Hepatitis C, Chronic
Conditions
Keywords
Treatment failure
Brief summary
This study involves treatment with boceprevir or placebo in combination with pegylated interferon alfa-2b (PegIntron, PEG2b) + Ribavirin (RBV) (weight-based dosing \[WBD\]) in adult subjects with chronic hepatitis C (CHC) genotype 1 who demonstrated interferon responsiveness (a decrease in hepatitis C virus RNA \[HCV-RNA\] viral load \>=2 log10 by Week 12 or undetectable HCV-RNA at end of treatment) but who failed to achieve sustained virologic response (SVR) on prior treatment with any combination therapy of peginterferon alpha and RBV. This trial includes three arms, one control arm (PEG2b + RBV for 48 weeks) and two experimental arms (PEG2b + RBV + boceprevir). One of the experimental arms, Arm 3, consists of treatment with all three drugs for 44 weeks after the lead-in. The other experimental arm, Arm 2, consists of all three drugs for 32 weeks after the lead-in. Participants in Arm 2 who were undetectable for HCV-RNA at Treatment Week 8 will complete treatment at that point. Those who were not undetectable for HCV-RNA at Treatment Week 8 will receive an additional 12 weeks of PEG2b + RBV + boceprevir placebo. It is hypothesized that the addition of a third active anti-HCV drug may lead to more rapid viral response than therapy with two drugs, and therefore, the addition of boceprevir to PEG2b plus RBV therapy after a 4-week lead-in period may allow for both increased rates of SVR and shorter treatment durations (in some populations) than treatment with peginterferon plus RBV alone.
Interventions
Boceprevir, 200 mg capsules, 800 mg TID PO
BIOLOGICALPegylated interferon alfa-2b (SCH 54031)
PEG2b 1.5 μg/kg/week subcutaneously (SC)
Ribavirin WBD 600 mg/day to 1400 mg/day by mouth (PO) divided twice daily (BID).
Boceprevir placebo, 200 mg capsules, 800 mg three times daily (TID) PO.
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
* Qualifying regimen defined as pegylated interferon alfa-2a plus ribavirin or pegylated interferon alfa-2b plus ribavirin for a minimum of 12 weeks. * During qualifying regimen, participants must have either a documented undetectable HCV-RNA within 30 days of end of treatment (EOT) and a subsequent detectable HCV-RNA during follow-up or a documented decline in HCV-RNA by \>=2 log10 by Treatment Week 12 * Previously documented CHC genotype 1 infection. * Liver biopsy with histology consistent with CHC and no other etiology. * Participants with bridging fibrosis or cirrhosis 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). * Participants participating in Schering-Plough Research Institute (SPRI) maintenance protocols P02570 (NCT00049842) or P02569 (NCT00048724) must have completed the study to be eligible for this protocol. * Participants must be \>=18 years of age. * Participants must weigh between 40 kg and 125 kg. * Participants and participant's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations. * Participants must be willing to give written informed consent.
Exclusion criteria
* Coinfection with the human immunodeficiency virus (HIV) or hepatitis B virus (Hepatitis B Surface Antigen \[HBsAg\] positive). * Discontinuation of previous interferon or ribavirin regimen for an adverse event (AE) considered by the investigator to be possibly or probably related to ribavirin and/or interferon. * Treatment with ribavirin within 90 days and any interferon-alpha within 1 month of Screening. * Treatment for hepatitis C with any investigational medication. Prior treatment with herbal remedies with known hepatotoxicity. * Treatment with any investigational drug within 30 days of the randomization visit. * Participation in any other clinical trial within 30 days of randomization or intention to participate in another clinical 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 participants with clinically significant ocular examination findings. * Pre-existing psychiatric conditions. * Clinical diagnosis of substance abuse of the specified drugs within the specified timeframes * Any known pre-existing medical condition that could interfere with the participant'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). Participants under evaluation for malignancy are not eligible. * Participants who are pregnant or nursing. Participants who intend to become pregnant during the study period. Male participants with partners who are, or intend to become, pregnant during the study period. * Any other condition which, in the opinion of a physician, would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study. * Participants who are part of the site personnel directly involved with this study. * Participants who are family members of the investigational study staff. * Participants who had life-threatening serious adverse event (SAE) during screening period. * Protocol-specified hematologic, biochemical, and serologic criteria: Hemoglobin \<12 g/dL for females and \<13 g/dL for males; Neutrophils \<1500/mm\^3 (Blacks: \<1200/mm\^3); Platelets \<100,000/mm\^3; Direct bilirubin \>1.5 x upper limit of normal (ULN). * Serum albumin \<lower limit of normal (LLN) * Thyroid-stimulating hormone (TSH) \>1.2 x ULN or \<0.8 x LLN of laboratory reference range, with certain exceptions. * Serum creatinine \>ULN of the laboratory reference. * Protocol-specified serum glucose concentrations. * Protocol-specified alpha fetoprotein range. * Prothrombin Time/Partial Thromboplastin Time (PT/PTT) values \>10% above laboratory reference range. * Anti-nuclear antibodies (ANA) \>1:320.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (SVR) Rate in the Full Analysis Set (FAS) Population. | At Follow-up Week 24 | SVR is defined as undetectable plasma hepatitis C virus RNA (HCV-RNA) at Follow-up Week 24. This outcome measure evaluates SVR after treatment with boceprevir and PEG2b plus RBV versus PEG2b plus RBV alone in participants with chronic hepatitis C (CHC) genotype 1 who failed prior treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (SVR) Rate in the Modified Intent to Treat (mITT) Population. | At Follow-up Week 24 | SVR is defined as undetectable plasma HCV-RNA at Follow-up Week 24. This outcome measure evaluates SVR after treatment with boceprevir and PEG2b plus RBV versus PEG2b plus RBV alone in participants with CHC genotype 1 who failed prior treatment. This key secondary efficacy endpoint was added as per the second protocol amendment on 02 DEC 2009. |
| Number of Participants With Early Virologic Response. | At Week 2, 4, 8, or 12 | Having undetectable HCV-RNA at Week 2, 4, 8, or 12 was considered Early Virologic Response. |
| Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | At Follow-up Week 12 and at 72 weeks after randomization | — |
Participant flow
Pre-assignment details
154 participants who discontinued during the treatment phase (including those from lead in and/or boceprevir/placebo) entered the follow up phase
Participants by arm
| Arm | Count |
|---|---|
| Placebo+PEG2b+RBV, x 44 Weeks Participants in Arm 1 (control) received pegylated interferon alfa 2b (PegIntron, PEG2b) + Ribavirin (RBV) (weight-based dosing \[WBD\]) for 4 weeks followed by boceprevir placebo + PEG2b + RBV (WBD) for 44 weeks with 24 weeks post-treatment follow-up. | 80 |
| Boceprevir+PEG2b+RBV, Response Guided Therapy Participants in Arm 2 (experimental) were assigned either a 36-week or 48-week course of therapy based on their HCV-RNA status at Treatment Week 8.
PEG2b + RBV (WBD) for 4 weeks followed by boceprevir + PEG2b + RBV (WBD) for 32 weeks, then:
* 36-week regimen: Participants who have undetectable HCV-RNA at Treatment Week 8 discontinue treatment and enter 36 weeks of post treatment follow-up.
* 48-week regimen: Participants who have detectable HCV-RNA at Treatment Week 8 are assigned an additional 12 weeks of therapy, followed by 24 weeks of post treatment follow-up. Placebo replaces boceprevir for the remaining 12 weeks of therapy, and this switch will occur in a blinded fashion. | 162 |
| Boceprevir+PEG2b+RBV, x 44 Weeks Participants in Arm 3 (experimental) received PEG2b + RBV (WBD) for 4 weeks followed by boceprevir + PEG2b + RBV (WBD) for 44 weeks with 24 weeks post-treatment follow-up. | 161 |
| Total | 403 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| FOLLOWUP | Adverse Event | 0 | 1 | 0 |
| FOLLOWUP | Lost to Follow-up | 1 | 6 | 4 |
| FOLLOWUP | Non-compliance with protocol | 5 | 0 | 1 |
| FOLLOWUP | Subject withdrawal unrelated to Tx | 3 | 4 | 5 |
| FOLLOWUP | Subject withdrew consent | 31 | 4 | 5 |
| Treatment (Tx): 4 WEEK LEAD-IN PERIOD | Adverse Event | 1 | 3 | 1 |
| Treatment (Tx): 4 WEEK LEAD-IN PERIOD | Randomized but not treated | 0 | 0 | 1 |
| Treatment (Tx): 4 WEEK LEAD-IN PERIOD | Subject withdrawal related to Tx | 0 | 1 | 0 |
| Treatment (Tx): 4 WEEK LEAD-IN PERIOD | Subject withdrawal unrelated to Tx | 1 | 0 | 0 |
| Treatment (Tx): 4 WEEK LEAD-IN PERIOD | Subject withdrew consent | 0 | 2 | 0 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Administrative | 0 | 1 | 0 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Adverse Event | 1 | 10 | 19 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Lost to Follow-up | 0 | 1 | 0 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Non-compliance with protocol | 0 | 1 | 1 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Subject withdrawal related to Tx | 2 | 0 | 1 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Subject withdrawal unrelated to Tx | 3 | 1 | 4 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Subject withdrew consent | 0 | 2 | 1 |
| Tx: RECEIVING BOCEPREVIR/PLACEBO | Treatment Failure | 49 | 36 | 29 |
Baseline characteristics
| Characteristic | Placebo+PEG2b+RBV, x 44 Weeks | Boceprevir+PEG2b+RBV, Response Guided Therapy | Boceprevir+PEG2b+RBV, x 44 Weeks | Total |
|---|---|---|---|---|
| Age, Continuous | 52.9 years STANDARD_DEVIATION 8.1 | 52.9 years STANDARD_DEVIATION 7.4 | 52.3 years STANDARD_DEVIATION 7.7 | 52.7 years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 22 Participants | 64 Participants | 49 Participants | 135 Participants |
| Sex: Female, Male Male | 58 Participants | 98 Participants | 112 Participants | 268 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 | 77 / 80 | 159 / 162 | 160 / 161 |
| serious Total, serious adverse events | 4 / 80 | 16 / 162 | 23 / 161 |
Outcome results
Primary
Sustained Virologic Response (SVR) Rate in the Full Analysis Set (FAS) Population.
SVR is defined as undetectable plasma hepatitis C virus RNA (HCV-RNA) at Follow-up Week 24. This outcome measure evaluates SVR after treatment with boceprevir and PEG2b plus RBV versus PEG2b plus RBV alone in participants with chronic hepatitis C (CHC) genotype 1 who failed prior treatment.
Time frame: At Follow-up Week 24
Population: FAS = all randomized subjects who received at least one dose of any study medication (Peg, RBV, or boceprevir/placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo+PEG2b+RBV, x 44 Weeks | Sustained Virologic Response (SVR) Rate in the Full Analysis Set (FAS) Population. | 21.3 Percentage of Participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Sustained Virologic Response (SVR) Rate in the Full Analysis Set (FAS) Population. | 58.6 Percentage of Participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Sustained Virologic Response (SVR) Rate in the Full Analysis Set (FAS) Population. | 66.5 Percentage of Participants |
p-value: <0.000195% CI: [25.7, 49.1]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [33.7, 56.8]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Early Virologic Response.
Having undetectable HCV-RNA at Week 2, 4, 8, or 12 was considered Early Virologic Response.
Time frame: At Week 2, 4, 8, or 12
Population: FAS = all randomized subjects who received at least one dose of any study medication (Peg, RBV, or boceprevir/placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 12 | 23 participants |
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 4 | 2 participants |
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 8 | 7 participants |
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 2 | 0 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Early Virologic Response. | Week 8 | 74 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Early Virologic Response. | Week 12 | 111 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Early Virologic Response. | Week 4 | 0 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Early Virologic Response. | Week 2 | 0 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 12 | 121 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 4 | 2 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 8 | 84 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Early Virologic Response. | Week 2 | 0 participants |
Secondary
Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization.
Time frame: At Follow-up Week 12 and at 72 weeks after randomization
Population: FAS = all randomized subjects who received at least one dose of any study medication (Peg, RBV, or boceprevir/placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | Follow-Up Week 12 | 16 participants |
| Placebo+PEG2b+RBV, x 44 Weeks | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | 72 Weeks Post Randomization | 17 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | Follow-Up Week 12 | 97 participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | 72 Weeks Post Randomization | 93 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | Follow-Up Week 12 | 105 participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Number of Participants With Undetectable HCV-RNA at Follow-up Week 12 and at 72 Weeks After Randomization. | 72 Weeks Post Randomization | 105 participants |
Secondary
Sustained Virologic Response (SVR) Rate in the Modified Intent to Treat (mITT) Population.
SVR is defined as undetectable plasma HCV-RNA at Follow-up Week 24. This outcome measure evaluates SVR after treatment with boceprevir and PEG2b plus RBV versus PEG2b plus RBV alone in participants with CHC genotype 1 who failed prior treatment. This key secondary efficacy endpoint was added as per the second protocol amendment on 02 DEC 2009.
Time frame: At Follow-up Week 24
Population: mITT = all randomized subjects who received at least one dose of boceprevir (experimental arms) or boceprevir placebo (control arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo+PEG2b+RBV, x 44 Weeks | Sustained Virologic Response (SVR) Rate in the Modified Intent to Treat (mITT) Population. | 21.8 Percentage of Participants |
| Boceprevir+PEG2b+RBV, Response Guided Therapy | Sustained Virologic Response (SVR) Rate in the Modified Intent to Treat (mITT) Population. | 60.9 Percentage of Participants |
| Boceprevir+PEG2b+RBV, x 44 Weeks | Sustained Virologic Response (SVR) Rate in the Modified Intent to Treat (mITT) Population. | 66.9 Percentage of Participants |
p-value: <0.000195% CI: [27.2, 51]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [33.4, 56.8]Cochran-Mantel-Haenszel