Hepatitis C, Chronic
Conditions
Brief summary
Based on previous experience with peginterferon alfa-2b/ribavirin in combination with boceprevir, the combination with peginterferon alfa- 2a/ribavirin and boceprevir is expected to be safe and well tolerated. Given the wide utilization of both peginterferons and the clear benefit of the addition of boceprevir to peginterferon alfa-2b/ribavirin, it is important to demonstrate the safety and efficacy of boceprevir in combination with peginterferon alfa-2a/ribavirin.
Interventions
DRUGBoceprevir
800 mg, using SCH 503034 200-mg capsules, three times a day (TID) orally (PO) for 48 weeks
OTHERPlacebo
800 mg, using placebo matching SCH 503034 200-mg capsules, three times a day (TID) orally (PO) for 48 weeks
BIOLOGICALPeginterferon alfa-2a
Peginterferon alfa-2a, pre-filled syringes, given 180 μg/week subcutaneously (SC) for 48 weeks
DRUGRibavirin
Ribavirin 200-mg capsules, weight-based dosing * \<75 kg, 1000 mg/day orally (PO), divided twice daily (BID) * \>=75 kg, 1200 mg/day PO, divided BID for 48 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have a qualifying regimen defined as peginterferon alfa-2a/ribavirin or peginterferon alfa-2b/ribavirin for a minimum of 12 weeks. * During the qualifying regimen, subjects must have either: * A documented undetectable Hepatitis C Virus-Ribonucleic Acid (HCV-RNA) within 30 days of the end-of-treatment and a subsequent detectable HCV-RNA during follow-up OR * A documented decline in HCV-RNA by \>=2 log10 after 12 weeks of treatment. * Subject must have previously documented chronic hepatitis C genotype 1 infection. * Subject must have a liver biopsy with histology consistent with chronic hepatitis C infection and no other etiology. * Subjects with bridging fibrosis or cirrhosis must have an ultrasound within 6 months with no findings suspicious for hepatocellular carcinoma (HCC). * Subject must be \>=18 years of age. * Subject must weigh between 40 kg and 125 kg. * Subject and subject's partner(s) must each agree to use acceptable methods of contraception. * Subjects must be willing to give written informed consent.
Exclusion criteria
Subject will be excluded from entry if ANY of the criteria listed below are met: * Subjects known to be coinfected with the human immunodeficiency virus (HIV) or hepatitis B virus (hepatitis B surface antigen \[HBsAg\] positive) and/or demonstrating signs and symptoms consistent with co-infection. * Subjects who required discontinuation of previous interferon or ribavirin regimen for an adverse event considered by the investigator to be possibly or probably related to ribavirin and/or interferon. * Treatment with ribavirin within 90 days and any interferon alfa within 1 month of Screening. * Treatment for hepatitis C with any investigational medication. Prior treatment with herbal remedies with known hepatotoxicity is exclusionary. * Treatment with any investigational drug within 30 days of the randomization visit in this study. * Participation in any other clinical trial within 30 days of randomization or intention to participate in another clinical trial during participation in this study. * Evidence of decompensated liver disease. * Diabetic and/or hypertensive subjects with clinically significant ocular examination findings. * Pre-existing psychiatric condition(s). * Clinical diagnosis of substance abuse. * Any known pre-existing medical condition that could interfere with the subject's participation in and completion of the study. * Evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). * Subjects who are pregnant or nursing. Subjects who intend to become pregnant during the study period. Male subjects with partners who are or who intend to become pregnant during the study period. * Any other condition which, in the opinion of a physician, would make the subject unsuitable for enrollment or could interfere with the subject participating in and completing the study. * Subjects who are part of the site personnel directly involved with this study. * Subjects who are family members of the investigational study staff. * Subjects who had a life-threatening serious adverse event (SAE) during the screening period. * Subjects with a history of pancreatitis, except for one episode clearly secondary to gallstone. Laboratory
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (SVR) Rate in Full Analysis Set (FAS) Population. | Follow-up Week 24 | SVR rate was the percentage of participants treated with at least one dose of study medication (PEG2a, Ribavirin, or Boceprevir/Placebo) who had achieved SVR. SVR was defined as undetectable Hepatitis C Virus-Ribonucleic Acid (HCV RNA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 | Follow-up Week 12 | — |
| SVR Rate in the Modified Intent-to-Treat (mITT) Population | Follow-up Week 24 | SVR rate was the percentage of participants treated with at least one dose of study medication (Boceprevir/PEG2a/Ribavirin or PEG2a/Ribavirin). Participants who discontinued study drugs during the 4-week PEG2a/Ribavirin lead-in period were not included in the mITT population. |
| Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | Day 1 to Treatment Week 12 | EVR was defined as the time to the first undectectable HCV-RNA result at Treatment Week (TW) 2, 4, 8, or 12. Participants with a detectable, but not quantifiable HCV-RNA result at TW 12 may have undergone retesting. Participants with a detectable result on retesting were to be discontinued per the 12-week futility rule. Participants with an undetectable result on retesting were allowed to continue on treatment, and the detectable but not quantifiable result was to be considered a false positive. |
| Mean Log Change From Baseline to TW 4 in Viral Load by Visit | From Baseline to TW 4 | HCV-RNA levels were quantified using the Roche Cobas Taqman 1.0 assay; lower limit of detection of 15 international units \[IU\]/mL. Changes in HCV-RNA IU/ml were expressed on a log10 scale. |
Participant flow
Recruitment details
A total of 202 participants were randomized but 1 participant was not treated.
Participants by arm
| Arm | Count |
|---|---|
| PEG2a/Ribavirin Peginterferon alfa-2a (PEG2a) (180 μg/week subcutaneously \[SC\]) plus ribavirin (1000 to 1200 mg/day orally \[PO\]) for 4 weeks followed by placebo (800 mg three times a day \[TID\] PO, using placebo matching SCH 503034 200-mg capsules) + PEG2a 180 μg/week SC plus ribavirin 1000 to 1200 mg/day PO divided twice daily (BID) for 48 weeks with 24 weeks post-treatment follow-up. | 67 |
| Boceprevir/PEG2a/Ribavirin PEG2a (180 μg/week SC) plus ribavirin (1000 to 1200 mg/day PO) for 4 weeks followed by boceprevir (800 mg TID PO, using SCH 503034 200-mg capsules) + PEG2a 180 μg/week SC plus ribavirin 1000 to 1200 mg/day PO divided BID for 48 weeks with 24 weeks post-treatment follow-up. | 134 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 23 |
| Overall Study | Lack of Efficacy | 43 | 21 |
| Overall Study | Non-Medical Reasons | 1 | 11 |
Baseline characteristics
| Characteristic | PEG2a/Ribavirin | Boceprevir/PEG2a/Ribavirin | Total |
|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 6.8 | 52.0 years STANDARD_DEVIATION 7.2 | 52.5 years STANDARD_DEVIATION 7.1 |
| Sex: Female, Male Female | 24 Participants | 37 Participants | 61 Participants |
| Sex: Female, Male Male | 43 Participants | 97 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 67 | 133 / 134 |
| serious Total, serious adverse events | 7 / 67 | 18 / 134 |
Outcome results
Primary
Sustained Virologic Response (SVR) Rate in Full Analysis Set (FAS) Population.
SVR rate was the percentage of participants treated with at least one dose of study medication (PEG2a, Ribavirin, or Boceprevir/Placebo) who had achieved SVR. SVR was defined as undetectable Hepatitis C Virus-Ribonucleic Acid (HCV RNA).
Time frame: Follow-up Week 24
Population: FAS Population: all randomized participants who received at least one dose of study medication (PEG2a, Ribavirin, or Boceprevir/Placebo). Follow-up (FU) Week (W) 12 value was Last Observation Carried Forward (LOCF), if last SVR value at or after FU W24 was not available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG2a/Ribavirin | Sustained Virologic Response (SVR) Rate in Full Analysis Set (FAS) Population. | 20.9 Percentage of Participants |
| Boceprevir/PEG2a/Ribavirin | Sustained Virologic Response (SVR) Rate in Full Analysis Set (FAS) Population. | 64.2 Percentage of Participants |
Secondary
Mean Log Change From Baseline to TW 4 in Viral Load by Visit
HCV-RNA levels were quantified using the Roche Cobas Taqman 1.0 assay; lower limit of detection of 15 international units \[IU\]/mL. Changes in HCV-RNA IU/ml were expressed on a log10 scale.
Time frame: From Baseline to TW 4
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEG2a/Ribavirin | Mean Log Change From Baseline to TW 4 in Viral Load by Visit | -2.44 log10 (IU/mL) | Standard Deviation 1.32 |
| Boceprevir/PEG2a/Ribavirin | Mean Log Change From Baseline to TW 4 in Viral Load by Visit | -2.33 log10 (IU/mL) | Standard Deviation 1.34 |
Secondary
Number of Participants With Undetectable HCV-RNA at Follow-up Week 12
Time frame: Follow-up Week 12
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG2a/Ribavirin | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 | 12 Participants |
| Boceprevir/PEG2a/Ribavirin | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 | 87 Participants |
Secondary
Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR
EVR was defined as the time to the first undectectable HCV-RNA result at Treatment Week (TW) 2, 4, 8, or 12. Participants with a detectable, but not quantifiable HCV-RNA result at TW 12 may have undergone retesting. Participants with a detectable result on retesting were to be discontinued per the 12-week futility rule. Participants with an undetectable result on retesting were allowed to continue on treatment, and the detectable but not quantifiable result was to be considered a false positive.
Time frame: Day 1 to Treatment Week 12
Population: FAS Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | <=TW 4 (PEG2a N = 2, Boceprevir N = 3) | 50.0 Percentage of Participants |
| PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | >TW 4 to TW 8 (PEG2a N = 7, Boceprevir N = 76) | 42.9 Percentage of Participants |
| PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | >TW 8 to TW 12 (PEG2a N = 9, Boceprevir N = 22) | 88.9 Percentage of Participants |
| Boceprevir/PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | <=TW 4 (PEG2a N = 2, Boceprevir N = 3) | 100.0 Percentage of Participants |
| Boceprevir/PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | >TW 4 to TW 8 (PEG2a N = 7, Boceprevir N = 76) | 82.9 Percentage of Participants |
| Boceprevir/PEG2a/Ribavirin | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR | >TW 8 to TW 12 (PEG2a N = 9, Boceprevir N = 22) | 68.2 Percentage of Participants |
Secondary
SVR Rate in the Modified Intent-to-Treat (mITT) Population
SVR rate was the percentage of participants treated with at least one dose of study medication (Boceprevir/PEG2a/Ribavirin or PEG2a/Ribavirin). Participants who discontinued study drugs during the 4-week PEG2a/Ribavirin lead-in period were not included in the mITT population.
Time frame: Follow-up Week 24
Population: mITT Population: all randomized participants who received at least one dose of study medication (Boceprevir/PEG2a/Ribavirin or PEG2a/Ribavirin). Participants who discontinued study drugs during the 4-week PEG2a/Ribavirin lead-in period were not included. FU W12 value was LOCF, if last SVR value at or after FU W24 was not available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG2a/Ribavirin | SVR Rate in the Modified Intent-to-Treat (mITT) Population | 20.9 Percentage of Participants |
| Boceprevir/PEG2a/Ribavirin | SVR Rate in the Modified Intent-to-Treat (mITT) Population | 66.2 Percentage of Participants |