Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Optimizing Outcomes: Balancing Disease-Modifying and Symptomatic Therapy in Multiple Sclerosis James D. Bowen, MD Medical Director Multiple Sclerosis Center Swedish Neuroscience Institute Seattle, Washington 1 Introduction and Case Presentation 2 Case—History 52-year-old male 1996 at age 36 – Right-hand numbness and weakness spreading to entire right body over 2 days – Told it was a “demyelinating event” but no other diagnosis or treatment given – Mild residual right tingling/heaviness Early 2000s – Diplopia – Urinary urgency – Erectile dysfunction 3 Case—History 2007 – Pain/burning in arms/legs – Diplopia – Weakness – Diagnosis uncertain MRI interpreted as possible strokes 4 Case—History December 2008 – Brain MRI Improvement in left cerebral peduncle lesion New right frontal lesion – C-spine MRI normal – Visual evoked potential and lumbar puncture normal December 2009 – Saw an MS specialist – Diagnosed with MS April 2010 – Started treatment with glatiramer acetate 5 Case—Current Presentation Patient transfers to our clinic, February 2011 Reports tolerating treatment well Admits incomplete adherence Has had occasional MS attacks 6 Efficacy of First-Line Disease-Modifying Therapies (DMTs) in Early MS 7 BENEFIT—IFN Beta-1b SC in Early MS IFN beta-1b 250 µg vs placebo for 2 years – 468 patients with clinically isolated syndrome and abnormal MRI Primary outcome: development of clinically definite MS (CDMS) IFN Beta-1b (n = 292) Placebo (n = 176) P-Value 28% 45% <.0001 Time to CDMS (25%) 618 days 255 days –– McDonald at 2 years 69% 85% <.00001 McDonald at 6 months 28% 51% –– Outcome CDMS at 2 years Kappos L, et al. Neurology. 2006;67:1242-1249. 8 REFLEX—IFN Beta-1a SQ in Early MS IFN beta-1a SQ 44 µg TIW vs QW vs placebo for 2 years – 517 patients with CIS and abnormal MRI Primary outcome: time to MS diagnosis by McDonald criteria Outcome at 2 Years IFN Beta1a TIW (n = 171) IFN Beta-1a QW (n = 175) Placebo (n = 171) P-Value 2-year probability of MS (McDonald) 62.5% 75.5% 85.8% <.0001 TIW .008 QW 2-year probability of CDMS 20.6% 21.6% 37.5% .004 TIW .0023 QW 0.6 RR 0.19 1.23 RR 0.37 2.70 <.0001 TIW <.0001 QW Combined unique active MRI lesions/person/scan, mean Abbreviations: CIS, clinically isolated syndrome; RR, rate ratio. Comi G, et al. Lancet Neurol. 2012;11:33-41. 9 PreCISe—Glatiramer Acetate in Early MS GA 20 mg/day vs placebo for 3 years – 481 patients with CIS and abnormal MRI Primary outcome: time to CDMS Outcome at 3 Years GA (n = 243) Placebo (n = 238) P-Value Time to CDMS (25%) 722 days 336 days .0005 25% 43% <.0001 0.7 1.8 <.0001 CDMS New T2 lesions, last observed value Abbreviations: CDMS, clinically definite MS, CIS, clinically isolated syndrome; GA, glatiramer acetate. Comi G, et al. Lancet. 2009;374:1503-1511. 10 PreCISe Open-Label Extension— Glatiramer Acetate in Early MS 2-year open-label phase following initial 3-year trial of GA vs placebo Early vs delayed GA treatment Early cohort = patients initially randomized to GA Delayed cohort = patients initially randomized to placebo Early GA (n = 243) Delayed GA (n = 238) P-Value CDMS 33% 49.5% .0005 Annualized relapse rate 0.22 0.29 NA -0.99% -1.27% .021 Outcome at 5 Years Brain volume change Abbreviations: CDMS, clinically definite MS; NA, not available. Martinelli V, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.006. 11 FREEDOMS—Fingolimod in Relapsing-Remitting MS (RRMS) Fingolimod 0.5 mg or 1.25 mg vs placebo for 2 years – – N = 1272 with RRMS Mean EDSS: 2.3, fingolimod 0.5 mg; 2.5, placebo Primary outcome: annualized relapse rate Outcome at 2 Years Fingolimod 0.5 mg (n = 425) Placebo (n = 418) P-Value 0.18 0.40 <.001 82.3% 75.9% .03 2.5 9.8 <.001 Annualized relapse rate Free of sustained progression Mean new/enlarging T2 lesions Kappos L, et al. N Engl J Med. 2010;362:387-401. 12 TRANSFORMS—Fingolimod vs IFN Beta-1a in RRMS Fingolimod 0.5 mg or 1.25 mg vs IFN beta-1a 30 µg IM for 1 year – – N = 1292 with RRMS Mean EDSS: 2.24, fingolimod 0.5 mg; 2.19, IFN Primary outcome: annualized relapse rate Outcome at 1 year Annualized relapse rate Fingolimod IFN 0.5 mg (n = 431) (n = 429) P-Value 0.16 0.33 <.001 Free of sustained progression 94.1% 92.1% .25 Mean new/enlarging T2 lesions 1.7 2.6 .004 No trials under way for fingolimod in CIS Cohen JA, et al. N Engl J Med. 2010;362:402-415. 13 TEMSO—Teriflunomide in Relapsing MS Teriflunomide (TFN) 7 mg and 14 mg vs placebo for 2 years – N = 1086 with relapsing MS, mean EDSS 2.68 Primary outcome: annualized relapse rate TFN 7 mg (n = 365) TFN 14 mg (n = 358) Placebo (n =363) Annualized relapse rate 0.37 0.37 0.54 <.001/ <.001 Sustained progression 21.7% 20.2% 27.3% .08/.03 Change in T2 lesion volume from baseline 1.31 mL 0.72 mL 2.21 mL .03/ <.001 Outcome at 2 Years O'Connor P, et al. N Engl J Med. 2011;365:1293-1303. P-Value 7 mg/ 14 mg 14 TOWER—Teriflunomide Multiple Sclerosis Oral Teriflunomide (TFN) 7 mg and 14 mg vs placebo for 48 wks + ≤18 months extension – N = 1165 with relapsing MS, mean EDSS 2.7 Primary outcome: annualized relapse rate TFN 7 mg (n = 407) TFN 14 mg (n = 370) Placebo (n = 388) P-Value 7 mg/ 14 mg Annualized relapse rate 0.389 0.319 0.50 .018/ .0001 Sustained progression 21.0% 22.2% 15.8% .76/.04 Outcome at 2 Years CIS trial under way—TOPIC (NCT00622700) Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153. 15 Importance of Early Treatment Studies of injectable first-line DMTs (IFN betas and GA) approved for RRMS have shown benefit in clinically isolated syndrome (CIS) – These often have a greater magnitude of benefit than the RRMS study Different populations studied, however No data yet on newer oral first-line DMTs – No CIS trial under way for fingolimod – TOPIC trial under way for teriflunomide in CIS 16 Case Continues—Findings at Presentation Occasional attacks, adherence poor Timed 25-Foot Walk – 14.2 sec Internuclear ophthalmoplegia (INO) on right gaze Motor: 4/5 throughout, spasticity right > left Decreased light touch/pin prick all 4 limbs, pain Gait: right >left hemiparetic Reflexes: 4+, right >left with clonus Urinary urgency/frequency, cognitive impairment, fatigue 17 Case—MRI Findings T2 FLAIR weighted MRI showing lesions typical for MS Graphic courtesy of James D. Bowen, MD. 18 Case—Issues to Address Issues with greatest impact for this patient – Nonadherence – Cognitive impairment – Mobility impairment Additional issues – Urinary urgency – Fatigue 19 Nonadherence 20 Case Continues—Assessment of Poor Adherence First priority = improve adherence Nurse discussed poor adherence with patient Identified reasons – Insurance lapses – Pharmacy refill interruptions – Cognitive impairment 21 Barriers to Adherence Financial Insurance/pharmacy Perceived lack of benefit Intolerance of injections Intolerance of side effects Laboratory abnormalities Treatment failure For more information on adherence, participate in a recent MS MedImage case by Dr. James D. Bowen: “Switching Disease-Modifying Therapy Due to Adherence Issues.” Find it at: http://mic.projectsinknowledge.com/neurology/multiple-sclerosis/SwitchingDisease-Modifying-Therapy-Due-to-Adherence-Issues.cfm?jn=2022.29 22 Financial Support Manufacturer support programs – Contact manufacturer for support for individual medication National Multiple Sclerosis Society Financial Assistance Program – http://www.nationalmssociety.org/living-withmultiple-sclerosis/society-programs-andservices/financial-assistanceprogram/index.aspx 23 Case Continues—Addressing Nonadherence Nurse put into place a system to remind patient about GA injections – Smart phone alarm Social worker stabilized insurance and worked with pharmacy to ensure refills Patient has remained adherent since 24 Cognitive Impairment 25 Cognitive Impairment in MS About 60% of MS patients have cognitive impairment – About 35% of those with low-disability relapsing-remitting MS May be subtle and difficult to recognize in clinic Most common − processing speed and episodic memory Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342. 26 Cognitive Screening Tests Paced Auditory Serial Addition Test (PASAT)1 – Takes 2 or 3 minutes 1 5 3 6 7 8 10 Symbol Digit Modality Test (SDMT)2 – Takes about 90 seconds X ∧ 1 2 3 1. National MS Society. Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual. 2001. Accessed 10/1/12 at: http://www.nationalmssociety.org/forprofessionals/researchers/clinical-study-measures/msfc/index.aspx. 2. Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342. Graphics courtesy of Dr. James D. Bowen. 27 Medications for Cognitive Impairment in MS Disease-modifying therapies Other1 – Potassium-channel blockers 3,4-diaminopyridine, 4-aminopyridine – Dopaminergic antiparkinsonism agents Amantadine – Stimulants Modafinil, methylphenidate, L-amphetamine – Acetylcholinesterase inhibitors Donepezil, rivastigmine Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342. 28 DMTs in MS-Related Cognitive Impairment—Rationale MS lesions and attacks likely contribute to cognitive impairment1 Nonlesion damage may also contribute (atrophy, normal appearing white matter changes, gray matter changes)1,2 DMTs alter exacerbations, MRI lesion activity, atrophy, and noncognitive disability 1. Calabrese M, et al. Arch Neurol. 2009;66:1144-1450. 2. Calabrese M, et al. Expert Rev Neurother. 2011;11:425-432. 29 DMTs in MS-Related Cognitive Impairment—Interferon Betas IFN beta-1a IM vs placebo for 2 years1 – – – – – N = 166 with relapsing MS Significant benefit for information processing/memory; P = .036 Trend to benefit for visuospacial/executive; P = .005, corrected for baseline, P = .085 No effect on verbal ability/attention span; P = .60 Sustained PASAT deterioration: IFN 19.5%, placebo 36.6%; P = .023 IFN beta-1a SQ 22 µg vs 44 µg TWI for 2 years, open label2 – – N = 356 with RRMS Proportion with ≥3 impaired cognitive tests: 22 µg = 26.5%, 44 µg = 17.0%; P = .034 30 1. Fischer JS, et al. Ann Neurol. 2000;48:885-892. 2. Patti F, et al. Ther Adv Neurol Disord. 2009;2:67-77. DMTs in MS-Related Cognitive Impairment—Glatiramer Acetate GA vs placebo, phase III1 – – – N = 248 with relapsing-remitting MS 5 cognitive domains No difference between GA and placebo groups – However, no measurable decline in cognition in placebo group Patients had little baseline impairment GA for 3 months2 – – N = 30 with MS PASAT improved from 42.16 to 47.76, P <.05, in those with Gd+ MRI images 1. Weinstein A, et al. Arch Neurol. 1999;56:319-324. 2. Mori F, et al. Neurology. 2012;78:P04.118. 31 DMTs in MS-Related Cognitive Impairment—Natalizumab, Fingolimod, and Teriflunomide Natalizumab – AFFIRM phase III trial – natalizumab vs placebo – 43% reduction in risk of PASAT-3 worsening, P = .013 Fingolimod – Little data Teriflunomide – Little data Weinstock-Guttman B, et al. J Neurol. 2012;259:898-905. 32 3,4-Diaminopyridine (DAP) 3,4-DAP up to 100 mg/day vs nicotinic acid (NA) 10 mg/day N = 36 with MS – Randomized, double-blind, crossover design Outcome 3,4-DAP NA P-Value Improvement in defined deficit* 22 2 .0005 Selective Reminding Test, mean 37.5 36.9 NS 10/36 Spatial Recall, mean 18.8 17.2 NS Symbol Digit Modality Test, mean 34.2 34.5 NS PASAT, mean 66.6 65.4 NS Word List Generation, mean 28.6 27.7 NS *Primary outcome – leg weakness in 34 patients, arm ataxia in 2. Bever CT, et al. Neurology. 1996;47:1457-1462. 33 L-Amphetamine 4 doses: L-amphetamine 15, 30, and 45 mg or placebo – N = 19 with MS, suspected cognitive deficit – Counterbalanced within-subjects design Outcome: neuropsychological testing 2 h after dose Test Outcome PASAT Significant only for 45 mg SDMT Significant only for 45 mg, trend 30 mg TMT, Part A Significant only for 45 mg TMT, Part B; RAVLT; BVMTR Not significant Abbreviations: BVMTR, Brief Visuospatial Memory Test – Revised; PASAT, Paced Auditory Serial Addition Test; RAVLT, Rey Auditory Verbal Learning Test; SDMT, Symbol Digit Modalities Test; TMT, Trail Making Test. 34 Benedict RH, et al. J Neurol. 2008;255:848-852. L-Amphetamine L-amphetamine 30 mg vs placebo for 29 days – N = 151 with MS, cognitive deficit – Randomized, double-blind, controlled trial Test Outcome SDMT (primary outcome) No significant difference CVLT2-TL No significant difference CVLT2-DR Significantly better BVMTR-TL Significantly better BVMTR-DR Significantly better PASAT No significant difference Abbreviations: Brief Visual Memory Test-Revised-Total Learning (BVMTR-TL); Brief Visual Memory TestRevised-Delayed Recall (BVMTR-DR); California Verbal Learning Test, second edition-Delayed Recall (CVLT2-DR); California Verbal Learning Test, second edition-Total Learning (CVLT2-TL); Paced Auditory Serial Addition Test (PASAT); Symbol Digit Modalities Test (SDMT). 35 Morrow SA, et al. J Neurol. 2009;256:1095-1102. Donepezil Donepezil 10 mg/day vs placebo for 24 weeks – N = 120 with MS, memory deficit – Multi-center, double-blind, randomized trial Donepezil (n = 61) Placebo (n = 59) P-Value SRT (primary outcome) 1.6 1.7 NS 10/36 Spatial Recall -0.4 1.6 NS SDMT 0.6 2.0 NS PASAT 2 + 3 3.8 3.5 NS COWA 1.0 0.6 NS D-KEFS Sort 0.6 0.5 NS JOLO 0.6 0.6 NS Outcome, Mean Abbreviations: COWA, Controlled Oral Word Association; D-KEFS Sort, Delis-Kaplan Executive Function System Sorting; JOLO, Judgment of Line Orientation; PASAT, Paced Auditory Serial Addition Test; SDMT, Symbol Digit Modalities Test; SRT, Selective Reminding Test. 36 Krupp LB, et al. Neurology. 2011;76:1500-1507. Methylphenidate Single dose: methylphenidate 10 mg vs placebo – N = 26 with MS, attention deficit (PASAT score <25th percentile) – Double-blind, placebo-controlled – All patients treated with IFN beta-1a ≥6 months Test Methylphenidate (n = 14) Placebo (n = 12) Baseline 1 Hour After Baseline 1 Hour After PASAT 3 33.3 40.9* 37.8 39.5† PASAT 2 24.6 30.9* 28.0 28.3† *P = <.001; †P = NS. Harel Y, et al. J Neurol Sci. 2009;276:38-40. 37 Modafinil IM IFN beta-1a vs IM IFN beta-1a + modafinil – N = 60 with RRMS, attention deficit – 49 completed study Improvement in multiple cognitive outcomes However: – No placebo control – High dropout – Multiple comparisons Wilken JA, et al. Int J MS Care. 2008;10:1-10. 38 Drugs with No Significant Cognitive Effects 4-aminopyridine (AP) vs placebo1 N = 20 with MS; randomized, double-blind, crossover 4-AP 32 mg/d vs placebo for 6 mo2 N = 54 with progressive MS; randomized, doubleblind, crossover design Amantadine vs pemoline vs placebo for 6 wk3 – – N = 45 with MS and severe fatigue Only written Symbol Digit Modalities Test showed significance for amantadine Rivastigmine 3 mg BID vs placebo for 12 wk4 – N = 60 with MS and cognitive impairment; doubleblind, randomized, controlled trial 1. Smits RC, et al. Neurology. 1994;44:1701-1705. 2. Rossini PM, et al. Mult Scler. 2001;7:354-358. 3. Geisler MW, et al. Arch Neurol. 1996;53:185-188. 4. Shaygannejad V, et al. Can J Neurol Sci. 2008;35:476-481. 39 Medications for Cognition in MS None proven effective Stimulants may have some benefit – Perhaps nonspecific due to increased alertness, decreased fatigue 40 Cognitive Rehabilitation Few studies Psychology for stress reduction Neuropsychology for identification of specific areas of deficit Speech therapy for help with organizational skills Occupational or physical therapy for energy conservation Assistive technology 41 Case Continues—Addressing Cognitive Impairment Neuropsychological testing offered to patient, but refused Family recognized that cognitive loss was due to MS Reminders put in place – Cell phone, memory book – With these, patient and family believe he is functioning adequately If reminders fail, will consider further testing or cognitive rehabilitation with speech/language pathology and neuropsychology 42 Mobility Impairment 43 Contributors to MS-Related Mobility Loss Spasticity Proprioceptive deficits Balance deficit Psychological contributors 44 Spasticity Weakness Stiffness (clasp knife) Spastic leg jumps Hyperreflexia (clonus) Babinski response 45 Balance Deficit Loss of position sense Visual loss Vestibular loss Ataxia 46 Oral Medications for Spasticity Baclofen Tizanidine Benzodiazepines Dantrolene Cannabis 47 Physical Therapy for Mobility Stretching Strengthening Cardiovascular Balance 48 Botulinum Toxin Prevents acetylcholine release at neuromuscular junction1 Typically lasts about 3 months1 Ideal for relatively localized muscle groups (eg, footdrop, hand flexors) Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712. 49 Intrathecal Baclofen Ideal patient is one in whom oral baclofen works but sedation is excessive1 – Also for patients with severe spasticity who require higher dose than can be delivered orally Delivered directly into CSF by lumbar catheter1 Typically, a test dose is given first1 Complications/adverse effects2 – Mechanical pump/catheter failure, infection, sedation, dizziness, impaired vision, slurred speech 1. National MS Society. Intrathecal baclofen. Accessed 10/2/12 at: http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-aboutms/treatments/medications/baclofen-intrahecal/index.aspx. 2. Beard S, et al. Health Technol Assess. 2003;7:1-111. 50 Surgical Options Nerve blocks – phenol Neurectomy Rhizotomy Tenotomy 51 Dalfampridine—Mechanism of Action Demyelinated axons have excessive potassium channels that lead to – Potassium leakage out of the cell – Signal failure Dalfampridine blocks these channels – Improving signal conduction Jeffery DR, et al. Core Evid. 2010;5:107-112. 52 Dalfampridine Phase III Trials— Responder Analysis Responder analysis = percentage of patients in each group who respond – Not mean differences between groups Best means of capturing response when some individuals have a high level of response, while others have little or no response Facilitates assessing patient-perceived value of response 53 Dalfampridine-Extended Release (ER) Phase IIIb Trial Oral dalfampridine 10 mg BID vs placebo for 9 weeks – N = 239, MS-related gait impairment – Relapsing-remitting MS, primary-progressive MS, secondary-progressive MS, progressive-relapsing MS – Double-blind, randomized, controlled trial Primary outcome = proportion of “timed walk responders” – Timed 25-Foot Walk Timed walk responder = subject whose walking speed on at least 3 of the 4 “on-drug” visits is faster than the fastest speed during any of the 5 “off-drug” visits Goodman AD, et al. Ann Neurol. 2010;68:494-502. 54 Dalfampridine-ER Phase IIIb Trial Outcomes Proportion of Timed Walk Responder (TWR) – Dalfampridine 42.9% vs placebo 9.3%; P <.0001 Walking speed, change from baseline – Dalfampridine TWRs 24.7% vs placebo 7.7% 12-Item MS Walking Scale, change from baseline – TWRs -6.04 vs nonresponders 0.85; P <.001 Leg strength improvement – Dalfampridine TWRs 0.145 U vs placebo 0.042 U; P = .028 Goodman AD, et al. Ann Neurol. 2010;68:494-502. 55 Dalfampridine-ER in Clinical Practice Approved to improve walking in MS patients1 – Benefit is seen in patients with progressive MS, as well as RRMS2 Contraindication1 – Renal failure or seizure history Adverse effects3,4 – Only drug approved for this indication Urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, fatigue, back pain In those patients who respond, dalfampridine results in a significant improvement in walking and quality of life 1. Jeffery DR, et al. Core Evid. 2010;5:107-112. 2. Pozzilli C, et al. Neurology. 2011;76(suppl 4):A73. 56 3. Goodman AD, et al. Lancet. 2009;373:732-738. 4. Goodman AD, et al. Ann Neurol. 2010;68:494-502. Gait Aids Canes, staffs, trekking poles Forearm crutches Walkers Orthoses – Ankle-foot orthoses, knee, Hip Flexion Assist Device Functional electrical stimulation – Tibialis, quadricep 57 Dalfampridine ER + Walking Aids Dalfampridine improved walking speeds in phase III trials in patients already requiring walking aids (EDSS 6.0+)1-3 Clinical experience suggests synergy between physical therapy, exercise, walking devices, and pharmacotherapy with dalfampridine 1. Goodman AD, et al. Lancet. 2009;373:732-738. 2. Goodman AD, et al. Ann Neurol. 2010;68:494-502. 58 3. Brown T, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstract P07.164. Case Continues and Conclusion 59 Case Continues—Addressing Mobility Impairment Spasticity identified as a major source of symptoms Physical therapy – Patient started doing leg stretching at home with therapist oversight Gait aids – Single point cane recommended Pathogenesis of imbalance due to sensory loss described Patient resistant in past, but now will consider – Ankle-foot orthoses recommended but patient refused 60 Case Continues—Addressing Mobility Impairment Botulinum toxin – Injected into gastrocnemius with excellent results Baclofen – Started baclofen 10 mg TID, but continued marked hyperreflexia – Dose gradually increased to 20 mg TID with marked improvement in spasticity 61 Case—Mobility Issue Follow-Up Spasticity under much better control Still having falls due to decreased balance – Most likely due to sensory loss in legs After other issues addressed, patient still had gait dysfunction Dalfampridine Extended Release trial – Improvement in Timed 25-Foot Walk from 14.2 seconds to 10.1 seconds – Patient reports that this led to an improvement in his daily function with better gait 62 Case Continues—Other Issues Now that the issues with greatest impact on patient have been addressed, focus can turn to other issues – Urinary urgency – Fatigue Management strategies for each 63 Practical Considerations of Balancing DMTs and Symptomatic Therapies Generally add 1 medication at a time Increase dose to effectiveness or tolerability limit Discontinue medications that fail Try to dose as few times a day as possible Use PRN when possible (fatigue, bladder) Review medications at each visit Emphasize nonmedical therapy (exercise) 64 Conclusions Optimal patient care requires balance between DMTs and symptomatic therapy – Patients often more concerned about symptoms than disease modification – Must address both symptoms and DMT Often intertwined: optimal DMT use requires that symptoms be addressed – Symptoms and DMT adherence often interconnected – Prioritize those symptoms that interfere with DMT adherence 65