
Modest
Occasionally
10 Yes
9
Very Moderate
10 Yes
6 Yes
Small
9
B
3 Yes
A
114 Confidential draft: not for distribution, dissemination, or publication
1 2 Statement 9 3 4 Clinicians should offer DMTs to patients with relapsing forms of MS with recent clinical relapses or MRI activity. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
0
0
4
Very 0
Moderate
0
6
Modest
2
10
Usually
AF
Occasionally
0
Large
1
R/U
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
11 Yes
Critically Important
10 Yes
Minimal
4 Yes
Always
2 Yes
Small
1 Yes
T
Mildly 0
Strength of recommendation
5 Consensus
6
C
14
Moderate
B
8
A
7 Statement 10a 8 9 Clinicians should monitor for medication adherence, side effects, tolerability, safety and effectiveness of the therapy in patients with MS on DMTs. D
R
6 115 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
Mildly 8
Modest
0
1
Occasionally
3
Usually
0
Large
4
Moderate
0
0
10 Yes
10 Yes
10 Yes
10 Yes
5
B
13
Critically Important
7
Minimal
11
Always
11
Small
10
T
C
Yes
Benefit >>> Harm
2
0
Moderate
R/U
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
Statement 10b 3 4 Clinicians should follow up either annually or according to medication‐specific risk evaluation and mitigation strategies (REMS) in patients with MS on DMTs. Domain
AF
2 Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
R
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
Axioms true
Strength of recommendation
5 Consensus
Benefit > Harm
0
Mildly 0
2
0
7
Usually
0
Large
0
R/U
8
Modest
Occasionally
7
Moderate
0
C
8
B
10 Yes
10 Yes
Yes
10 Yes
Benefit >>> Harm
4
Very Moderate
0
10
Benefit >> Harm
0
0
10
10 Yes
11 Yes
Critically Important
7 Yes
Minimal
6 Yes
Always
8 Yes
Small
7 Yes
A
6 Statement 11 7 8 Clinicians should monitor patient’s reproductive plans and counsel on reproductive risks and on use of birth control while on a DMT in women of childbearing years with MS. 116 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
0
9
Moderate
Modest
0
3
7
Occasionally
Usually
0
6
Large
Moderate
0
0
3
10 Yes
10 Yes
10 Yes
10 Yes
B
10
Critically Important
6
Minimal
5
Always
9
Small
12
T
C
Yes
Benefit >>> Harm
Very 0
R/U
10
5
Mildly 100%
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
3 Statement 12 4 5 Clinicians must counsel men with MS on their reproductive plans regarding treatment implications before initiating teriflunomide or cyclophosphamide. AF
2 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Domain
Rating
< 50%
50% to < 80%
D
R
Rationale is logical
Strength of recommendation
6 Benefit > Harm
0
1
Mildly 0
2
Very 1
Moderate
0
5
Modest
2
Occasionally
0
2
Usually
0
Large
0
R/U
80% to < 100%
Consensus
3
Moderate
0
C
7 Statement 13 8 Clinicians should not prescribe mitoxantrone to patients for MS. 4
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
12
Critically Important
9
Minimal
11
Always
12
Small
11
A
Yes
Yes
Yes
Yes
Yes
117 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 4
Modest
0
0
Occasionally
3
Usually
1
Large
0
Moderate
0
0
10 Yes
10 Yes
10 Yes
10 Yes
3
B
13
Critically Important
11
Minimal
12
Always
14
Small
12
T
C
Yes
Benefit >>> Harm
1
0
Moderate
R/U
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
< 50%
Yes
Yes
Yes
Yes
Yes
A
3 Statement 14 4 Clinicians should prescribe alemtuzumab, fingolimod or natalizumab for patients with very active MS. Domain
AF
2 Rating
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Rationale is logical
D
Axioms true
R
Evidence statements accurate
Strength of recommendation
5 Consensus
Benefit > Harm
0
Mildly 0
R/U
10 Yes
6 Yes
0 Yes
Always
12
Moderate
5
C
10 Yes
4 Yes
10
1
1
10 Yes
Minimal
Usually
Large
10 Yes
Critically Important
9
4
0
Yes
Benefit >>> Harm
Modest
Occasionally
100%
11
Very Moderate
1
10
Benefit >> Harm
0
0
10
2 Yes
Small
8
B
1 Yes
A
6 7 8 Statement 15a 9 Clinicians may direct patients with MS who are candidates for DMTs to support programs. 118 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
2
Mildly 0
0
Moderate
2 Yes
7 Yes
Always
7
0 Yes
Small
6
B
8 Yes
T
C
10
Minimal
Moderate
1
R/U
10 Yes
5
8
0
10 Yes
9 Yes
Usually
Large
10 Yes
13
3
Occasionally
10 Yes
Critically Important
Modest
0
10 Yes
4
Very 0
Strength of recommendation
1 Consensus
< 50%
A
Statement 15b 3 4 Clinicians should recommend one of the following DMTs (azathioprine, cladribine, minocycline, leflunomide) for patients with relapsing forms of MS who do not have access to approved DMTs Domain
AF
2 Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
R
Evidence statements accurate
10
100%
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
Axioms true
Strength of recommendation
5 Consensus
6 7 8 Statement 16 Benefit > Harm
0
2
Mildly 1
2
R/U
1 Yes
0 Yes
Always
11
Moderate
3
C
2 Yes
9
3
0
10 Yes
Minimal
Usually
Large
10 Yes
Critically Important
12
5
0
10 Yes
Benefit >>> Harm
Modest
Occasionally
10 Yes
11
Very Moderate
1
10
Benefit >> Harm
Yes
1 Yes
Small
9
B
3 Yes
A
119 Confidential draft: not for distribution, dissemination, or publication
1 2 Clinicians should not initiate natalizumab treatment in patients with positive JC virus antibodies in serum unless there are overwhelming reasons to do so. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
N/A
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
N/A
< 50%
50% to < 80%
80% to < 100%
100%
N/A
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly Benefit >>> Harm
6
2
Occasionally
10
1 Yes
Usually
8
T
2
Always
Large
1
Moderate
1
C
B
4 Yes
A
5 Statement 17 6 For patients with PPMS clinicians should not initiate currently approved DMTs. R
Rating
Consensus
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Rationale is logical
AF
R/U
4 Yes
Small
8
D
Evidence statements accurate
Strength of recommendation
7 7 Yes
Minimal
4 Domain
7 Yes
Critically Important
Modest
1
10 Yes
5
1
Moderate
Yes
High
10
Very 0
100%
10
Benefit >> Harm
1
0
Strength of recommendation
3 Consensus
Benefit > Harm
3
0
Mildly 0
0
Moderate
0
14
Modest
5
Occasionally
0
10
Usually
2
Large
2
R/U
4
Very 3
Moderate
1
C
4
B
8 9 Switching DMT Recommendations (21 statements) 10 Yes
10 Yes
10 Yes
N/A
10 Yes
10
11
Critically Important
4
Minimal
3
Always
13
Small
11
A
Yes
Yes
Yes
Yes
Yes
120 Confidential draft: not for distribution, dissemination, or publication
1 Statement 1a 2 3 4 Clinicians should periodically monitor MRI disease activity during the first 5 years from the clinical onset of disease to detect the accumulation of new lesions in order to inform treatment decisions in patients with MS on DMTs. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 10
10
8 Yes
5 Yes
AF
C
1 Yes
Always
12
Moderate
1
R/U
Minimal
12
Usually
2
1
10 Yes
9
1
Large
Yes
Critically Important
Modest
Occasionally
10 Yes
Benefit >>> Harm
T
1
Yes
6
1
Moderate
Yes
100%
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
5 Consensus
1 Yes
Small
13
B
0 Yes
A
Statement 1b 7 8 Clinicians should recognize that relapses or new MRI lesions may develop after initiation of a DMT and before the treatment becomes effective in patients with MS on DMTs. Domain
Rationale is logical
R
6 < 50%
50% to < 80%
80% to < 100%
10
100%
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
10 Consensus
Evidence statements accurate
Strength of recommendation
9 Rating
Benefit > Harm
0
Mildly 0
R/U
5 Yes
5 Yes
Always
8
Moderate
1
C
9 Yes
9
0
0
10 Yes
Minimal
Usually
Large
Yes
Critically Important
10
1
1
10 Yes
Benefit >>> Harm
Modest
Occasionally
10 Yes
6
Very Moderate
0
10
Benefit >> Harm
0
0
10
Yes
7 Yes
Small
7
B
7 Yes
A
Statement 1c 121 Confidential draft: not for distribution, dissemination, or publication
1 2 3 4 Clinicians should discuss switching from one DMT to another in patients who have been on a DMT long enough to take full effect and are adherent to their therapy when a patient has experienced one or more relapses, two or more unequivocally new MRI lesions, or increased disability on examination, over a 1‐year period on a DMT. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 10 Yes
3 Yes
Minimal
0 Yes
Always
12
AF
Moderate
3
C
Yes
4 Yes
10
Usually
2
0
10 Yes
Critically Important
11
5
Large
Yes
Benefit >>> Harm
Modest
Occasionally
10 Yes
10
1
R/U
10
Very Moderate
0
10
T
0
10
Benefit >> Harm
0
0
Strength of recommendation
5 Consensus
B
1 Yes
Small
12
0 Yes
A
7 Statement 2 8 9 Clinicians may evaluate the amount of disease activity, adherence, adverse event profiles, and mechanism of action of DMTs when switching DMTs in patients with breakthrough disease on DMTs. D
10 R
6 122 Confidential draft: not for distribution, dissemination, or publication
Domain
Rating
Rationale is logical
< 50%
50% to < 80%
Evidence statements accurate
< 50%
Axioms true
100%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
10
10
Benefit > Harm
0
Mildly 0
Moderate
8
Modest
1
3
Occasionally
9
Usually
1
Large
11
Moderate
0
2
10 Yes
Yes
10 Yes
10 Yes
6
B
10
Critically Important
7
Minimal
2
Always
3
Small
7
T
C
No
Benefit >>> Harm
5
Very 0
R/U
10
Benefit >> Harm
0
0
Strength of recommendation
1 Consensus
80% to < 100%
Yes
Yes
Yes
Yes
Yes
A
Statement 3 3 4 Clinicians should discuss a change to a non‐injectable or less frequently injectable DMT in patients who report pain with the injections or in those who report “injection fatigue” on injectable DMTs. Domain
AF
2 Rating
Rationale is logical
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
R
Evidence statements accurate
< 50%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
7 8 9 Benefit > Harm
0
0
Mildly 0
1
R/U
3 Yes
2 Yes
Always
16
Moderate
3
C
7 Yes
13
0
0
10 Yes
Minimal
Usually
Large
10 Yes
Critically Important
14
2
0
N/A
Benefit >>> Harm
Modest
Occasionally
Yes
11
Very Moderate
1
10
Benefit >> Harm
Yes
100%
80% to < 100%
D
10
100%
50% to < 80%
Strength of recommendation
6 10
< 50%
Axioms true
5 Consensus
2 Yes
Small
12
B
3 Yes
A
123 Confidential draft: not for distribution, dissemination, or publication
1 Statement 4a 2 3 Clinicians should inquire about medication adverse effects with patients with MS who are taking a DMT and attempt to manage these adverse effects, as appropriate. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
0
Mildly 2
Very 0
0
11
Modest
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
13
Critically Important
4
Minimal
10
Always
9
Small
9
T
Moderate
0
1
Occasionally
0
4
Usually
1
Large
0
5
Moderate
1
AF
Strength of recommendation
4 Consensus
R/U
C
5
B
Yes
Yes
Yes
Yes
Yes
A
Statement 4b 6 7 Clinicians should discuss a medication switch with patients for whom these adverse effects negatively influence adherence. Domain
R
5 50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
9 Consensus
< 50%
Rationale is logical
Strength of recommendation
8 Rating
Benefit > Harm
0
0
Mildly 0
0
1
R/U
6 Yes
Always
6
Moderate
2
C
10
4 Yes
7
2
0
10 Yes
Minimal
Usually
Large
10 Yes
9 Yes
10
0
0
10 Yes
Critically Important
Modest
Occasionally
10 Yes
5
Very Moderate
10 Yes
6 Yes
Small
8
B
4 Yes
A
124 Confidential draft: not for distribution, dissemination, or publication
1 Statement 5a 2 3 Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as outlined in the medication's package insert) in patients with MS who are on a DMT. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
Mildly 10
Yes
10 Yes
10 Yes
10 Yes
Benefit >>> Harm
2
0
9
Modest
13
Critically Important
6
Minimal
7
Always
10
Small
6
T
Moderate
Yes
100%
10
Very 0
100%
10
Benefit >> Harm
0
0
0
Occasionally
0
8
Usually
0
Large
0
5
Moderate
0
AF
Strength of recommendation
4 Consensus
R/U
C
9
B
Yes
Yes
Yes
Yes
Yes
A
Statement 5b 6 7 8 Clinicians should discuss switching DMT or reducing dose or frequency (where there is data on different doses [e.g., interferons, teriflunomide, azathioprine) when there are persistent laboratory abnormalities. Domain
< 50%
D
Rationale is logical
R
5 10 Consensus
50% to < 80%
80% to < 100%
10
100%
Yes
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
N/A
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
N/A
< 50%
50% to < 80%
80% to < 100%
100%
N/A
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Strength of recommendation
9 Rating
Benefit > Harm
1
Mildly 2
R/U
8
0
2
3 No
Always
10
Moderate
0
C
5 Yes
Minimal
Usually
Large
9 Yes
Critically Important
7
2
0
Benefit >>> Harm
Modest
Occasionally
4 Yes
Small
9
B
Yes
High
3
Very Moderate
1
10
Benefit >> Harm
1
0
10
100%
3 Yes
A
125 Confidential draft: not for distribution, dissemination, or publication
1 Statement 6a 2 3 Clinicians should counsel patients considering natalizumab, fingolimod, and dimethyl fumarate about the risk of PML associated with these agents. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
2
Mildly 10
0
10 Yes
10 Yes
10 Yes
10 Yes
4
Modest
10
Critically Important
11
Minimal
11
Always
13
Small
13
T
Moderate
Yes
Benefit >>> Harm
3
Very 0
100%
10
Benefit >> Harm
0
1
1
Occasionally
0
2
Usually
1
Large
1
1
Moderate
0
AF
Strength of recommendation
4 Consensus
R/U
C
1
B
Yes
Yes
Yes
Yes
Yes
A
Statement 6b 6 7 Clinicians should discuss switching to a DMT with a lower risk of PML in patients taking natalizumab who are JC virus antibody positive or become JC virus antibody positive while on therapy. Domain
R
5 50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
9 Consensus
< 50%
Rationale is logical
Strength of recommendation
8 Rating
Benefit > Harm
0
0
Mildly 0
0
Moderate
0
6
Modest
1
Occasionally
0
9
Usually
1
Large
0
R/U
5
Very 6
Moderate
0
C
9
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
10
Critically Important
9
Minimal
5
Always
8
Small
6
A
Yes
Yes
Yes
Yes
Yes
126 Confidential draft: not for distribution, dissemination, or publication
1 Statement 7a 2 3 Clinicians should counsel that new DMTs without long‐term safety data have an undefined risk of malignancy and infection in patients starting or using new DMTs. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
10
Mildly 10
1
Yes
Yes
10 Yes
8
Modest
13
Critically Important
6
Minimal
9
Always
12
Small
12
T
Moderate
10 Yes
Benefit >>> Harm
0
Very 1
10 Yes
100%
10
Benefit >> Harm
2
0
1
Occasionally
0
5
Usually
1
Large
0
2
Moderate
0
AF
Strength of recommendation
4 Consensus
R/U
C
3
B
Yes
Yes
Yes
Yes
Yes
A
Statement 7b 6 7 8 If a patient with MS develops a malignancy while on a DMT, clinicians should promptly discuss switching to an alternate DMT, especially for patients on azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate. Domain
< 50%
D
Rationale is logical
R
5 10 Consensus
50% to < 80%
80% to < 100%
10
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Strength of recommendation
9 Rating
Benefit > Harm
1
Mildly R/U
10 Yes
9 Yes
8 Yes
Minimal
6
Usually
1
6 Yes
Always
6
Moderate
1
C
Yes
Critically Important
6
1
Large
Yes
100%
Benefit >>> Harm
Modest
Occasionally
1
10
Yes
100%
5
0
0
10
Very Moderate
2
10
Benefit >> Harm
0
1
10
Yes
100%
8 Yes
Small
6
B
7 Yes
A
Statement 7c 127 Confidential draft: not for distribution, dissemination, or publication
1 2 Patients with serious infections potentially linked to their DMT should switch DMTs (note this does not pertain to management of PML in patients on DMT). Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
Mildly 10
5
Usually
0
5
Moderate
1
C
7
B
Yes
Yes
Yes
Yes
Yes
A
AF
R/U
10 Yes
10
Critically Important
7
Minimal
7
Always
9
Small
6
T
0
Large
Yes
Benefit >>> Harm
7
1
Occasionally
Yes
100%
10
Modest
1
Yes
100%
10
3
0
Moderate
Yes
100%
10
Very 0
100%
10
Benefit >> Harm
1
0
Strength of recommendation
3 Consensus
5 Statement 8a 6 7 Clinicians should check for natalizumab antibodies in patients who have infusion reactions prior to subsequent infusions, or in patients who experience breakthrough disease on natalizumab. Domain
R
4 50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
9 Consensus
< 50%
Rationale is logical
Strength of recommendation
8 Rating
Benefit > Harm
0
Mildly 0
8
Usually
2
Large
0
R/U
9
Modest
Occasionally
8
Moderate
1
C
10
B
10 Yes
Yes
100%
Yes
10 Yes
Benefit >>> Harm
4
0
0
10
Very Moderate
0
10
Benefit >> Harm
0
0
10
10 Yes
11
Critically Important
6
Minimal
7
Always
5
Small
4
A
Yes
Yes
Yes
Yes
Yes
128 Confidential draft: not for distribution, dissemination, or publication
1 Statement 8b 2 Clinicians should switch DMTs in patients who have persistent natalizumab antibodies. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 10
10
4 Yes
2 Yes
8
4 Yes
T
1
0
5 Yes
Small
9
B
AF
C
Always
8
Moderate
3
R/U
10 Yes
Minimal
Usually
Large
Yes
Critically Important
12
1
Occasionally
Yes
Benefit >>> Harm
Modest
1
10 Yes
9
0
Moderate
Yes
100%
10
Very 1
100%
10
Benefit >> Harm
0
0
Strength of recommendation
3 Consensus
2 Yes
A
4 Statement 9a 5 6 Physicians must counsel patients considering discontinuation of natalizumab that there is an increased risk of MS relapse or MRI disease activity within 6 months of discontinuation. 50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Benefit >> Harm
Benefit >>> Harm
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
Evidence statements accurate
8 Consensus
< 50%
Rationale is logical
Strength of recommendation
7 Rating
R
Domain
Benefit > Harm
0
0
Mildly 0
0
Moderate
0
5
Modest
1
Occasionally
0
2
Usually
0
Large
1
R/U
6
Very 2
Moderate
0
C
2
B
10 Yes
10 Yes
10 Yes
10 Yes
10 Yes
10
9
Critically Important
10
Minimal
12
Always
13
Small
12
A
Yes
Yes
Yes
Yes
Yes
Statement 9b 129 Confidential draft: not for distribution, dissemination, or publication
1 2 3 Physicians and patients choosing to switch from natalizumab to fingolimod should initiate treatment within 8 weeks after discontinuation of natalizumab (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
0
Mildly T
AF
B
6 Clinicians should counsel women to stop their DMT prior to conception. 7 R
Statement 10a 3 Yes
A
Consensus
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Strength of recommendation
Benefit > Harm
1
Mildly 9
Usually
0
Large
7
Moderate
1
C
9
B
Yes
N/A
10 Yes
Yes
N/A
High
Benefit >>> Harm
10
1
1
10
Modest
Occasionally
100%
100%
6
0
0
10
Very Moderate
2
10
Benefit >> Harm
1
0
R/U
Rating
50% to < 80%
D
9 1 Yes
Small
< 50%
Rationale is logical
8 4 Yes
Always
9
5 Domain
6 Yes
14
Moderate
C
10 Yes
7 Yes
8
3
R/U
10 Yes
Minimal
Usually
0
0
10 Yes
Critically Important
9
2
Large
10 Yes
Benefit >>> Harm
Modest
Occasionally
Yes
8
0
Moderate
1
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
4 Consensus
10
Critically Important
8
Minimal
6
Always
11
Small
7
A
Yes
Yes
Yes
Yes
Yes
130 Confidential draft: not for distribution, dissemination, or publication
1 Statement 10b 2 3 Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk of the specific DMT during pregnancy. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly AF
C
6 Clinicians should not initiate DMTs during pregnancy. 9 Yes
Always
12 Yes
Small
2
B
10 Yes
A
R
Rating
Consensus
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Rationale is logical
D
Evidence statements accurate
8 9 Yes
Minimal
0
Moderate
0
R/U
Yes
6 Yes
2
1
1
10 Yes
Critically Important
Usually
Large
10 Yes
Benefit >>> Harm
4
1
Statement 10c Strength of recommendation
7 10
Modest
Occasionally
10 Yes
High
T
1
Yes
6
0
Moderate
5 Domain
10
Very 0
100%
10
Benefit >> Harm
0
0
Strength of recommendation
4 Consensus
Benefit > Harm
1
Mildly 0
1
0
7
Usually
0
Large
1
R/U
7
Modest
Occasionally
6
Moderate
0
C
7
B
Yes
N/A
10 Yes
10 Yes
N/A
High
Benefit >>> Harm
6
Very Moderate
0
10
Benefit >> Harm
0
0
10
100%
11
Critically Important
11
Minimal
10
Always
12
Small
10
A
Yes
Yes
Yes
Yes
Yes
9 131 Confidential draft: not for distribution, dissemination, or publication
1 Stopping DMT Recommendations 2 Statement 1a 3 4 5 In patients with relapsing remitting MS who are stable on DMT and wish to discontinue therapy, clinicians should counsel patients regarding the uncertain risks of stopping therapy and the need for ongoing follow‐up and periodic re‐evaluation of the decision to discontinue DMT. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
10
10
10
Benefit >> Harm
10 Yes
Yes
10 Yes
Yes
10 Yes
Benefit >>> Harm
T
Benefit > Harm
0
1
Mildly 0
4
Very 1
Moderate
2
AF
0
10
Modest
Occasionally
0
Strength of recommendation
6 Consensus
0
Large
4
Moderate
0
1
R/U
9
Usually
C
7
B
10
Critically Important
4
Minimal
4
Always
11
Small
7
Yes
Yes
Yes
Yes
Yes
A
Statement 1b 8 9 Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability progression, stable imaging) on DMT should be allowed to continue on their current DMT. D
Domain
R
7 Consensus
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Strength of recommendation
10 Rating
Benefit > Harm
0
Mildly R/U
10
100%
100%
N/A
Yes
Yes
9 Yes
Critically Important
6 Yes
Minimal
4 No
Always
10
Moderate
7 Yes
Small
13
B
Yes
Benefit >>> Harm
10
2
Yes
High
11
1
C
10
Usually
Large
0
10
Modest
4
0
100%
9
1
Occasionally
100%
100%
Very Moderate
0
10
Benefit >> Harm
0
0
10
3 Yes
A
132 Confidential draft: not for distribution, dissemination, or publication
1 2 Statement 2a 3 4 5 Clinicians should advise discontinuation of DMT in patients with SPMS who do not have ongoing relapses (or gadolinium enhancing lesions on MRI), and in addition who have not been ambulatory (EDSS ≥7) for at least 2 years. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
100%
10
10
10
Benefit >> Harm
1
2
Mildly 0
4
0
1
R/U
C
5 Yes
1 Yes
Minimal
1 Yes
Always
2
Moderate
1
10 Yes
8
Usually
Large
10 Yes
10
4
Occasionally
Yes
Critically Important
Modest
AF
2
10 Yes
7
Very Moderate
Yes
Benefit >>> Harm
T
Benefit > Harm
0
Strength of recommendation
6 Consensus
13 Yes
Small
5
B
8 Yes
A
Statement 2b 8 9 Clinicians should assess the likelihood of future relapse by assessing patient age and relapse history (e.g., frequency, severity, time since most recent relapse or gadolinium enhancing lesion). D
Domain
R
7 Consensus
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
< 50%
50% to < 80%
80% to < 100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Strength of recommendation
10 Rating
Benefit > Harm
0
Mildly R/U
Yes
N/A
Benefit >>> Harm
5 No
Critically Important
1 Yes
Minimal
1 Yes
Always
8
Moderate
4 Yes
Small
10
B
Yes
High
10
1
C
10
Usually
1
0
10 Yes
100%
10
2
Large
Yes
100%
Modest
Occasionally
100%
6
3
1
10
Very Moderate
1
10
Benefit >> Harm
3
0
10
3 Yes
A
133 Confidential draft: not for distribution, dissemination, or publication
1 Statement 3 2 3 Clinicians should discuss discontinuation of currently approved DMTs in patients with PPMS with no MRI disease activity currently receiving such treatments. Domain
Rating
Rationale is logical
< 50%
50% to < 80%
80% to < 100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
100%
Confidence in Inference Very low
Low
Moderate
High
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
Benefit > Harm
1
Mildly 10
10
5 Yes
3 Yes
AF
C
2 Yes
Always
3
Moderate
0
R/U
Minimal
9
Usually
0
1
10 Yes
12
4
Large
10 Yes
Critically Important
Modest
Occasionally
Yes
Benefit >>> Harm
T
0
Yes
100%
7
0
Moderate
Yes
100%
10
Very 0
100%
10
Benefit >> Harm
2
0
Strength of recommendation
4 Consensus
12 Yes
Small
6
B
8 Yes
A
Statement 4 6 7 Clinician should review the risk of continuing DMTs vs the risk of stopping DMT in patients with CIS on DMTs. Domain
R
5 50% to < 80%
80% to < 100%
100%
Evidence statements accurate
< 50%
50% to < 80%
80% to < 100%
100%
Axioms true
< 50%
50% to < 80%
80% to < 100%
100%
Related evidence strong & applicable
Internal inferences logically follow
< 50%
50% to < 80%
80% to < 100%
100%
< 50%
50% to < 80%
80% to < 100%
Confidence in Inference Very low
Low
Moderate
Benefit relative to Harm
Harm > Benefit
Importance of outcomes
Not Important or Variation in preferences
Large
Feasible
Rarely
Cost relative to net benefit
Very Large
D
9 Consensus
< 50%
Rationale is logical
Strength of recommendation
8 Rating
Benefit > Harm
1
Mildly R/U
C
9 Yes
4 Yes
Minimal
4 Yes
Always
8
Moderate
9 Yes
Small
13
B
Yes
High
12
1
N/A
Critically Important
Usually
1
0
100%
14
1
Large
10 Yes
Benefit >>> Harm
Modest
Occasionally
Yes
8
0
0
10
Very Moderate
1
10
Benefit >> Harm
0
0
10
10 Yes
4 Yes
A
134 Confidential draft: not for distribution, dissemination, or publication
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