| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Part A: To evaluate the safety and tolerability (as measured by the frequency of SAEs, dose reductions and discontinuations due to AEs) through end of treatment (maximum of 48 weeks) plus 30 days of pegIFNλ administered with RBV + a single direct antiviral agent (DAA) (BMS-790052 or BMS-650032)
• Part B: To evaluate the safety and tolerability (as measured by the frequency of SAEs, dose reductions and discontinuations due to AEs) through end of treatment (maximum of 48 weeks) plus 30 days of pegIFNλ administered with or without RBV + 2 DAA (BMS-790052 and BMS-650032)
• To describe the antiviral activity as determined by the proportion of HCV genotype 1 subjects with 24-week sustained virologic response (SVR24) for Part A and Part B |
|
| E.2.2 | Secondary objectives of the trial |
• To describe the antiviral activity as determined by the proportion of HCV genotype 1 subjects with PDR for Part A or Part B
• To assess serum HCV RNA levels, as measured by the Roche COBAS Taqman test version 2
• To describe the antiviral activity as determined by the proportion of HCV genotype 1 subjects with SVR4 and the proportion with SVR12 for Part A and Part B
• To investigate the relationship between pegIFNλ and BMS-650032 or
BMS-790052 exposure and antiviral responses
• To describe DAA-resistant variants associated with virologic failure
+ Exploratory Objectives:
• To investigate the effect on patient reported outcomes (PROs) of
repeat dosing with pegIFNλ in combination with DAAs ± RBV
• To investigate the relationship between PD biomarkers and clinical
responses to pegIFNλ
• To investigate the association of host genetic factors with clinical
responses to treatment with pegIFNλ
• To evaluate the immunogenicity of pegIFNλ |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive Pharmacokinetics (PK) sub study - see section 5.5 of the study Protocol.
In the PK sub-study group, Cmax, Tmax, Cmin, AUC(TAU) will be determined at Dose 5 (Study Visit Week 4): 0 - 12 h for BMS-650032, 0 - 24 h for BMS-790052, and 0 - 168 h for pegIFNλ and pegIFNα-2a. The number of subjects for the PK sub-studies will be 8 per cohort in Part A and 4 per cohort in Part B, respectively.
Frequency of genotypic substitutions associated with virologic failure will be summarized by treatment regimen. |
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| E.3 | Principal inclusion criteria |
•Chronic Hepatitis C, Genotype 1
•HCV RNA >100,000 IU/mL at screening;
•Seronegative for HIV and HBsAg;
•Liver biopsy within prior 2 years; subjects with compensated cirrhosis can enroll and will be capped at approximately 10%
|
|
| E.4 | Principal exclusion criteria |
•Any evidence of liver disease other than HCV;
•Co-infection with HIV;
•Diagnosed or suspected hepatocellular carcinoma;
•Medical history or laboratory value abnormalities that would prohibit the use of Pegylated Interferon Alpha-2a or Ribavirin
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Assessments (Parts A and B):
1) Safety: Frequency of SAEs, dose reductions and discontinuations due
to AEs through end of treatment (maximum of 48 weeks) plus 30 days
2) Efficacy: Proportion of HCV genotype 1 subjects with 24-week
sustained virologic response (SVR24), defined as undetectable HCV RNA
at end of treatment (maximum of 48 weeks) and follow-up Week 24
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) During treatment Weeks 4, 12 and 24
2) Post-treatment Week 24
|
|
| E.5.2 | Secondary end point(s) |
Secondary Assessments (Parts A and B):
1) Proportion of HCV genotype 1 subjects with PDR. Part A PDR is defined as HCV RNA at Week 4 < LLOQ and Week 12 undetectable; Part B PDR is defined as HCV RNA at Week 2 ≥ 2 log10 decrease (or < LLOQ if baseline HCV RNA < 2400 IU/mL), Week 4 < LLOQ and Week 12 undetectable
2) Serum HCV RNA levels as measured by the Roche COBAS Taqman test version 2, over time (Days 1, 3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment [Week 16, 24 or 48 depending on treatment assignment]);
3) Proportion of subjects with undetectable HCV RNA over time (Days 1,3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment [Week 16, 24 or 48 depending on treatment assignment]);
4)Proportion of subjects with 12-week sustained virologic response (SVR12),
defined as undetectable HCV RNA at end of treatment (maximum of 48 weeks)
and follow-up Week 12;
5)Proportion of subjects with 4-week sustained virologic response (SVR4), defined as undetectable HCV RNA at end of treatment (maximum of 48 weeks) and follow-up Week 4
6) Time to viral clearance, defined as an absence of detectable HCV RNA;
7) Proportion of subjects with either a 2-log or greater decrease in HCV
RNA levels from baseline or undetectable levels of HCV RNA at Weeks 2,
4 and 12;
8) Proportion of subjects with viral breakthrough, defined as confirmed > 1 log(10) increase in HCV RNA over nadir or confirmed HCV RNA ≥ LLOQ after confirmed undetectable HCV RNA while on treatment;
9) Proportion of subjects with undetectable relapse, defined as HCV RNA at the end of treatment followed bydetectable levels of HCV RNA in any follow-up visit window. Detectable measurements should be confirmed with 2 weeks of receipt of the initial HCV RNA result. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Weeks 4 and 12 during treatment and post-treatment Week 24
2) During treatment
3) During treatment and post-treatment Week 24 and/or 48 depending on response
4) During treatment and post-treatment; time point(s) depends on treatment assignment and response
5) Weeks 2, 4, and 12
6) Post-treatment Week 48
7) Post-treatment Week 48 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| HPSS-D; Global Fatigue & Physical Symptoms; Beck Depression Inventory II; Resistance; Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Italy |
| Japan |
| New Zealand |
| Puerto Rico |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last visit for the last subject to complete the study. The last visit is defined as the last post-treatment follow-up subject visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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