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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00423670
First received: January 17, 2007
Last updated: March 17, 2014
Last verified: March 2014
Results First Received: May 13, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Chronic Hepatitis C
Interventions: Drug: boceprevir (SCH 503034)
Drug: peginterferon-alfa 2b (PegIntron)
Drug: ribavirin
Drug: ribavirin (low-dose)

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

765 participants were screened in the study, 598 were randomized of which 3 participants were not

treated (Arm 1-7). Participants were assigned to Part I (with standard dosing for ribavirin) or Part II (to explore low-dose ribavirin). All participants that completed or discontinued treatment were scheduled to enter follow-up phase per protocol.


Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants in Arm 1 (Part I) who had detectable Hepatitis C Virus-ribonucleic acid (HCV-RNA) at Treatment Week (TW) 24 were offered boceprevir in addition to PegIntron and ribavirin for an additional 24 weeks of treatment, and switched to a new arm, Arm 8.

Reporting Groups
  Description
Arm 1. PEG +RBV for 48 Wks (Part I)

PegIntron (1.5 μg/kg, once weekly [QW]) plus 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, ribavirin, and boceprevir (800 mg, thrice a day [TID]) for 24 additional weeks. Total treatment duration was up to 54 weeks.

Arm 2. PEG + RBV + BOC for 28 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 28 weeks.
Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead-in 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.
Arm 4. PEG +RBV + BOC for 48 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 48 weeks.
Arm 5. PEG + RBV + BOC (From Wk 4) for 44 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead-in 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.
Arm 6. PEG + RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (800 to 1400 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.
Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (400 to 1000 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.
Arm 8. PEG + RBV + BOC (From Wk 24) for 48 Wks (Part I) 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), ribavirin (800 to 1400 mg/day). Participants that took the option of crossing over to receive 24 weeks of PegIntron, ribavirin, and boceprevir (800 mg TID) for 24 additional weeks constitute Arm 8. The total treatment duration was up to 54 weeks.

Participant Flow for 2 periods

Period 1:   Treatment Period
    Arm 1. PEG +RBV for 48 Wks (Part I)     Arm 2. PEG + RBV + BOC for 28 Wks (Part I)     Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I)     Arm 4. PEG +RBV + BOC for 48 Wks (Part I)     Arm 5. PEG + RBV + BOC (From Wk 4) for 44 Wks (Part I)     Arm 6. PEG + RBV + BOC for 48 Wks (Part II)     Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II)     Arm 8. PEG + RBV + BOC (From Wk 24) for 48 Wks (Part I)  
STARTED     104     107     103     103     103     16     59     36 [1]
COMPLETED     52     77     76     63     76     8     28     15  
NOT COMPLETED     52     30     27     40     27     8     31     21  
Switched to Arm 8 at TW 24                 36                 0                 0                 0                 0                 0                 0                 0  
Adverse Event                 8                 12                 15                 20                 9                 4                 7                 2  
Protocol-defined clinical event                 0                 7                 4                 12                 5                 4                 16                 15  
Lost to Follow-up                 2                 1                 3                 1                 6                 0                 3                 1  
Subject withdrew (not treatment related)                 3                 9                 4                 4                 5                 0                 3                 0  
Investigator decision                 0                 0                 0                 0                 0                 0                 0                 1  
Non-compliance with protocol                 3                 1                 1                 3                 2                 0                 2                 2  
[1] Arm 8 were Arm 1 participants that were positive for HCV-RNA at TW 24 and had the option to switch.

Period 2:   Follow-up Period
    Arm 1. PEG +RBV for 48 Wks (Part I)     Arm 2. PEG + RBV + BOC for 28 Wks (Part I)     Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I)     Arm 4. PEG +RBV + BOC for 48 Wks (Part I)     Arm 5. PEG + RBV + BOC (From Wk 4) for 44 Wks (Part I)     Arm 6. PEG + RBV + BOC for 48 Wks (Part II)     Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II)     Arm 8. PEG + RBV + BOC (From Wk 24) for 48 Wks (Part I)  
STARTED     97     100     96     96     91     14     50     35  
COMPLETED     94     84     85     91     89     14     41     32  
NOT COMPLETED     3     16     11     5     2     0     9     3  
Lost to Follow-up                 0                 12                 8                 3                 1                 0                 5                 0  
Subject withdrew (not treatment related)                 1                 4                 2                 1                 1                 0                 1                 1  
Non-compliance with protocol                 2                 0                 1                 1                 0                 0                 3                 2  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm 1. PEG +RBV for 48 Wks (Part I)

PegIntron (1.5 μg/kg QW) plus ribavirin (800 to 1400 mg/day) for 48 weeks.

• Participants with detectable HCV-RNA levels after 24 weeks of treatment had to receive 24 weeks of PegIntron, ribavirin and boceprevir (800 mg TID) for 24 additional weeks. Total treatment duration was up to 54 weeks.

Arm 2. PEG + RBV + BOC for 28 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 28 weeks.
Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead in 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.
Arm 4. PEG +RBV + BOC for 48 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 48 weeks.
Arm 5. PEG + RBV+ BOC (From Wk 4) for 44 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead in 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.
Arm 6. PEG + RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (800 to 1400 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.
Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (400 to 1000 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.
Total Total of all reporting groups

Baseline Measures
    Arm 1. PEG +RBV for 48 Wks (Part I)     Arm 2. PEG + RBV + BOC for 28 Wks (Part I)     Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I)     Arm 4. PEG +RBV + BOC for 48 Wks (Part I)     Arm 5. PEG + RBV+ BOC (From Wk 4) for 44 Wks (Part I)     Arm 6. PEG + RBV + BOC for 48 Wks (Part II)     Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II)     Total  
Number of Participants  
[units: participants]
  104     107     103     103     103     16     59     595  
Age [1]
[units: years]
Mean ± Standard Deviation
  48.3  ± 6.9     46.4  ± 8.0     47.7  ± 7.4     46.7  ± 8.8     47.6  ± 8.3     50.3  ± 8.5     48.7  ± 5.8     47.5  ± 7.7  
Gender [2]
[units: participants]
               
Female     34     44     52     40     45     7     18     240  
Male     70     63     51     63     58     9     41     355  
[1] Overall age characteristics were displayed for Arm 1 through Arm 7. Participants from Arm 1 (Part I) who had detectable HCV-RNA at TW 24, had the option to switch to a new arm, Arm 8.
[2] Overall gender characteristics were displayed for Arm 1 through Arm 7. Participants from Arm 1 (Part I) who had detectable HCV-RNA TW 24, had the option to switch to a new arm, Arm 8.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With Sustained Virologic Response (SVR)   [ Time Frame: From follow-up week (FW) 24 up to end of follow-up (EOF) ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Number of Participants With Sustained Virologic Response (SVR)
Measure Description

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

  1. he/she had undetectable HCV-RNA at FW 12 or later
  2. 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.

Time Frame From follow-up week (FW) 24 up to end of follow-up (EOF)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat (ITT) population: All randomized participants who received at least one dose of any study medication (PegIntron, ribavirin, or boceprevir).

Reporting Groups
  Description
Arm 1. PEG +RBV for 48 Wks (Part I)

PegIntron (1.5 μg/kg QW) plus ribavirin (800 to 1400 mg/day) for 48 weeks.

• Participants with detectable HCV-RNA levels after 24 weeks of treatment had to receive 24 weeks of PegIntron, ribavirin and boceprevir (800 mg TID) for 24 additional weeks. Total treatment duration was up to 54 weeks.

Arm 2. PEG + RBV + BOC for 28 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 28 weeks.
Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead in 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.
Arm 4. PEG +RBV + BOC for 48 Wks (Part I) Boceprevir (800 mg TID) plus PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for up to 48 weeks.
Arm 5. PEG + RBV+ BOC (From Wk 4) for 44 Wks (Part I) PegIntron (1.5 μg/kg QW) and ribavirin (800 to 1400 mg/day) for 4 weeks lead in 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.
Arm 6. PEG + RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (800 to 1400 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.
Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II) PegIntron (1.5 μg/kg QW), ribavirin (400 to 1000 mg/day) and boceprevir (800 mg TID) for up to 48 weeks.

Measured Values
    Arm 1. PEG +RBV for 48 Wks (Part I)     Arm 2. PEG + RBV + BOC for 28 Wks (Part I)     Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I)     Arm 4. PEG +RBV + BOC for 48 Wks (Part I)     Arm 5. PEG + RBV+ BOC (From Wk 4) for 44 Wks (Part I)     Arm 6. PEG + RBV + BOC for 48 Wks (Part II)     Arm 7. PEG +Low-dose RBV + BOC for 48 Wks (Part II)  
Number of Participants Analyzed  
[units: participants]
  104     107     103     103     103     16     59  
Number of Participants With Sustained Virologic Response (SVR)  
[units: Participants]
  39     58     58     69     77     8     21  


Statistical Analysis 1 for Number of Participants With Sustained Virologic Response (SVR)
Groups [1] Arm 1. PEG +RBV for 48 Wks (Part I) vs. Arm 2. PEG + RBV + BOC for 28 Wks (Part I)
Method [2] Cochran-Mantel Haenszel Chi-square test
P Value [3] 0.0126
Percent difference in SVR [4] 16.7
95% Confidence Interval ( 3.5 to 30 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted for baseline stratification factors: black versus non-black, and cirrhosis versus no cirrhosis.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Number of Participants With Sustained Virologic Response (SVR)
Groups [1] Arm 1. PEG +RBV for 48 Wks (Part I) vs. Arm 3. PEG + RBV + BOC (From Wk 4) for 24 Wks (Part I)
Method [2] Cochran-Mantel Haenszel Chi-square test
P Value [3] 0.0048
Percent difference in SVR [4] 18.8
95% Confidence Interval ( 5.5 to 32.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted for baseline stratification factors: black versus non-black, and cirrhosis versus no cirrhosis.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Number of Participants With Sustained Virologic Response (SVR)
Groups [1] Arm 1. PEG +RBV for 48 Wks (Part I) vs. Arm 4. PEG +RBV + BOC for 48 Wks (Part I)
Method [2] Cochran-Mantel Haenszel Chi-square test
P Value [3] <0.0001
Percent difference in SVR [4] 29.5
95% Confidence Interval ( 16.5 to 42.5 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted for baseline stratification factors: black versus non-black, and cirrhosis versus no cirrhosis.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Number of Participants With Sustained Virologic Response (SVR)
Groups [1] Arm 1. PEG +RBV for 48 Wks (Part I) vs. Arm 5. PEG + RBV+ BOC (From Wk 4) for 44 Wks (Part I)
Method [2] Cochran-Mantel Haenszel Chi-square test
P Value [3] <0.0001
Percent difference in SVR [4] 37.3
95% Confidence Interval ( 24.7 to 49.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted for baseline stratification factors: black versus non-black, and cirrhosis versus no cirrhosis.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Number of Participants With SVR Based on a 4-week lead-in Treatment With PegIntron and Ribavirin   [ Time Frame: From FW 24 up to EOF ]

3.  Secondary:   Number of Participants With SVR Based on Duration of Boceprevir Treatment   [ Time Frame: From FW 24 up to EOF ]

4.  Secondary:   Number of Participants Negative for HCV-RNA at FW 12   [ Time Frame: At FW 12 ]

5.  Secondary:   Number of Participants Negative for HCV-RNA at 72 Weeks Post Randomization   [ Time Frame: 72 weeks post randomization ]

6.  Secondary:   Number of Participants With an Early Virologic Response (EVR) That Achieved SVR   [ Time Frame: At TW 12, and at FW 24 up to EOF ]

7.  Secondary:   Number of Participants With a Virologic Response at Follow-up Week 12 That Achieved SVR   [ Time Frame: At FW 12 and FW 24 up to EOF ]

8.  Secondary:   Number of Participants With a Virologic Response at 72 Weeks Post Randomization That Achieved SVR   [ Time Frame: At FW 24 up to EOF and at 72 weeks post randomization ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information