Download ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and

Accepted Manuscript
ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and 100% Sustained
Virologic Response With or Without Ribavirin in Treatment-experienced Patients
with HCV Genotype 1b Infection
Pietro Andreone , MD Massimo G. Colombo , MD Jeffrey V. Enejosa , MD Iftihar
Koksal , MD Peter Ferenci , MD Andreas Maieron , MD Beat Müllhaupt , MD Yves
Horsmans , MD Ola Weiland , MD Henk W. Reesink , MD Lino Rodrigues Jr., MD
Yiran B. Hu , MS Thomas Podsadecki , MD Barry Bernstein , MD
PII:
DOI:
Reference:
S0016-5085(14)00603-9
10.1053/j.gastro.2014.04.045
YGAST 59121
To appear in: Gastroenterology
Accepted Date: 29 April 2014
Please cite this article as: Andreone P, Colombo MG, Enejosa JV, Koksal I, Ferenci P, Maieron A,
Müllhaupt B, Horsmans Y, Weiland O, Reesink HW, Rodrigues Jr L, Hu YB, Podsadecki T, Bernstein
B, ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and 100% Sustained Virologic
Response With or Without Ribavirin in Treatment-experienced Patients with HCV Genotype 1b Infection,
Gastroenterology (2014), doi: 10.1053/j.gastro.2014.04.045.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as
corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT
ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and 100% Sustained Virologic Response
With or Without Ribavirin in Treatment-experienced Patients with HCV Genotype 1b Infection
Short Title: ABT-450/r/Ombitasvir and Dasabuvir for HCV
Pietro Andreone MD1, Massimo G Colombo MD2, Jeffrey V Enejosa MD3, Iftihar Koksal MD4, Peter
RI
PT
Ferenci MD5, Andreas Maieron MD6, Beat Müllhaupt MD7, Yves Horsmans MD8, Ola Weiland MD9, Henk
W Reesink MD10, Lino Rodrigues-Jr MD3, Yiran B Hu MS3, Thomas Podsadecki MD3, Barry Bernstein MD3
1
University of Bologna, Bologna, Italy; 2Ospedale Maggiore Policlinico, University of Milan, Milan, Italy;
AbbVie Inc., North Chicago, IL, USA; 4Karadeniz Technical University, Trabzon, Turkey; 5Medical
SC
3
M
AN
U
University of Vienna, Internal Medicine III, Vienna, Austria; 6Elisabeth Hospital, Linz, Austria; 7University
Hospital, Zurich, Switzerland; 8Université Catholique de Louvain, Brussels, Belgium; 9Karolinska
University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; 10Academic Medical Center,
Amsterdam, The Netherlands
TE
D
Abbreviations: AE, adverse event; DAA, direct-acting antiviral agent; LLN, lower limit of normal; pegIFN,
peginterferon; RAV, resistance-associated variant; RBV, ribavirin; SVR, sustained virologic response;
SVR12, sustained virologic response 12 weeks after treatment; TEAE, treatment-emergent adverse event;
AC
C
Correspondence:
EP
ULN, upper limit of normal
Pietro Andreone
Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna
Via Massarenti, 9
40138 Bologna, Italy
Email: [email protected]
Phone: +39 051 6363618
1
ACCEPTED MANUSCRIPT
Fax: +39 051 345806
Conflicts of Interest:
Pietro Andreone has received research support from Roche, Merck, and Gilead Sciences; served on
RI
PT
advisory committees for Roche, Merck, Janssen Cilag, AbbVie, Boehringer Ingelheim, Gilead Sciences,
and BMS; and been a consultant for Merck and BMS. Massimo G Colombo has received grant/research
support from Merck, Roche, BMS, and Gilead Sciences; served on advisory committees for Merck,
SC
Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck,
Abbott, Boehringer Ingelheim, GSK, GenSpera, and AbbVie; and served on speakers bureaus for Tibotec,
M
AN
U
Roche, Novartis, Bayer, BMS, Gilead Sciences, and Vertex. Iftihar Koksal has served on advisory
committees and speaker’s bureaus for Roche, MSD, Janssen Therapeutics, AbbVie, Gilead Sciences, and
BMS. Peter Ferenci has served on advisory committees and speakers bureaus for Roche, RottapharmMadaus; been a consultant for AbbVie, Boehringer Ingelheim, Janssen, BMS Austria, Idenix, Achillion,
TE
D
GSK, Gilead Sciences, and MSD; and received research grants from Roche Austria. Andreas Maieron has
served on advisory committees for MSD, Janssen Therapeutics, AbbVie, Boehringer Ingelheim, Gilead
Sciences, BMS, and Rottapharm-Madaus; and received research grants from Roche and MSD. Beat
EP
Müllhaupt has served on advisory committees for Roche, MSD, Janssen Therapeutics, AbbVie,
Boehringer Ingelheim, Gilead Sciences, and BMS; been a consultant for Gilead Sciences and AbbVie; and
AC
C
received research grants from Roche and Gilead Sciences. Yves Horsmans has been a consultant for
Janssen Pharmaceuticals, BMS, Merck Sharp & Dohme, Roche, Gilead Sciences, AbbVie and Boehringer
Ingelheim. Ola Weiland has served on speaker’s bureaus and advisory committees for AbbVie, Gilead
Sciences, BMS, Medivir, Johnson & Johnson, and Merck. Henk W Reesink has been a consultant for
AbbVie, Astex, BMS, Gilead Sciences, GSK, Janssen-Cilag, Merck, PRA-International, Roche, Tibotec, RPharm, and Regulus; received research support from AbbVie, BMS, Boehringer Ingelheim, Gilead
Sciences, Janssen-Cilag, Merck, PRA-International, Roche, and Santaris. Jeffrey V Enejosa, Lino
2
ACCEPTED MANUSCRIPT
Rodrigues-Jr, Yiran B Hu, Thomas Podsadecki, and Barry Bernstein are employees of AbbVie and may
hold stock or options.
RI
PT
Writing Assistance: Medical writing support was provided by Douglas E. Dylla, PhD, employee of AbbVie.
Author Contributions: PA was the coordinating investigator of the trial, was involved in the study setup,
SC
and was responsible for the clinical supervision of patients and performance of the study. MGC, IK, PF,
AM, BM, YH, OW, and HWR were investigators in the study, responsible for the treatment of patients
M
AN
U
and were involved in the acquisition, analysis, and interpretation of the data. YBH performed the
statistical analysis and provided input to the analysis plans. TP and BB provided scientific input in the
clinical study design, reviewed and provided input with regards to the analysis plans. JVE and LRJ were
responsible for the conduct and overview of the trial, analysis of the data, and review of the Clinical
AC
C
EP
TE
D
Study Report. All authors provided critical input and revisions to the writing of the manuscript.
3
ACCEPTED MANUSCRIPT
ABSTRACT
Background & Aims: The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir
RI
PT
(an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy
in patients with hepatitis C virus (HCV) genotype 1b infection—the most prevalent subgenotype
worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and
SC
dasabuvir to produce high rates of sustained virologic response (SVR) in these patients.
Methods: We performed a multicenter, open-label phase 3 trial of 179 patients with HCV genotype 1b
M
AN
U
infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were randomly
assigned (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (Group 1) or
without (Group 2) for 12 weeks. The primary endpoint was SVR 12 weeks after treatment (SVR12). We
assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar
TE
D
population treated with telaprevir, peginterferon, and ribavirin.
Results: Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of
response to the combination of telaprevir, peginterferon, and ribavirin (Group1: 96.6%; 95% confidence
EP
interval [CI], 92.8%–100% and Group 2: 100%; 95% CI, 95.9%–100%). The rate of response in Group 2
was noninferior to that of Group 1. No virologic failure occurred during the study. Two patients (1.1%)
AC
C
discontinued the study due to adverse events, both in Group 1. The most common adverse events in
Groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases
in hemoglobin to below the lower limit of normal were more frequent in Group 1 (42.0% vs 5.5% in
Group 2, P<.001), although only 2 patients had hemoglobin levels below 10 g/dL.
Conclusions: The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or
without RBV, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b
4
ACCEPTED MANUSCRIPT
infection. Both regimens are well tolerated, evidenced by the low rate of discontinuations and generally
mild adverse events. ClinicalTrials.gov number: NCT01674725
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
Keywords: PEARL-II; ribavirin-free; IFN; interferon-free therapy; clinical trial
5
ACCEPTED MANUSCRIPT
INTRODUCTION
Untreated chronic hepatitis C virus (HCV) infection is a leading cause of liver damage, cirrhosis, and
RI
PT
hepatocellular carcinoma.1 Prevalence of HCV infection is estimated at 3% worldwide and results in
approximately 350 000 deaths annually.2, 3 Genotype 1 accounts for approximately 70% of all HCV
infections and subgenotype 1b is most predominant in Europe and Eastern Asia. Approved direct-acting
antiviral agents (DAAs), telaprevir, boceprevir, sofosbuvir, and simeprevir, given with peginterferon
SC
(pegIFN) and ribavirin (RBV) have reported sustained virologic response (SVR) rates of 67% to 89% in
HCV genotype 1-infected patients. Response rates with DAA regimens are generally lower in patients
M
AN
U
who have failed previous pegIFN-containing treatment regimens than in treatment-naïve patients, and
noticeably lower among prior null responders.4-8 Additionally, the toxicity of pegIFN and long duration of
therapy (up to 48 weeks with some regimens) are a hardship for patients.9 Notably, pegIFN-based
treatment regimens have a well-documented adverse event (AE) profiles including influenza-like
TE
D
symptoms and depression that have led to unfavorable discontinuation rates in clinical trials,6, 9-12 while
RBV also has associated side effects including teratogenicity, hemolytic anemia, and rash.13, 14
All-oral and interferon-free HCV treatment regimens with DAAs provide wider treatment access to
EP
patients in need with chronic liver disease. ABT-450 is an NS3/4A protease inhibitor with in vitro
nanomolar antiviral activity and is co-dosed with the CYP3A4 inhibitor, ritonavir, which significantly
AC
C
increases peak and trough drug concentrations enabling once-daily dosing.15 The multi-targeted, all-oral
combination of the three DAAs (3D regimen) ABT-450/ritonavir, ombitasvir (formerly ABT-267), an HCV
NS5A inhibitor with pangenotypic picomolar antiviral activity,16 and dasabuvir (formerly ABT-333), an
HCV NS5B RNA nonnucleoside polymerase inhibitor, with RBV has shown in a phase 2b trial to achieve
high rates of sustained virologic response 12 weeks post-treatment (SVR12) in treatment-naïve and experienced genotype 1-infected patients. With this regimen, a 93% SVR12 rate was achieved in
6
ACCEPTED MANUSCRIPT
genotype 1-infected non-cirrhotic patients with prior null response to pegIFN/RBV, and 100% SVR12 in
the genotype 1b patient subset.17 These high response rates in prior null responders, considered difficult
to treat, are promising and require confirmation in a large phase 3 trial. While ABT-
RI
PT
450/ritonavir/ombitasvir and dasabuvir with RBV may achieve high SVR12 rates, determining the benefit
gained by including RBV in the regimen has not been assessed in these patients. This phase 3 study
(PEARL-II) evaluated the efficacy and safety of 12-week treatment with coformulated ABT-
AC
C
EP
TE
D
M
AN
U
treatment-experienced HCV genotype 1b-infected patients.
SC
450/ritonavir/ombitasvir and dasabuvir with or without RBV exclusively in non-cirrhotic pegIFN/RBV
7
ACCEPTED MANUSCRIPT
METHODS
Patients. Adults were 18 to 70 years old at the time of screening from 43 sites in Austria, Belgium, Italy,
RI
PT
The Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. Patients
were required to have documentation that they previously failed treatment with pegIFN/RBV. Eligible
patients were required to be non-cirrhotic with chronic HCV genotype 1b-infection for at least 6 months
with an HCV RNA level > 10 000 IU/mL at screening. Patients were excluded if they had evidence of co-
SC
infection with any HCV genotype other than 1b or tested positive for Hepatitis B surface antigen or anti-
M
AN
U
HIV antibody at screening. Detailed eligibility criteria are provided in the Supplementary Appendix.
Study design. Patients were stratified by type of previous non-response to pegIFN/RBV treatment (null
responders, partial responders, and relapsers) and randomized 1:1 to receive the 12-week regimen of
coformulated ABT-450/ritonavir/ombitasvir (150mg/100mg/25mg once daily) and dasabuvir (250mg
twice daily) with either weight-based RBV dosed twice daily (1000mg daily if body weight was less than
TE
D
75kg, 1200mg daily if body weight was greater than or equal to 75kg) for Group 1 or without RBV for
Group 2. After 12 weeks of treatment, patients were followed for 48 additional weeks. Additional details
EP
on study design are in the Supplementary Appendix.
The study was conducted in accordance with the International Conference of Harmonisation guidelines,
AC
C
applicable regulations, and guidelines governing clinical study conduct and ethical principles that have
their origin in the Declaration of Helsinki. All patients provided written informed consent. All authors
had access to relevant data, critically reviewed, revised, and approved the manuscript.
Safety Assessments. Adverse event assessments were reported from the time of study drug
administration until 30 days after last dose and were judged mild, moderate, or severe; clinical
laboratory testing was performed at each study visit. Serious AEs were collected throughout the study.
8
ACCEPTED MANUSCRIPT
Efficacy Endpoints. Plasma samples were collected at screening and each study visit and HCV RNA levels
determined using the Roche COBAS TaqMan real-time RT-PCR assay v2.0 at a central lab. A fixedsequence testing procedure was used to control Type I error at 0.05. The primary efficacy endpoint was
RI
PT
noninferiority of the SVR12 rates (assessed by HCV RNA < 25 IU/mL) of Group 2 and Group 1 to the
historical SVR12 rate for telaprevir plus pegIFN/RBV in HCV genotype 1b-infected patients who were
relapsers, partial responders, or null-responders to previous pegIFN/RBV treatment,4 adjusted for non-
SC
cirrhotic patients in this study. Group 1 and Group 2 noninferiority could be claimed if the SVR12 lower
bound of the 95% confidence interval (CI) was greater than the upper bound of the CI for the historical
M
AN
U
rate minus a 10.5% noninferiority margin (64%). Further details of historical noninferiority calculations
are provided in the Supplementary Appendix. Secondary efficacy endpoints in the fixed-sequence
included the following: (1) comparison of the percentage of patients with a decrease in hemoglobin to
below the lower limit of normal (LLN) at the end of treatment; (2) superiority of Group 1 and Group 2 to
TE
D
the historical rate for telaprevir plus pegIFN/RBV (75%); and (3) noninferiority of Group 2 to Group 1
using a 10.5% noninferiority margin for the SVR12 difference. The percentage of patients with ontreatment virologic failure and post-treatment relapse was also assessed.
EP
Virologic failure criteria. Virologic failure leading to discontinuation of study drug was determined if the
following criteria occurred: confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV
AC
C
RNA measurements greater than 1 log10 IU/mL above nadir) at any point during treatment; failure to
achieve HCV RNA < 25 IU/mL by Week 6; and confirmed HCV RNA ≥ 25 IU/mL in two consecutive
measurements at any point during treatment after HCV RNA < 25 IU/mL. Post-treatment relapse was
confirmed in patients with HCV RNA < 25 IU/mL at the end of treatment and subsequent RNA ≥ 25
IU/mL in two consecutive measurements.
9
ACCEPTED MANUSCRIPT
Statistical Analyses. Efficacy analyses were performed using the intent-to-treat population defined as all
randomized HCV genotype 1b-infected patients who received at least one dose of coformulated ABT450/ritonavir/ombitasvir. The safety population included all patients that received at least one dose of
RI
PT
study drug. A population of 90 patients per treatment arm was calculated to provide greater than 90%
power to achieve noninferiority of the active regimen to the historical threshold (64%).
SAS software for the UNIX operating system was used for all analyses. All statistical tests and all
AC
C
EP
TE
D
M
AN
U
SC
confidence intervals were two-sided with a significance level of .05.
10
ACCEPTED MANUSCRIPT
RESULTS
Baseline Patient Demographics and Characteristics. Patient screening began 14 August 2012 and the last
RI
PT
SVR12 data were collected 16 January 2014. Of 324 patients screened, 187 were randomized and 186
received study drug (91 Group 1, 95 Group 2) (Figure 1). Null-responders, partial-responders, and
relapsers to previous pegIFN/RBV treatment made up 34.9%, 28.5%, and 36.6% of the study population,
respectively, evenly stratified between treatment arms (Table 1). Reasons for screen failures are
SC
provided in the Supplemental Appendix. Seven randomized patients, three in Group 1 and four in Group
2 were not included in the intent-to-treat efficacy population. Of these, six patients were enrolled prior
M
AN
U
to a protocol amendment and received non-coformulated ABT-450/ritonavir/ombitasvir, 3 of whom
were genotype 1a; a seventh patient’s HCV subgenotype was not determined.
Efficacy. After 12 weeks of treatment, 96.6% (85/88; 95% CI, 92.8 – 100) of Group 1 and 100% (91/91;
95% CI, 95.9 – 100) of Group 2 patients achieved SVR12 using the intent-to-treat population for both
TE
D
groups (Table 2). For the primary endpoint, SVR12 rates in both treatment groups were noninferior to
the historical SVR rate for telaprevir plus pegIFN/RBV in comparable treatment-experienced patients.
Both treatment groups were also superior to the historical rate. Noninferiority of Group 2 to Group 1
EP
was met as the treatment difference in SVR12 rates was 3.4% (95% CI, -0.4 – 7.2).
AC
C
No patients from either treatment group experienced on-treatment virologic failure or post-treatment
relapse. Of the three patients in Group 1 that did not achieve SVR12, two (2.3%) patients discontinued
study drug due to AEs, and one patient was lost to follow-up after SVR4 (Table 3).
Sustained virologic responses in both groups were not influenced by previous non-response, age, race,
or IL28B genotype. Among Group 1 null-responders, partial-responders, and relapsers to previous
pegIFN/RBV treatment, SVR12 rates were 93.5%, 96.0%, and 100%, respectively. Group 1 rates were
11
ACCEPTED MANUSCRIPT
similarly high regardless of IL28B genotype (CC: 100%, CT: 96.4%, TT: 95.5%), or sex (male: 95.3%,
female: 97.8%). Group 2 SVR12 rates were 100% in all subgroups.
RI
PT
Lastly, the seven patients excluded from the efficacy subset due to receiving non-coformulated study
drug, confirmed genotype 1a, or undetermined genotype all completed treatment and achieved SVR12.
Safety. Treatment-emergent AEs (TEAE) were experienced by 79.1% of patients in Group 1 and 77.9% of
SC
patients in Group 2. Most TEAEs were mild with the most commonly reported events in Group 1 and
Group 2 being fatigue (31.9% vs. 15.8%, P = .015), headache (24.2% vs. 23.2%, P = NS), and nausea
M
AN
U
(20.9% vs. 6.3%, P = .005), respectively (Table 3). Patients in Group 1 also experienced statistically
significantly more events of insomnia, anemia, rash, and increased blood bilirubin, all known to be
associated with RBV use; no patient discontinued study drug due to these events.
Overall, two (1.1%) patients discontinued treatment due to AEs, both in Group 1. One patient
TE
D
experienced two serious AEs of pancreatitis that were considered by the investigator not to be study
drug related. This patient had elevated amylase on Day 1 prior to receiving study drug; on Day 11, the
patient reported abdominal pain and was hospitalized on Day 13, at which point study drugs were
EP
discontinued. The patient experienced another mild episode of pancreatitis on Day 31 that resolved by
Day 36. This patient had an HCV RNA level of 28 IU/mL on Day 8. Resistance analysis performed on
AC
C
baseline and post-treatment samples revealed no NS3 or NS5B resistance-associated variants (RAVs)
present at baseline. The NS5A R30Q variant was present at baseline, and R30Q and Y93H were present
at post-treatment Week 12. Another patient reported anxiety, tachycardia, fever, and dyspnea on Day
36 that led to study discontinuation; HCV RNA on Day 32 prior to discontinuation was < 15 IU/mL. This
patient had no RAVs in NS3 or NS5A at baseline; NS5B variants C316N and S556G were present at
baseline and post-treatment Week 4. Excluding the event of pancreatitis, 3 other serious TEAEs
12
ACCEPTED MANUSCRIPT
(cellulitis, nephrolithiasis, and osteoarthritis) were reported; none were judged to be study drug-related
or led to study drug discontinuation.
RI
PT
Hemoglobin levels below the LLN at end of treatment, a secondary endpoint, was experienced more
often by patients in Group 1 compared to Group 2 (42.0% vs. 5.5%, respectively, P < .001), although
clinically significant grade 2 hemoglobin declines to below 10 g/dL at the end of treatment occurred in
only 2 (1.1%) of patients, both in Group 1. No patient required a blood transfusion or erythropoietin.
SC
Elevations in total bilirubin greater than 2 x the upper limit of normal (ULN) were reported in 15.4% of
patients in Group 1 and 1.1% of patients in Group 2 (P < .001), with 8.8% of patients in Group 1 and 0%
M
AN
U
in Group 2 reporting greater than 3 x ULN. Mean levels of total bilirubin peaked at Week 1
(predominantly indirect bilirubin) and were reduced at Week 2 in both groups, though remained
elevated throughout the treatment period only in Group 1 (Supplemental Figure S3). The mean total
bilirubin at Week 1 was 1.6 mg/dL in Group 1 and 0.9 mg/dL in Group 2; by Week 2, the mean levels
TE
D
were reduced to 1.2 and 0.7 mg/dL, respectively. Five (5.5%) patients in Group 1 and 2 (2.1%) patients in
Group 2 reported hyperbilirubinaemia; three (3.3%) patients in Group 1 reported jaundice. One
hyperbilirubinaemia and one jaundice event were moderate in severity and the remaining events were
EP
judged mild; none led to study drug discontinuation. Ribavirin dose modification occurred in five
patients, three due to anemia, one due to hyperbilirubinaemia, and one was dose adjusted due to
AC
C
decrease in weight; all achieved SVR12.
The percentage of patients with post-baseline alanine aminotransferase (ALT) levels greater than 3 x
ULN was similarly low for both treatment groups. No patient experienced post-baseline ALT level greater
than 5 x ULN. One patient in Group 2 had an aspartate aminotransferase (AST) level greater than 5 x
ULN at a single time study visit, with all subsequent values normal. Twelve weeks of treatment with
these regimens normalized liver enzymes in almost all patients with elevated baseline liver enzymes:
13
ACCEPTED MANUSCRIPT
96.9% (63/65) and 100% (66/66) of Group 1 and Group 2 patients, respectively, with high baseline ALT
levels reached normal values following treatment; AST levels were normalized in 98.4% (60/61) and
91.8% (56/61) of Group 1 and Group 2 patients, respectively. Median changes from baseline in
AC
C
EP
TE
D
M
AN
U
SC
-36.0 U/L; AST: -22.0 vs. -21.0 U/L for Group 1 and Group 2, respectively).
RI
PT
aminotransferase values at final treatment visit were similar comparing treatment groups (ALT: -35.0 vs.
14
ACCEPTED MANUSCRIPT
DISCUSSION
PEARL-II examined an all-oral, interferon-free regimen with or without RBV exclusively in pegIFN/RBV
RI
PT
treatment-experienced, non-cirrhotic patients with HCV genotype 1b infection. The intent-to-treat
SVR12 rates of 96.6% to 100% in patients receiving the 12-week regimen of ABT-
450/ritonavir/ombitasvir and dasabuvir with or without RBV, respectively, were superior to the
historical rate of telaprevir plus pegIFN/RBV. The SVR12 rates of this multi-targeted regimen with RBV
SC
confirm results of the Phase 2b AVIATOR study17 in prior null-responders, the most difficult to treat of
pegIFN/RBV non-responders, and further expands efficacy conclusions to patients who were partial
M
AN
U
responders and relapsers to pegIFN/RBV treatment. In addition, PEARL-II demonstrated noninferiority of
the RBV-free regimen to the RBV-containing regimen, supporting the use of ABT450/ritonavir/ombitasvir and dasabuvir without RBV for 12 weeks in the treatment of HCV genotype 1binfected pegIFN/RBV-experienced patients without cirrhosis.
TE
D
The TEAEs associated with either group in this 12-week regimen were generally mild and manageable.
Overall, only two (1.1%) treated patients discontinued treatment due to AEs, and the five serious TEAEs
reported in four patients were considered to be unrelated to study drug by the investigators. As
EP
expected, known RBV AEs (fatigue, nausea, insomnia, rash, anemia, and increased bilirubin) were
statistically more prevalent in Group1RBV, although frequency and severity appear reduced compared to
AC
C
when RBV is combined with pegIFN.7, 18 Hemoglobin declines were also more frequent in Group 1
although few (2.2%) reached clinical significance, and AEs leading to RBV dose reduction occurred in
only four patients. Elevated bilirubin levels in Group 1 were predominantly due to indirect bilirubinemia,
consistent with the hemolysis associated with RBV and the known effect of ABT-450 on the bilirubin
transporter OATP1B1, though lack of sustained bilirubin elevations in Group 2 suggest the predominant
15
ACCEPTED MANUSCRIPT
cause was RBV-related hemolysis. Liver enzyme normalization was consistent with the high rate of
virologic response.
RI
PT
The SVR12 rates reported here compare favorably to published reports of other interferon-free
regimens using the NS5B RNA polymerase inhibitor sofosbuvir in combination with NS5A inhibitors
(daclatasvir or ledipasvir), or with an NS3/4A protease inhibitor (simeprevir). Combinations of sofosbuvir
plus daclatasvir with or without RBV have shown greater than or equal to 95% SVR12 in 41 treatment-
SC
experienced genotype 1 patients, of which only eight patients were genotype 1b.19 Similar SVR12 rates
have been reported in treatment-experienced genotype 1 patients with sofosbuvir plus ledipasvir with
M
AN
U
(21/21, 100%) or without RBV (18/19, 95%), although only six genotype 1b patients were included.20 In
13 genotype 1b-infected patients receiving the combination of simeprevir plus sofosbuvir with or
without RBV, 100% SVR8 was reported.21 A larger study of daclatasvir in combination with asunaprevir in
pegIFN/RBV treatment-experienced genotype 1b-infected patients showed SVR12 rates of 80% (70/87)
TE
D
with patients not achieving an SVR primarily due to lack of efficacy and AEs.22 Together with the results
from PEARL-II, these data support a multi-targeted approach to achieve SVR; however, no other studies
have exclusively analyzed, nor had the statistical power to draw conclusions regarding efficacy, including
EP
the contribution of RBV, in treatment-experienced HCV genotype 1b patients as the PEARL-II study does.
AC
C
One of the strengths of the PEARL-II study includes its large sample size in genotype 1b-infected
patients, the most prevalent subgenotype worldwide, including patients with previous null response and
relapse to pegIFN/RBV treatment. Treatment-experienced genotype 1b-infected patients have not been
extensively studied with currently approved or investigational IFN-free regimens, hence this large
patient population represents a group with unmet need. Study limitations include the open label study
design, the exclusion of patients with cirrhosis, HBV or HIV coinfection, and that these findings may be
specific to genotype 1b-infected patients. However, the efficacy and safety of this regimen has recently
16
ACCEPTED MANUSCRIPT
been described from phase 3 studies in treatment-naïve patients infected with genotype 1a and 1b,23
and in patients with cirrhosis.24
RI
PT
In conclusion, a 12-week regimen of ABT 450/ritonavir/ombitasvir and dasabuvir with or without RBV
was generally well-tolerated in pegIFN/RBV treatment experienced, non-cirrhotic, HCV genotype 1binfected adults, as evidenced by the low rate of treatment discontinuation and serious AEs. Additionally,
the regimen without RBV was associated with fewer AEs of fatigue, nausea, insomnia, rash, and a lower
SC
rate of laboratory abnormalities including bilirubin elevation and hemoglobin decrease. Sustained
virologic response rates of 96.6% and 100% were achieved, including 93.5% and 100% in the difficult to
M
AN
U
treat previous pegIFN/RBV null-responders, with or without RBV, respectively. Therefore, ABT450/ritonavir/ombitasvir and dasabuvir without RBV is sufficient to achieve optimal treatment of HCV
AC
C
EP
TE
D
genotype 1b infection in this population.
17
ACCEPTED MANUSCRIPT
ACKNOWLEDGEMENTS
The authors would like to express their gratitude to the trial participants, and coordinators who made
RI
PT
this study possible, as well as Sara Siggelkow, Nela Hayes, Karmin Robinson-Morgan, Lisa Rhiner,
Ruxandra-Maria Stanica, Lorena De Castillo, Mia Poteracki, Manal Abunimeh, Kristine Richards, Lois
Larsen, Sailaja Settivari, Yan Xie, Xiangdong Zhou, Prajakta Badri and the M13-389 Study Team for their
contributions to the study. Authors thank the study investigators including Avanish M. Aggarwal,
SC
Sanjeev Arora, David Bernstein MD, Bal Raj Bhandari, Maurizia Rossana Brunetto, Filipe Calinas, Nicola
M
AN
U
Caporaso, Andreas Cerny MD, J-F. Dufour, Francque Sven MA, MD, PhD, Giovanni B. Gaeta, W. Jeffrey
Fessel MD, Michael Gschwantler MD, Gurel Selim MD PhD, Camilla Håkanård, Jason McNeese, Ivan
Melendez-Rivera MD, Christophe Moreno MD PhD, Frederik Nevens, Gunnar Norkrans MD PhD, Resat
Ozaras MD, Ronald Pruitt MD, Giovanni Raimondo MD, H. Reynaert MD PhD, Federico Rodriguez-Perez
MD, Lorenzo Rossaro MD, Rui Tato Marinho MD PhD, Hans Van Vlierberghe, Wolfgang Vogel MD, Debra
TE
D
Weinstein MD, Cihan Yurdaydin, Philippe J. Zamor. AbbVie sponsored the study (NCT01674725),
contributed to its design, participated in the collection, analysis, and interpretation of the data, and in
the writing, reviewing, and approval of the final manuscript. Medical writing support was provided by
AC
C
EP
Douglas E. Dylla, PhD, of AbbVie.
18
ACCEPTED MANUSCRIPT
REFERENCES
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
RI
PT
SC
7.
M
AN
U
6.
TE
D
5.
EP
4.
World Health Organization. Media Centre - Hepatitis C, 2014.
Gravitz L. Introduction: a smouldering public-health crisis. Nature 2011;474:S2-4.
Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C
virus infections to cirrhosis and primary liver cancer worldwide. Journal of Hepatology
2006;45:529-38.
Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med
2011;364:2417-28.
Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1
infection. New England Journal of Medicine 2011;364:1207-17.
D'Ambrosio R, Aghemo A, Colombo M. Treatment of experienced and naive patients with
hepatitis C: focus on telaprevir. Biologics 2012;6:363-70.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C
infection. New England Journal of Medicine 2013;368:1878-87.
Zeuzem S, Berg T, Gane E, et al. Simeprevir Increases Rate of Sustained Virologic Response
Among Treatment-Experienced Patients With HCV Genotype-1 Infection: A Phase IIb Trial.
Gastroenterology 2013.
Chung RT. A watershed moment in the treatment of hepatitis C. New England Journal of
Medicine 2012;366:273-5.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis
C virus infection. New England Journal of Medicine 2002;347:975-82.
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared
with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised
trial. Lancet 2001;358:958-65.
Hezode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with
HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC)
- NCT01514890. J Hepatol 2013;59:434-41.
Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic
hepatitis C virus infection. New England Journal of Medicine 2011;364:2405-16.
Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1
infection. New England Journal of Medicine 2011;364:1195-206.
Menon RM, Klein CE, Lawal AA, et al. Pharmacokinetics and Tolerability of the HCV Protease
Inhibitor ABT-450 Following Single Ascending Doses in Healthy Adult Volunteers With and
Without Ritonavir. HepDART. Kohala Coast, HI, 2009.
Pilot-Matias T, Koev G, Krishnan P, et al. In vitro combinatory effect of HCV NS3/4A protease
inhibitor ABT-450, NS5A inhibitor ABT-267, and non-nucleoside NS5B polymerase inhibitor ABT333, In 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona,
Spain, 2012.
Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b Trial of Interferon-free Therapy for Hepatitis C
Virus Genotype 1. New England Journal of Medicine 2014;370:222-232.
Jacobson IM, Kowdley KV, Kwo PY. Anemia management in the era of triple combination
therapy for chronic HCV. Gastroenterol Hepatol (N Y) 2012;8:1-16.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus Sofosbuvir for Previously
Treated or Untreated Chronic HCV Infection. New England Journal of Medicine 2014;370:211221.
AC
C
1.
2.
3.
19
ACCEPTED MANUSCRIPT
22.
23.
24.
RI
PT
21.
Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and
without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C
virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014;383:515-23.
Lawitz E, Ghalib R, Rodriguez-Torres M, et al. COSMOS Study: SVR4 results of a once daily
regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV
genotype 1 null responders, In 20th Conference of Retroviruses and Opportunistic Infections,
Atlanta, GA, USA, 2013.
Chayama K, Suzuki Y, Ikeda K, et al. All-oral Combination of Daclatasvir Plus Asunaprevir in
Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected
with HCV Genotype 1b: Results from a Phase 3 Trial. Hepatology 2013;58:313A.
Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r–Ombitasvir and
Dasabuvir with Ribavirin. New England Journal of Medicine 2014;370:1594-1603.
Poordad F, Hezode C, Trinh R, et al. ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin for
Hepatitis C with Cirrhosis. New England Journal of Medicine. DOI:10.1056/NEJMoa1402869.
AC
C
EP
TE
D
M
AN
U
Author names in bold designate shared co-first authorship.
SC
20.
20
ACCEPTED MANUSCRIPT
FIGURE LEGENDS
Figure 1. Patient flow diagram.
RI
PT
Figure 2. ITT genotype 1b efficacy subset treatment response over time. Percent of patients achieving
virologic response (± 95% confidence intervals) are presented for Week 4 of treatment (RVR), end of
treatment (EOTR), 4 weeks post-treatment (SVR4), and 12 weeks post-treatment (SVR12), as well as n/N
AC
C
EP
TE
D
M
AN
U
SC
within the bars graphs.
21
ACCEPTED MANUSCRIPT
Table 1. Baseline demographics and characteristics, n (%)
Group 2
3D + RBV
3D
Parameter
(N = 91)
(N = 95)
Sex, male
45 (49.5)
RI
PT
Group 1
57 (60.0)
Race
84 (92.3)
Black
3 (3.3)
4 (4.4)
M
AN
U
Ethnicity, Hispanic/Latino
86 (90.5)
SC
White
Geographic region
North America
6 (6.3)
2 (2.1)
14 (15.4)
19 (20.0)
77 (84.6)
76 (80.0)
54.2 ± 10.9
54.2 ± 10.5
26.2 ± 4.1
27.5 ± 4.3
10 (11.0)
7 (7.4)
81 (89.0)
88 (92.6)
6.56 ± 0.56
6.48 ± 0.53
Null responder
32 (35.2)
33 (34.7)
Partial-responder
26 (28.6)
27 (28.4)
Relapser
33 (36.3)
35 (36.8)
64 (70.3)
61 (64.2)
Europe
BMI (kg/m2), mean (±SD)
IL28B genotype
EP
CC
TE
D
Age (years), mean (±SD)
Non-CC
AC
C
HCV RNA (log10 IU/mL), mean (±SD)
Previous pegIFN/RBV non-response
Baseline fibrosis stage
F0 – F1
ACCEPTED MANUSCRIPT
F2
13 (14.3)
21 (22.1)
F3
14 (15.4)
13 (13.7)
Fibrosis scoring information is provided in the Supplemental Appendix. 3D, three direct-acting antivirals;
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
RBV, ribavirin; BMI, body mass index; pegIFN, peginterferon.
ACCEPTED MANUSCRIPT
Table 2. Intent-to-treata virologic response, n/N (%)
Group 2
Treatment difference
3D + RBV
3D
(95% CI)
85/88 (96.6)
91/91 (100)
3.4 (-0.4, 7.2)
Null responder
29/31 (93.5)
32/32 (100)
6.5 (-2.2, 15.1)
Non/partial responder
24/25 (96.0)
26/26 (100)
4.0 (-3.7, 11.7)
Relapser
32/32 (100)
33/33 (100)
Parameter
SVR12
RI
PT
Group 1
M
AN
U
Sex
0 (N/A)
Male
41/43 (95.3)
54/54 (100)
4.7 (-1.6, 10.9)
Female
44/45 (97.8)
37/37 (100)
2.2 (-2.1, 6.5)
3/3 (100)
5/5 (100)
0 (N/A)
82/85 (96.5)
86/86 (100)
3.5 (-0.4, 7.5)
10/10 (100)
7/7 (100)
0 (N/A)
54/56 (96.4)
64/64 (100)
3.6 (-1.3, 8.4)
21/22 (95.5)
20/20 (100)
4.5 (-4.2, 13.2)
Race
TE
D
Black
Non-black
IL28B genotype
TT
AC
C
CT
EP
CC
a
SC
Previous non-response
Intent-to-treat genotype 1b efficacy population includes all patients with subgenotype 1b infection who
were assigned to and treated with ABT-450/ritonavir/ombitasvir co-formulated drug.
3D, three direct-acting antivirals; RBV, ribavirin; SVR12, 12-week sustained virologic response.
ACCEPTED MANUSCRIPT
Table 3. Patients Reporting TEAEs, n (%)
Group 2
3D + RBV
3D
Parameter
(N = 91)
(N = 95)
Any TEAE
72 (79.1)
74 (77.9)
Any severe TEAE
0 (0)
1 (1.1)
Any serious TEAE
2 (2.2)
TEAE leading to discontinuation
2 (2.2)
SC
2 (2.1)
M
AN
U
Common TEAEsa
Fatigue
P value
RI
PT
Group 1
0 (0)
29 (31.9)
15 (15.8)
22 (24.2)
22 (23.2)
19 (20.9)
6 (6.3)
0.005
13 (14.3)
3 (3.2)
0.008
13 (14.3)
8 (8.4)
12 (13.2)
12 (12.6)
11 (12.1)
7 (7.4)
10 (11.0)
0 (0)
< 0.001
8 (8.8)
0 (0)
0.003
8 (8.8)
1 (1.1)
0.017
37 (42.0)
5 (5.5)
< 0.001
8 (8.8)
0 (0)
0.003
ALT > 5X ULN
0 (0)
0 (0)
AST > 5X ULN
0 (0)
1 (1.1)
Headache
Nausea
TE
D
Insomnia
Pruritus
Diarrhea
EP
Asthenia
Anemia
Rash
AC
C
Blood bilirubin increased
0.015
Chemistry and Hematologic values of interest during treatment
Hemoglobin below LLN at end of treatmentb
Total bilirubin > 3X ULN
ACCEPTED MANUSCRIPT
a
Investigator-reported TEAEs present in ≥ 10 % of either treatment group or with a statistically
significant difference between treatment groups.
b
N’s = 88 and 91 for Group 1 and Group 2, respectively, using the intent-to-treat genotype 1b efficacy
RI
PT
population.
TEAE, treatment-emergent adverse event; 3D, three direct-acting antivirals; RBV, ribavirin; LLN, lower
limit of normal; ULN, upper limit of normal; ALT, alanine aminotransferase; AST, aspartate
AC
C
EP
TE
D
M
AN
U
SC
aminotransferase.
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
ACCEPTED MANUSCRIPT
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Table of Contents
Investigators............................................................................................................................................ 3
RI
PT
PEARL-II Eligibility Criteria........................................................................................................................ 4
Randomization Methods ......................................................................................................................... 7
Blinding ................................................................................................................................................... 7
Collection of Samples for HCV RNA Measurement ................................................................................... 7
SC
HCV RNA Measurement .......................................................................................................................... 7
Virologic Failure Criteria .......................................................................................................................... 7
M
AN
U
Noninferiority and Superiority Analyses................................................................................................... 8
Sample Size Determination...................................................................................................................... 9
Ranked Efficacy Endpoint Analyses .......................................................................................................... 9
Figure S1. PEARL-II Study Design. ........................................................................................................... 10
Figure S2. HCV RNA Suppression Over Time. .......................................................................................... 11
Figure S3. PEARL-II Mean Total Bilirubin Values Over Time. ................................................................... 12
TE
D
Table S1. PEARL-II Primary Reasons for Not Meeting Study Eligibility ..................................................... 13
Table S2. Fibrosis Scoring....................................................................................................................... 15
Table S3. PEARL-II Adverse Events Occurring in > 5% of Patients in Either Treatment Group, n (%) ........ 16
Table S4. Grade 3 and 4 Laboratory Abnormalities, n (%) ....................................................................... 17
EP
Table S5. Potentially Clinically Significant Laboratory Abnormalities, n/N (%) ........................................ 18
AC
C
References ............................................................................................................................................ 19
1
ACCEPTED MANUSCRIPT
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
ABT-450 was identified as a lead compound by AbbVie and Enanta Pharmaceuticals.
2
ACCEPTED MANUSCRIPT
Investigators
PEARL-II investigators included:
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
Austria: Peter Ferenci, Michael Gschwantler, Andreas Maieron, Wolfgang Vogel Belgium: Sven
Francque, Yves Horsmans, Christophe Moreno, Frederik Nevens, Hendrik Reynaert, Hans Van
Vlierberghe Italy: Pietro Andreone, Maurizia Rossana Brunetto, Nicola Caporaso, Massimo Colombo,
Giovanni B Gaeta, Giovanni Raimondo Netherlands: Henk W Reesink Portugal: Filipe Calinas, Rui Tato
Marinho Puerto Rico: Ivan Melendez-Rivera, Federico Rodríguez-Pérez Sweden: Camilla Hakangard,
Gunnar Norkrans, Ola Weiland Switzerland: Andreas Cerny, Jean-Francois Dufour, Beat Müllhaupt
Turkey: Selim Gurel, Iftihar Koksal, Resat Ozaras, Cihan Yurdaydin United States: Avanish Aggarwal,
Sanjeev Arora, David Bernstein, Bal Raj Bhandari, Jeffrey Fessel, Edward Galen, Jason McNeese, Ronald
Pruitt, Lorenzo Rossaro, John Vierling, Debra Weinstein, and Philippe Zamor.
3
ACCEPTED MANUSCRIPT
PEARL-II Eligibility Criteria
Main Inclusion:
1. Male or female between 18 and 70 years of age, inclusive, at time of Screening.
2. Female who is:
practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle)
•
sexually active with female partners only
•
not of childbearing potential, defined as:
postmenopausal for at least 2 years prior to screening (defined as amenorrheic for
longer than 2 years, age appropriate, and confirmed by a follicle-stimulating hormone
[FSH] level indicating a postmenopausal state), or
o
surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or
hysterectomy) or has a vasectomized partner(s).
SC
o
of childbearing potential and sexually active with male partner(s):
of childbearing potential and sexually active with male partner(s) currently using at
least one effective method of birth control at the time of screening and two effective
methods of birth control while receiving study drugs (as outlined in the patient
informed consent or other patient information documents), starting with Study Day 1
and for 7 months after stopping study drug as directed by the local ribavirin label.
(Note: Hormonal contraceptives, including oral, topical, injectable or implantable
varieties, may not be used during study drug treatment.)
TE
D
o
M
AN
U
•
RI
PT
•
3. Females must have had negative results for pregnancy tests performed: at screening by serum
specimen within 35 days prior to initial study drug administration; and at baseline (prior to
dosing) by urine specimen.
AC
C
EP
4. Sexually active males must have been surgically sterile or have had male partners only or if
sexually active with female partner(s) of childbearing potential must have agreed to practice 2
effective forms of birth control (as outlined in the patient information and consent form or
other patient information documents) throughout the course of the study, starting with Day 1
and for 7 months after stopping study drug or as directed by the local ribavirin (RBV) label.
(Note: Contraceptives containing ethinyl estradiol or depo progesterone were considered
effective if used by the female partners of male patients.)
5. Patient must have had documentation that they were adherent to prior pegIFN/RBV
combination therapy and met 1 of the following categories:
•
•
Null responders: received at least 12 weeks of pegIFN/RBV for the treatment of HCV and
failed to achieve a 2 log10 IU/mL reduction in HCV RNA at Week 12. Patients were
considered to have met this definition if the lack of treatment response was documented
following 10 to 16 weeks of treatment;
Nonresponders/partial responders: received at least 20 weeks of pegIFN/RBV for the
treatment of HCV and achieved ≥ 2 log10 IU/mL reduction in HCV RNA at Week 12, but
failed to achieve HCV RNA undetectable at the end of treatment. Patients were considered
4
ACCEPTED MANUSCRIPT
to have met this definition if the lack of treatment response was documented following 10
to 16 weeks of treatment; or
•
Relapsers: received at least 36 weeks of pegIFN/RBV for the treatment of HCV and was
undetectable at the end of treatment, but HCV RNA was detectable within 52 weeks of
treatment follow-up.
RI
PT
Viral loads documenting the type of prior nonresponse were to be obtained during the previous
pegIFN/RBV treatment. PegIFN/RBV therapy must have been completed no less than 2 months
prior to the Screening Visit.
6. Chronic HCV genotype 1b-infection for at least 6 months prior to Screening. Chronic HCV
infection is defined as one of the following:
positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before screening, and
positive for HCV RNA and anti-HCV Ab at the time of screening or
•
positive for anti-HCV Ab and HCV RNA at the time of screening with a liver biopsy consistent
with chronic HCV infection.
SC
•
M
AN
U
7. Per local standard practice, documented results of 1 of the following:
liver biopsy within 24 months prior to or during screening demonstrating the absence of
cirrhosis, e.g., a Metavir score of 3 or less or an Ishak score of 4 or less;
•
screening FibroTest score of ≤ 0.72 and aspartate aminotransferase (AST) to platelet ratio
index (APRI) ≤ 2; or
•
screening FibroScan® result of < 9.6 kPa;
•
patients with a nonqualifying FibroTest/APRI or FibroScan could have only been enrolled if
they had a qualifying liver biopsy within 24 months prior to or during screening.
TE
D
•
8. Patient had plasma HCV RNA level > 10,000 international units (IU)/mL at screening.
Main Exclusion:
EP
9. Patient's HCV genotype was subgenotype 1b at screening without coinfection with any other
genotype/subgenotype.
AC
C
1. Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse
that could preclude adherence to the protocol.
2. Positive test result for Hepatitis B surface antigen (HBsAg) or anti-Human immunodeficiency
virus antibody (HIV Ab).
3. Patient's HCV subgenotype at screening was not subgenotype 1b or indicated coinfection of 1b
with any other genotype/subgenotype.
4. History of uncontrolled seizures, uncontrolled diabetes as defined by a glycated hemoglobin
(hemoglobin A1C) level > 8.5% at the Screening visit, active or suspected malignancy or history of
malignancy (other than basal cell skin cancer or cervical carcinoma in situ) in the past 5 years.
5. Any current or past clinical evidence of cirrhosis such as ascites or esophageal varices, or prior
biopsy showing cirrhosis, e.g., a Metavir score of >3 or Ishak score of > 4.
5
ACCEPTED MANUSCRIPT
•
hemochromatosis;
•
alpha-1 antitrypsin deficiency;
•
Wilson's disease;
•
autoimmune hepatitis;
•
alcoholic liver disease;
•
drug-related liver disease.
RI
PT
6. Any cause of liver disease other than chronic HCV infection, including but not limited to the
following:
SC
Steatosis and steatohepatitis on a liver biopsy coincident with HCV-related changes would not
have been considered exclusionary unless the steatohepatitis was considered to be the primary
cause of the liver disease.
7. Screening laboratory analyses showing any of the following abnormal laboratory results:
Alanine aminotransferase (ALT) > 5 × upper limit of normal (ULN)
•
Aspartate aminotransferase (AST) > 5 × ULN
•
Calculated creatinine clearance (using Cockcroft-Gault method) < 60 mL/min
•
Albumin < Lower limit of normal (LLN)
•
Prothrombin time/International normalized ratio (INR) > 1.5. Patients with a known inherited
blood disorder and INR > 1.5 may be enrolled with permission of the AbbVie Study
Designated Physician, even if the INR > 1.5
•
Hemoglobin < LLN
•
Platelets < 120,000 cells per mm3
•
Absolute neutrophil count (ANC) < 1500 cells/μL (< 1200 cells/µL for patients of African
descent who are black)
•
Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN
EP
TE
D
M
AN
U
•
AC
C
8. Use of any medications listed below, as well as those that are contraindicated for ritonavir and
ribavirin, within 2 weeks prior to study drug administration or 10 half-lives (if known),
whichever is longer, including but not limited to:
Alfuzosin
Amiodarone
Astemizole
Bepridil
Bosentan
Buprenorphine
Carbamazepine
Cisapride
Clarithromycin
Conivaptan
Lovastatin
Methadone
Midazolam (oral)
Mifepristone
Modafinil
Montelukast
Nefazodone
Phenobarbital
Phenytoin
Pimozide
Pioglitazone
Propafenone
Quercetin
Quinidine
Rifabutin
Rifampin
Rosiglitazone
Salmeterol
Simvastatin
St. John's Wort
Telithromycin
Terfenadine
Triazolam
Trimethoprim
Troglitazone
Troleandomycin
Voriconazole
6
ACCEPTED MANUSCRIPT
Randomization Methods
Patients who met the eligibility criteria were enrolled via the Interactive Response Technology (IRT)
system on Study Day 1. Prior to the study, contact information and user guidelines for the IRT system
were provided to each site.
RI
PT
For enrollment of eligible patients on Day 1, the site contacted the IRT system in order to receive a
unique randomization number and study drug kit numbers. The study drug kit numbers were assigned
according to a randomization schedule computer generated before the start of the study by the AbbVie
Statistics Department.
SC
Initial randomization occurred in a 1:1 ratio to the two treatment groups. Randomization of patients was
stratified by the type of nonresponse to previous pegIFN/RBV treatment (null responders,
nonresponders/partial responders and relapsers). The number of nonresponders/partial responders
plus relapsers enrolled across Arms 1 and 2 was limited to 130 to ensure that at least 80 null responders
were enrolled. In addition, the relapsers were limited to 60 patients (approximately 30% of all patients).
Blinding
M
AN
U
This is an open-label study. There was no blinding between the arms.
Collection of Samples for HCV RNA Measurement
TE
D
Plasma samples for HCV RNA measurement were obtained at screening. Additional samples for HCV
RNA measurement were obtained at each scheduled visits every 1-2 weeks through the final treatment
visit or premature discontinuation. Following administration of the last dose of study drug, samples for
HCV RNA measurement were collected at post-treatment weeks 2, 4, 8, 12, 24, 36, and 48 or at the time
of premature discontinuation.
Plasma samples were also collected at screening to assess HCV genotype and subtype using the Versant
HCV Genotype Inno-LiPA Assay, version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown,
NY), and for IL28B rs12979860 haplotype analysis.
EP
HCV RNA Measurement
AC
C
Plasma HCV RNA levels were determined for each sample collected by the central laboratory using the
®
Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v2.0. The lower limit of
detection (LLOD) is 15 IU/mL and the LLOQ (lower limit of quantification) is 25 IU/mL.
Virologic Failure Criteria
The following criteria were considered evidence of virologic failure leading to discontinuation of study
drug for individual patients being treated with active drugs:
•
•
•
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements >
1 log10 IU/mL above nadir) at any time point during treatment;
Failure to achieve HCV RNA < LLOQ by Week 6;
Confirmed HCV RNA ≥ LLOQ (defined as two consecutive HCV RNA measurements ≥ LLOQ) at
any point during treatment after HCV RNA < LLOQ.
7
ACCEPTED MANUSCRIPT
If any of the above criteria were met, the patient was to discontinue study treatment.
Patients who completed the treatment with HCV RNA < LLOQ at the end of treatment and who had a
confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements ≥ LLOQ) at any point in
the post-treatment period were considered to have relapsed.
RI
PT
Noninferiority and Superiority Analyses
SC
Historical SVR rates for telaprevir plus pegIFN and RBV are not included in the US Prescribing
Information (USPI) or SmPC on non-cirrhotic treatment-experienced patients by subgenotype and type
of non-response, therefore, data from the REALIZE study1 were used, with an adjustment factor to
account for the exclusion of cirrhotic patients from that study. REALIZE data are presented in the table
below.
M
AN
U
For non-cirrhotic genotype 1b-infected patients in PEARL-II, the upper bound of the 95% confidence
interval (CI) of SVR rate for telaprevir plus peg/IFN/RBV therapy was 75%, representing a threshold
relevant to the overall population enrolled in PEARL-II. For the study regimen to be considered superior
to the historical SVR rate for telaprevir, the lower bound of the SVR rate 95% CI must exceed the upper
confidence bound of the historical SVR rate for telaprevir based therapy presented in the table below
(i.e., 75%). To be considered noninferior to the historical SVR rate for telaprevir, a noninferiority margin
of 10.5% was used. Thus, noninferiority to the historical SVR rate for telaprevir based therapy was met if
the lower bound of the 95% CI for the regimen SVR rate was greater than the upper confidence bound
of SVR rate for the telaprevir based therapy minus 10.5% (i.e., 64%). The 2-sided 95% confidence
intervals are created using the normal approximation to the binomial.
TE
D
Estimated SVR Rates for Telaprevir plus pegIFN/RBV Therapy in Treatment-Experienced, Non-cirrhotic
Patients with HCV Subgenotype 1b, REALIZE study1
GT1b
T12/PR48
n/N (%)
Relapsers
AC
C
Partial responders
Null responders
Projected
Enrollment in
PEARL-II (%)
123/140 (87.9)
88.4
30
27/40 (67.5)
79.5
30
22/59 (37.3)
46.5
30
EP
Previous non-response
With Increase
for Excluding
Cirrhotics (%)
PopulationBased Weighted
Average
% [95% CI]
69 [62, 75]
GT, genotype; T, telaprevir; PR, pegIFN/RBV
To test noninferiority of the RBV-free group compared to the RBV-containing group, the 2-sided 95%
confidence interval for the difference in SVR12 rates will be calculated using the normal approximation
to the binomial distribution. If the lower bound of the 2-sided 95% confidence interval for the difference
was above the noninferiority margin of -10.5%, noninferiority can be claimed for the regimen without
RBV compared to regimen with RBV.
8
ACCEPTED MANUSCRIPT
Sample Size Determination
RI
PT
PEARL-II planned to enroll 210 patients in a 1:1 ratio to the DAA combination regimen with RBV or
without RBV, so that at least 200 patients were dosed with the coformulated tablets of ABT450/ritonavir/ombitasvir. Based on a 2-sided significance level of 0.05, and an underlying SVR12 rate of
82% or higher in Group 1 and 82% or higher in Group 2, a sample size of 90 patients per group provides
> 90% power to demonstrate noninferiority of the ABT-450/ritonavir/ombitasvir + dasabuvir regimen ±
RBV to the historical SVR rate for telaprevir plus pegIFN and RBV therapy (64%). No adjustment for
dropout was applicable because patients without data at Post-Treatment Week 12 (after imputing) are
counted as failures for SVR12.
SC
Ranked Efficacy Endpoint Analyses
In order to control the Type I error rate at 0.05, a fixed-sequence testing procedure2 was used to
proceed through the primary and secondary efficacy endpoints in the order shown below.
M
AN
U
PEARL-II had the following primary efficacy endpoints: (1) non-inferiority of Group 2’s SVR12 rate to the
historical rate for telaprevir plus pegylated interferon and RBV; and (2) non-inferiority of the SVR12 rate
in RBV-containing treatment group (Group 1) to the historical rate for telaprevir plus pegylated
interferon and RBV.
TE
D
Secondary efficacy endpoints in the fixed sequence are: (3) comparison of the percentage of patients
with a decrease in hemoglobin to below the lower limit of normal (LLN) at the end of treatment with
ABT-450/ritonavir/ombitasvir and dasabuvir with RBV vs. without RBV; (4) superiority of SVR12 rate in
RBV-containing treatment group to the historical rate for telaprevir plus pegIFN and RBV; (5) superiority
of SVR12 rate in treatment group without RBV to the historical rate for telaprevir plus pegIFN and RBV;
(6) noninferiority of Group 2 to Group 1 using a 10.5% noninferiority margin.
AC
C
EP
Other secondary endpoint analyses not included in the fixed-sequence testing procedure are the
percentage of patients in each treatment group with on-treatment virologic failure (including failure to
suppress and rebound) and post-treatment relapse.
9
SC
RI
PT
ACCEPTED MANUSCRIPT
Figure S1. PEARL-II Study Design. PEARL-II was a phase 3, open-label, randomised trial of 12-week
AC
C
EP
TE
D
M
AN
U
treatment with ABT-450/r/ombitasvir, dasabuvir with or without RBV in HCV genotype 1b-infected
patients with previous null response, partial response, or relapse to prior treatment with pegIFN/RBV. r,
ritonavir; RBV, ribavirin; SVR12, sustained virologic response 12 weeks post-treatment.
10
ACCEPTED MANUSCRIPT
80
74.7
73.6
65/87
67/91
100
100
86/86
91/91
100
100
40
20.7
21.1
18/87
19/90
20
0
Week 1
Week 2
Week 4
Treatment Visit
83/83
87/87
Week 12
Group 2
M
AN
U
Group 1
RI
PT
60
SC
% Patients with
HCV RNA < LLOQ
100
Figure S2. HCV RNA Suppression Over Time. Percentage of patients in PEARL-II with HCV RNA <
AC
C
EP
TE
D
LLOQ at treatment visits, in patients with data at the treatment visit, during the treatment period (ITT
genotype 1b efficacy subset). Numbers in bars are n/N for each time point.
11
ACCEPTED MANUSCRIPT
RI
PT
4
3
SC
2
1
0
1 2
4
6
M
AN
U
Bilirubin mg/dL
5
8
10
12
PT4
Week
Group 2
TE
D
Group 1
Figure S3. PEARL-II Mean Total Bilirubin Values Over Time. Mean total and indirect bilirubin
AC
C
EP
values of the safety population (all patients receiving at least one dose of study drug) are plotted over
time during the treatment period and for the week-4 post-treatment follow-up (PT4). Solid lines depict
total bilirubin; dashed lines depict indirect bilirubin.
12
ACCEPTED MANUSCRIPT
Table S1. PEARL-II Primary Reasons for Not Meeting Study Eligibility
# OF SCREEN FAILURES
7
1
24
Patient's HCV genotype is subgenotype 1b at Screening without co-infection with
any other genotype/subgenotype.
EXCLUSION CRITERIA
Recent (within 6 months prior to study drug administration) history of drug or
alcohol abuse that, in the opinion of the investigator, could preclude adherence to
the protocol.
Positive test result for hepatitis B surface antigen (HBsAg) or anti-HIV antibodies
(anti-HIV Ab).
Patient's HCV subgenotype at Screening is not subgenotype 1b or indicates co-infection
of 1b with any other genotype/subgenotype.
Positive result of a urine drug screen at the Screening Visit for opiates, barbiturates,
amphetamines, cocaine, benzodiazepines, phencyclidine, propoxyphene, or alcohol
with the exception of a positive result associated with documented short-term use
or chronic stable use of a prescribed medication in that class.
Clinically significant abnormalities, other than HCV infection, based upon the results of a
medical history, physical examination, vital signs, laboratory profile and a 12-lead
AC
C
# OF SCREEN FAILURES
EP
TE
D
21
M
AN
U
SC
RI
PT
22
INCLUSION CRITERIA
Patient must have documentation that they were adherent to prior pegIFN/RBV
combination therapy and meet one of the following categories:
● Null responders: received at least 12 weeks of pegIFN/RBV for the treatment of HCV
and failed to achieve a 2 log10 IU/mL reduction in HCV RNA at Week 12. Patients will be
considered to meet this definition if the lack of treatment response was documented
following 10 to 16 weeks of treatment;
● Non-responders/partial responders: received at least 20 weeks of pegIFN/RBV for the
treatment of HCV and achieved ≥ 2 log10 IU/mL reduction in HCV RNA at Week 12, but
failed to achieve HCV RNA undetectable at the end of treatment. Patients will be
considered to meet this definition if the lack of treatment response was documented
following 10 to 16 weeks of treatment; or
● Relapsers: received at least 36 weeks of pegIFN/RBV for the treatment of HCV and
was undetectable at the end of treatment, but HCV RNA was detectable within 52
weeks of treatment follow-up.
● Viral loads documenƟng the type of prior non-response should be obtained during the
previous pegIFN/RBV treatment. PegIFN/RBV therapy must have been completed no
less than 2 months prior to the Screening Visit.
Chronic HCV genotype 1b-infection for at least 6 months prior to Screening.
Chronic HCV infection is defined as one of the following:
● PosiƟve for anƟ-HCV antibody or HCV RNA at least 6 months before Screening, and
positive for HCV RNA and anti-HCV antibody at the time of Screening; or
● PosiƟve for anƟ-HCV antibody and HCV RNA at the time of Screening with a liver
biopsy consistent with chronic HCV infection.
Per local standard practice, documented results of one of the following:
● Liver biopsy within the 24 months prior to or during screening demonstraZng the
absence of cirrhosis, e.g., a Metavir score of 3 or less or an Ishak score of 4 or less, or
● A screening FibroTest score of ≤ 0.72 and an Aspartate Aminotransferase to Platelet
Ratio Index (APRI) ≤ 2, or
● A screening FibroScan® result of < 9.6 kPa.
● Patients with a non-qualifying Fibrotest/APRI or Fibroscan result may only be enrolled
if they have a qualifying liver biopsy performed within 24 months prior to or during
screening.
Patient has a plasma HCV RNA level > 10,000 International Units (IU)/mL at Screening.
1
2
4
3
3
13
ACCEPTED MANUSCRIPT
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
electrocardiogram (ECG) that make the patient an unsuitable candidate for this study in
the opinion of the Investigator.
History
of uncontrolled seizures, uncontrolled diabetes as defined by a glycated
6
hemoglobin A1c level > 8.5% at the Screening visit, active or suspected malignancy or
history of malignancy (other than basal cell skin cancer or cervical carcinoma in situ) in
the past 5 years.
Any
cause of liver disease other than chronic HCV infection, including but not limited to
3
the following:
● Hemochromatosis
● Alpha-1 antitrypsin deficiency
● Wilson's disease
● Autoimmune hepaƟƟs
● Alcoholic liver disease
● Drug-related liver disease
Steatosis and steatohepatitis on a liver biopsy coincident with HCV-related changes
would not be considered exclusionary unless the steatohepatitis is considered to be the
primary cause of the liver disease.
Screening
laboratory analyses show any of the following abnormal laboratory
28
results:
● Alanine aminotransferase (ALT) > 5 × upper limit of normal (ULN),
● Aspartate aminotransferase (AST) > 5 × ULN,
● Calculated creaƟnine clearance (using CockcroŌ-Gault method) < 60 mL/min,
● Albumin < lower limit of normal (LLN),
● Prothrombin time/International normalized ration (INR) > 1.5. Patients with a known
inherited blood disorder may be enrolled with permission of the AbbVie Study
Designated Physician even if the INR > 1.5,
● Hemoglobin < LLN,
● Platelets < 120,000 cells per mm3,
● Absolute neutrophil count (ANC) < 1500 cells/μL (< 1200 cells/μL for patients of
African descent who are black,
● Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN.
Use
of any medications that are contraindicated for ritonavir and ribavirin, within 2
0
weeks prior to study drug administration or 10 half-lives (if known), whichever is
longer.
Receipt
of any investigational product within a time period equal to 10 half-lives of
1
the product, if known, or a minimum of 6 weeks prior to study drug administration.
Consideration by the Investigator, for any reason, that the patient is an unsuitable
1
candidate to receive ABT-450, ombitasvir, dasabuvir, ritonavir, or RBV.
Current
enrollment in another clinical study, previous enrollment in this study, or
2
previous use of any investigational or commercially available anti-HCV therapy (other
than interferon and/or pegIFN/RBV), including previous exposure to boceprevir,
telaprevir, ABT-450, ombitasvir, or dasabuvir. Patients who previously participated in
trials of investigational anti-HCV agents may be enrolled with the approval of the
AbbVie Study Designated Physician if they can produce documentation that they
received only placebo. Concurrent participation in a non-interventional, epidemiologic
or registry trial may be permitted with approval by the AbbVie Study Designated
Physician.
The primary reasons for failing to meet inclusion or exclusion criteria are listed for each patient.
14
ACCEPTED MANUSCRIPT
Table S2. Fibrosis Scoring
Liver Biopsy Metavir or
Batts-Ludwig or Knodell
or IASL or Scheuer Score
0 or 1
2
3 (or higher)
Liver Biopsy
Ishak Score
0, 1, or 2
3
4 (or higher)
FibroScan
(kPa)
<8.8
>8.8 to <9.6
>9.6
FibroTest
<0.48
0.49 to 0.58
>0.59
RI
PT
Baseline Fibrosis
Stage, Metavir
Equivalents
F0-F1
F2
F3 (or higher)
AC
C
EP
TE
D
M
AN
U
SC
Baseline fibrosis stage is defined based on available liver biopsy findings, FibroScan scores, or FibroTest
scores. Fibrosis score was determined by a single score in patients with multiple scores available. If
biopsy results were present, they were used to categorize the patient, regardless of the
FibroScan/FibroTest score. Similarly, if a FibroScan score was present along with a FibroTest score, then
the FibroScan score was used to categorize the patient. For patients who have only liver biopsy range
available, the highest value for the range was used as their biopsy score.
15
ACCEPTED MANUSCRIPT
Table S3. PEARL-II Adverse Events Occurring in > 5% of Patients in Either Treatment Group, n (%)
TE
D
Hyperbilirubinaemia
Hypertension
Irritability
Cough
Influenza
EP
Palpitations
29 (31.9)
22 (24.2)
19 (20.9)
13 (14.3)
13 (14.3)
12 (13.2)
11 (12.1)
10 (11.0)
8 (8.8)
8 (8.8)
8 (8.8)
8 (8.8)
8 (8.8)
6 (6.6)
6 (6.6)
6 (6.6)
6 (6.6)
5 (5.5)
5 (5.5)
15 (15.8)
22 (23.2)
6 (6.3)
3 (3.2)
8 (8.4)
12 (12.6)
7 (7.4)
0
0
2 (2.1)
3 (3.2)
2 (2.1)
1 (1.1)
6 (6.3)
4 (4.2)
6 (6.3)
8 (8.4)
1 (1.1)
1 (1.1)
P-value
0.015
0.005
0.008
RI
PT
Group 2
N = 95
M
AN
U
Fatigue
Headache
Nausea
Insomnia
Pruritus
Diarrhoea
Asthenia
Anaemia
Blood bilirubin increased
Decreased appetite
Dizziness
Dyspnoea
Rash
Arthralgia
Myalgia
Nasopharyngitis
Pyrexia
Constipation
Dyspnoea exertional
Group 1
N = 91
SC
MEDDRA 16.0 PREFERRED TERM
5 (5.5)
2 (2.1)
5 (5.5)
4 (4.2)
5 (5.5)
1 (1.1)
5 (5.5)
2 (2.1)
3 (3.3)
7 (7.4)
2 (2.2)
6 (6.3)
<0.001
0.003
0.017
AC
C
P-value for comparisons between treatment groups using fisher’s exact test. Only p-values ≤ 0.05 are presented.
16
ACCEPTED MANUSCRIPT
Table S4. Grade 3 and 4 Laboratory Abnormalities, n (%)
Treatment Group
Post-baselineb
Baseline
ALT (U/L)
Grade 3
0
1 (1.1)
Grade 4
0
0
N = 90
0
0
Grade 4
0
0
1 (1.1)
2 (2.1)
Total bilirubin (µmol/L)
Grade 3
0
Grade 4
0
a
0
1 (1.1)
0
0
6 (6.6)
10 (10.5)
0
0
0
0
8 (8.8)
0
0
0
0
M
AN
U
0
0
0
Alkaline phosphatase (U/L)
At least grade 2
0
N = 90
Grade 3
Grade 1
0
SC
AST (U/L)
Group 2
N = 95a
RI
PT
Parameter (unit) Grade
Group 1
N = 91a
Group 2
N = 95a
Group 1
N = 91a
Number of patients with baseline and at least 1 post-baseline value.
Values during treatment up to 2 days post-dosing are used.
AC
C
EP
TE
D
b
17
ACCEPTED MANUSCRIPT
Table S5. Potentially Clinically Significant Laboratory Abnormalities, n/N (%)
Group 1
N = 91
0/91
Group 2
N = 95
0/95
AST (> 5 × ULN and ≥ 2 × baseline)
0/90
1/95 (1.1)
Alkaline phosphatase (> 1.5 × ULN)
0/91
1/95 (1.1)
14/91 (15.4)
1/95 (1.1)
Creatinine (≥ 132.605 µmol/L)
0/91
2/95 (2.1)a
Creatinine clearance, calculated (< 50 mL/m)
0/91
BUN (> 5 × ULN)
0/91
SC
Bilirubin, total (≥ 2 × ULN)
RI
PT
Variable (criteria)
ALT (> 5 × ULN and ≥ 2 × baseline)
Uric acid (> 713.817 µmol/L)
Phosphate, inorganic (< 0.6 mmol/L)
Calcium (< 1.75 mmol/L)
0/95
0/91
0/95
0/91
1/95 (1.1)c
0/91
0/95
M
AN
U
Calcium (> 3.1 mmol/L)
2/95 (2.1)b
0/91
0/95
0/91
0/95
0/91
0/95
0/91
0/95
0/91
1/95 (1.1)b
0/91
0/95
0/91
0/95
0/91
1/95 (1.1)d
0/91
0/95
0/91
0/95
0/91
0/95
Cholesterol (> 10.34 mmol/L)
0/91
0/95
Triglycerides (> 5.7 mmol/L)
0/91
1/95 (1.1)b
Magnesium (> 1.23 mmol/L)
Magnesium (< 0.4 mmol/L)
Sodium (> 155 mmol/L)
Sodium (< 130 mmol/L)
Potassium (> 6 mmol/L)
Glucose (> 13.9 mmol/L)
Glucose (< 2.2 mmol/L)
Albumin (< 20 g/L)
a
EP
Protein, total (< 50 g/L)
TE
D
Potassium (< 3 mmol/L)
AC
C
Patient had an elevation in creatinine on Day 44 while hospitalized for cellulitis which returned to
normal 4 days later, then again had elevated creatinine at Post-Treatment Week 4. The other patient
had an elevation in creatinine on Day 85 only.
b
Single time point abnormality only.
c
Decrease in phosphate occurred on Days 8 and 15, which subsequently returned to normal for the
remainder of the study.
d
Glucose elevation noted at baseline and throughout the study in a patient with a history of diabetes.
18
ACCEPTED MANUSCRIPT
References
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
1.
Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med
2011;364:2417-28.
2.
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing
procedures. J Stat Plan Inference 2001;99:25-40.
19