Chronic Hepatitis C Genotype 1
Conditions
Brief summary
The purpose of this study is to determine whether Boceprevir (BOC, SCH 503034, MK-3034) in combination with Peginterferon Alfa 2-b (PEG) plus Ribavirin (RBV) \[PEG+RBV=PR\] is effective in the treatment of chronic hepatitis C (CHC) genotype 1 among the Russian population. The primary hypothesis is that the percentage of participants achieving sustained virologic response in the BOC + PR group is superior to that in the Placebo (PBO) + PR group.
Interventions
DRUGBoceprevir
boceprevir 200-mg capsules, 800 mg 3 times a day (TID), orally (PO)
DRUGPlacebo
boceprevir-matched placebo four 200-mg capsules PO TID.
BIOLOGICALpeginterferon alfa-2b
peginterferon alfa-2b 1.5 μg/kg/wk subcutaneously (SC)
DRUGRibavirin
ribavirin (weight-based dosing) 800 to 1400 mg/day PO divided twice daily dose (BID).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* body weight ≥40 kg and ≤125 kg * previously documented CHC genotype 1 infection; * must have a liver biopsy with histology consistent with CHC and no other etiology * if cirrhosis present, must have an ultrasound within 6 months of the screening visit (or between screening and Day 1) with no findings suspicious for hepatocellular carcinoma (HCC) * agree to use acceptable methods of contraception with partner * previously untreated with pegylated-interferon (either alfa-2a or alfa-2b) plus RBV or failing prior treatment with pegylated-interferon (either alfa-2a or alfa-2b) plus RBV
Exclusion criteria
* co-infected with the human immunodeficiency virus (HIV) or hepatitis B virus (Hepatitis B surface antigen \[HBsAg\] positive). * required discontinuation of previous interferon or ribavirin regimen for an adverse event (possibly or probably related) * treatment with ribavirin within 90 days and any interferon-alpha, based on the amendment, should be within 1 month prior to screening * treatment with any investigational drug within 30 days of the screening visit in this trial * evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy * diabetic and/or hypertensive with clinically significant ocular examination findings * clinical diagnosis of substance abuse of specified drugs within specified timeframes * any known pre-existing medical condition that could interfere with the participant's participation in and completion of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response At Follow-up Week 24 (SVR24) Among Participants Who Received At Least One Dose of Any Trial Medication (Full Analysis Set Population) | Follow-up Week 24 (up to 72 weeks) | SVR24 was defined as an undetectable plasma Hepatitis C Virus-ribonucleic acid (HCV-RNA) level at Follow-up Week 24 (FW24). If a participant was missing FW24 data and had undetectable HCV-RNA at FW12, the participant was considered a sustained virologic responder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR24 Among Participants Who Received At Least One Dose of Experimental Trial Drug (Modified Intent-To-Treat [mITT] Population) | Follow-up Week 24 (up to 72 weeks) | SVR24 was defined as an undetectable plasma HCV-RNA level at FW24. If a participant was missing FW24 data and had undetectable HCV-RNA at FW12, the participant was considered a sustained virologic responder. |
| Percentage of Participants Achieving Early Virologic Response (EVR) At Treatment Week (TW) 8 | Treatment Week 8 | EVR was defined as an undetectable HCV-RNA level at TW 8. This analysis was conducted when all participants had completed 8 weeks of the study or had discontinued prior to TW 8. |
Participant flow
Recruitment details
A total of 18 Russian sites recruited participants for this boceprevir (BOC) trial.
Pre-assignment details
Of 238 randomized participants, 237 received at least 1 dose of peginterferon alpha-2b (PEG) + ribavirin (RBV) \[PR\] and comprised the Full Analysis Set (FAS). 4 discontinued (DC) treatment during the PR lead-in phase and did not receive BOC or Placebo (PBO). 27 from PBO Arm failed the futility time point and were rolled over into Crossover Phase.
Participants by arm
| Arm | Count |
|---|---|
| RGT BOC + PR Participants received PR for 4 weeks before addition of BOC. Participants then received response guided therapy (RGT) with BOC + PR for up to 32 weeks followed by PBO + PR for up to 20 weeks. | 159 |
| PBO + PR (Control) Participants received PR for 4 weeks before addition of BOC-matched PBO. Participants then received BOC + PR for up to 44 weeks. | 78 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Crossover Phase | Failure at futility timepoint | 0 | 0 | 3 |
| Crossover Phase | Other virologic failure criteria | 0 | 0 | 3 |
| Treatment Phase | DC during PR Lead-in Phase | 3 | 1 | 0 |
| Treatment Phase | Did not receive treatment | 0 | 1 | 0 |
| Treatment Phase | Failure at futility timepoint | 8 | 27 | 0 |
| Treatment Phase | Other virologic failure criteria | 5 | 3 | 0 |
| Treatment Phase | Unidentified reasons | 11 | 5 | 0 |
Baseline characteristics
| Characteristic | RGT BOC + PR | PBO + PR (Control) | Total |
|---|---|---|---|
| Age, Continuous | 38.6 years STANDARD_DEVIATION 9.8 | 38.1 years STANDARD_DEVIATION 10 | 38.4 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 65 Participants | 33 Participants | 98 Participants |
| Sex: Female, Male Male | 94 Participants | 45 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 153 / 159 | 71 / 78 | 22 / 27 |
| serious Total, serious adverse events | 17 / 159 | 9 / 78 | 1 / 27 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Virologic Response At Follow-up Week 24 (SVR24) Among Participants Who Received At Least One Dose of Any Trial Medication (Full Analysis Set Population)
SVR24 was defined as an undetectable plasma Hepatitis C Virus-ribonucleic acid (HCV-RNA) level at Follow-up Week 24 (FW24). If a participant was missing FW24 data and had undetectable HCV-RNA at FW12, the participant was considered a sustained virologic responder.
Time frame: Follow-up Week 24 (up to 72 weeks)
Population: Full Analysis Set (FAS); all randomized participants who received at least 1 dose of any trial medication (PEG, RBV, or BOC) in the Treatment Phase. Participants in the PBO Control Arm who switched to the Crossover Arm were considered failures for SVR24 in this analysis and are not reported here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RGT BOC + PR | Percentage of Participants Achieving Sustained Virologic Response At Follow-up Week 24 (SVR24) Among Participants Who Received At Least One Dose of Any Trial Medication (Full Analysis Set Population) | 74.8 percentage of participants |
| PBO + PR (Control) | Percentage of Participants Achieving Sustained Virologic Response At Follow-up Week 24 (SVR24) Among Participants Who Received At Least One Dose of Any Trial Medication (Full Analysis Set Population) | 46.2 percentage of participants |
Comparison: The primary statistical comparison was conducted on the FAS using the stratified Miettinen and Nurminen method at alpha level of 0.050 adjusted for stratification factors, including IL28B genotype and previous treatment as specified at the time of randomization.p-value: <0.000195% CI: [16.4, 41.5]Miettinen and Nurminen Method
Secondary
Percentage of Participants Achieving Early Virologic Response (EVR) At Treatment Week (TW) 8
EVR was defined as an undetectable HCV-RNA level at TW 8. This analysis was conducted when all participants had completed 8 weeks of the study or had discontinued prior to TW 8.
Time frame: Treatment Week 8
Population: Full Analysis Set (FAS); all randomized participants who received at least 1 dose of any trial medication (PEG, RBV, or BOC) in the Treatment Phase. The Crossover arm had zero participants at TW8 since the first opportunity for participants in the PBO + PR Control arm to roll over to the Crossover arm was at TW12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RGT BOC + PR | Percentage of Participants Achieving Early Virologic Response (EVR) At Treatment Week (TW) 8 | 87.4 percentage of participants |
| PBO + PR (Control) | Percentage of Participants Achieving Early Virologic Response (EVR) At Treatment Week (TW) 8 | 42.3 percentage of participants |
Comparison: The percentage of participants achieving EVR at TW8 was compared using the stratified Miettinen and Nurminen method at alpha level of 0.050 adjusted for stratification factors in the FAS population.p-value: <0.000195% CI: [33.2, 57]Miettinen and Nurminen Method
Secondary
Percentage of Participants Achieving SVR24 Among Participants Who Received At Least One Dose of Experimental Trial Drug (Modified Intent-To-Treat [mITT] Population)
SVR24 was defined as an undetectable plasma HCV-RNA level at FW24. If a participant was missing FW24 data and had undetectable HCV-RNA at FW12, the participant was considered a sustained virologic responder.
Time frame: Follow-up Week 24 (up to 72 weeks)
Population: mITT population included all randomized participants who received ≥1 dose of experimental trial drug: BOC (for Experimental RGT BOC + PR arm) or Placebo (for PBO + PR Control arm). Participants in the PBO Control Arm who switched to the Crossover Arm were considered failures for SVR24 in this analysis and are not reported here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RGT BOC + PR | Percentage of Participants Achieving SVR24 Among Participants Who Received At Least One Dose of Experimental Trial Drug (Modified Intent-To-Treat [mITT] Population) | 76.3 percentage of participants |
| PBO + PR (Control) | Percentage of Participants Achieving SVR24 Among Participants Who Received At Least One Dose of Experimental Trial Drug (Modified Intent-To-Treat [mITT] Population) | 46.8 percentage of participants |
Comparison: The key secondary statistical comparison was conducted on the mITT using the stratified Miettinen and Nurminen method at alpha level of 0.050 adjusted for stratification factors.p-value: <0.000195% CI: [17.3, 42.5]Miettinen and Nurminen Method