Safety and Efficacy of SCH 503034 in Previously Untreated Subjects With Chronic Hepatitis C Infected With Genotype 1 (Study P03523)

Study Overview
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Brief Summary
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This was an open-label, randomized safety and efficacy trial in adult, treatment-naïve Chronic Hepatitis C (CHC) participants with genotype 1 infection. The study conducted in 2 parts, compared standard-of-care PegIntron (1.5 μg/kg, once weekly [QW]), plus ribavirin (800 to 1400 mg/day), for 48 weeks to five treatment paradigms containing boceprevir (SCH 503034) 800 mg thrice a day (TID). The five treatments included boceprevir (BOC) plus standard-of-care for 28 or 48 weeks, with and without a 4-week lead-in with PegIntron (PEG) and ribavirin (RBV), and exploration of PegIntron plus low-dose ribavirin (400 to 1000 mg/day) plus boceprevir for 48 weeks.

Detailed Description
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The study was conducted in 2 parts. Part 1 of the study had 5 arms using weight based ribavirin 800-1400 mg/day and compared: PegIntron and ribavirin for 48 weeks (Arm 1 - Control) PegIntron, ribavirin, and boceprevir for 28 weeks (Arm 2) Lead-in with PegIntron and ribavirin for 4 weeks followed by PegIntron, ribavirin and boceprevir for 24 weeks (Arm 3) PegIntron, ribavirin and boceprevir for 48 weeks (Arm 4) Lead-in with PegIntron and ribavirin for 4 weeks, followed by PegIntron, ribavirin and boceprevir for 44 weeks (Arm 5) Participants from Arm 1 receiving PegIntron and ribavirin that were HCV positive after 24 weeks of treatment had the option to receive boceprevir in combination with PegIntron and ribavirin for an additional 24 weeks. All participants from Arm 1 that started boceprevir after Week 24 formed the crossover arm (Arm 8). Part 2 of the study assessed the safety and efficacy of low dose ribavirin (400-1000 mg/day) and compared: PegIntron, ribavirin (800-1400 mg/day) and boceprevir for 48 weeks (Arm 6) PegIntron, low-dose ribavirin (400-1000 mg/day) and boceprevir for 48 weeks (Arm 7) Follow-up for all participants was up to 72 weeks after randomization.

Official Title
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A Safety and Efficacy Study of SCH 503034 in Previously Untreated Subjects With Chronic Hepatitis C Infected With Genotype 1

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: boceprevir (SCH 503034)
* Drug: peginterferon-alfa 2b (PegIntron)
* Drug: ribavirin
* Drug: ribavirin (low-dose)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 60 years; Body weight between 45 and 125 kg; Documented chronic hepatitis C genotype 1; Liver biopsy with histology consistent with chronic hepatitis and no other etiology for chronic liver disease within of 5 years of Day 1; Participant and participant's partner(s) must each agree to use acceptable methods of contraception 2 weeks prior to Day 1 and at least 6 months after the last dose of study medication; Written informed consent. Exclusion Criteria: Include, but are not limited to, the following: Prior treatment for hepatitis C; Co-infection with HIV or hepatitis B virus (HBsAg positive); Evidence of decompensated liver disease; Diabetic and hypertensive participants with clinically significant ocular exam findings; Pre-existing psychiatric condition, including but not limited to: Current moderate or severe depression; History of depression associated with any of the following: Hospitalization for depression; Electroconvulsive therapy for depression; Depression that resulted in a prolonged absence from work and/or significant disruption of daily functions; Suicidal or homicidal ideation and/or attempt; History of severe psychiatric disorders (including but not limited to schizophrenia, psychosis, bipolar disorder, post-traumatic stress disorder or mania); Past history or current use of lithium; Past history or current use of antipsychotic drugs for listed conditions. Substance abuse within protocol specified timeframes; Pre-existing medical conditions that could interfere with the participant's participation in and completion of the study, including but not limited to chronic pulmonary disease, cardiac dysfunction or immunologically-mediated disease; Active or suspected malignancy or history of malignancy within the past 5 years; 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. Treatment with any investigational drug or participation in any clinical trial 30 days within Screening; 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; Other clinically significant laboratory test abnormalities.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1. PEG +RBV for 48 Wks (Part I)<br>Participants treated with PegIntron (1.5 μg/kg, once weekly [QW]) and Ribavirin (800 to 1400 mg/day) for 48 weeks. Participants with detectable HCV-RNA levels after 24 weeks of treatment had the option of crossing over to receive 24 weeks of PegIntron (1.5 μg/kg, QW), Ribavirin (800 to 1400 mg/day), and boceprevir (800 mg three times daily [TID]) for 24 additional weeks. The participants that crossed over to receive boceprevir formed Arm 8. The total treatment duration was up to 54 weeks. | Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 2. PEG + RBV + BOC for 28 Wks (Part I)<br>Participants receiving boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 28 weeks. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 3. PEG + RBV + BOC (from Wk 4) for 24 Wks (Part I)<br>Participants receiving a lead-in treatment with PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks, followed by boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 24 weeks. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 4. PEG +RBV + BOC for 48 Wks (Part I)<br>Participants receiving boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 48 weeks. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 5. PEG + RBV + BOC (from Wk 4) for 44 Wks (Part I)<br>Participants receiving a lead-in treatment with PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks, followed by boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 44 weeks. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 6. PEG + RBV + BOC for 48 Wks (Part II)<br>Participants receiving PegIntron (1.5 μg/kg QW), ribavirin (800 to 1400 mg/day) and boceprevir (800 mg TID) for up to 48 weeks during Part II of the study. Part II was initiated after participants were fully enrolled for Part I. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II)<br>Participants receiving PegIntron (1.5 μg/kg QW), low-dose ribavirin (400 to 1000 mg/day) and boceprevir (800 mg TID) for up to 48 weeks (Arm 7) during Part II of the study. Part II was initiated after participants were fully enrolled for Part I. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin (low-dose)<br>* 200 mg capsules in doses of 400 to 1000 mg/day (based on weight) taken orally divided twice daily<br>|
| Experimental: Arm 8. PEG + RBV + BOC (from Wk 24) for 48 Wks (Part I)<br>Participants that started in Arm 1 and had detectable HCV-RNA levels after 24 weeks of treatment had the option of receiving boceprevir (800 mg TID) with PegIntron (1.5 μg/kg QW), and ribavirin (800 to 1400 mg/day). Participants that took the option of crossing over to receive PegIntron, ribavirin, and boceprevir (800 mg TID) for 24 additional weeks constitute Arm 8. The total treatment duration was up to 54 weeks. | Drug: boceprevir (SCH 503034)<br>* 200 mg capsules taken as 800 mg orally three times daily (TID)<br>* Other names: Boceprevir, Victrelis, SCH 503034;Drug: peginterferon-alfa 2b (PegIntron)<br>* 1.5 μg/kg subcutaneously (SC) once weekly (QW)<br>Drug: ribavirin<br>* 200 mg capsules in doses of 800 to 1400 mg/day (based on weight) taken orally divided twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Virologic Response (SVR) | Participants with undetectable HCV-RNA at FW 24 up to EOF had achieved SVR. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected with reverse-transcriptase-polymerase chain reaction (RT-PCR) assay, with a lower limit of detection (LLD) of 29 international units/mL (IU/mL). A participant in Arm 2 with undetectable HCV-RNA at FW 24 had detectable HCV-RNA after FW 24. He is not considered to achieve SVR. | From follow-up week (FW) 24 up to end of follow-up (EOF) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With SVR Based on a 4-week lead-in Treatment With PegIntron and Ribavirin | Number of participants with SVR (undetectable plasma HCV-RNA at FW 24 up to EOF). To assess the effect of lead-in treatment on SVR, participants with (Arm 3 and Arm 5) or without (Arm 2 and Arm 4) lead-in were pooled. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | From FW 24 up to EOF | 
| Number of Participants With SVR Based on Duration of Boceprevir Treatment | Number of participants with SVR (undetectable plasma HCV-RNA at FW 24 up to EOF). Participants from treatment arms receiving boceprevir for 28-weeks (Arm 2 and Arm 3) were pooled, and those receiving boceprevir for 48-weeks (Arm 4 and Arm 5) were pooled for the analysis. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | From FW 24 up to EOF | 
| Number of Participants Negative for HCV-RNA at FW 12 | Participants who had undetectable plasma HCV-RNA at FW 12. Also reported are participants for whom the HCV-RNA values were missing. 36 participant who switched over to Arm 8 from Arm 1, are included in the missing values for Arm 1. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | At FW 12 | 
| Number of Participants Negative for HCV-RNA at 72 Weeks Post Randomization | Participants who had undetectable HCV-RNA at 72 weeks post randomization are reported. Participants with missing HCV-RNA values at 72 weeks post randomization are also reported. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | 72 weeks post randomization | 
| Number of Participants With an Early Virologic Response (EVR) That Achieved SVR | Participants with undetectable HCV-RNA at TW 12 have EVR, and with undetectable HCV-RNA at FW 24 (up to EOF) achieved SVR. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later if he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | At TW 12, and at FW 24 up to EOF | 
| Number of Participants With a Virologic Response at Follow-up Week 12 That Achieved SVR | Treatment-naïve adults with CHC genotype 1 were assigned study medication. Participants with undetectable HCV-RNA at FW 12 that achieved SVR (have undetectable HCV-RNA at FW 24 (up to EOF) are reported. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later if he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected with an RT-PCR assay. The LLD for the assay was 29 IU/mL. | At FW 12 and FW 24 up to EOF | 
| Number of Participants With a Virologic Response at 72 Weeks Post Randomization That Achieved SVR | Participants with undetectable HCV-RNA at 72 weeks post randomization that achieved SVR (have undetectable HCV-RNA at FW 24 up to EOF) are reported. Participants missing data at FW 24 were considered to achieve SVR if he/she had undetectable HCV-RNA at FW 12 or later if he/she returned later to the study center and had undetectable HCV-RNA. HCV-RNA in plasma samples was detected an the RT-PCR assay. The lower limit of detection (LLD) was 29 IU/mL. | At FW 24 up to EOF and at 72 weeks post randomization |