Efficacy and Safety Study of Pegylated Interferon Lambda-1a With Ribavirin and Daclatasvir, to Treat naïve Subjects With Chronic HCV Genotypes 1, 2, 3, and 4 Who Are Co-infected With HIV

Study Overview
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Brief Summary
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To evaluate Sustained Virologic Response at post treatment Week 12 (SVR12)following treatment with Lambda/RBV/DCV in chronic HCV GT-1, -2, -3 or -4 subjects co-infected with HIV-1

Detailed Description
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Study Classification: Safety/Efficacy and Pharmacokinetics/dynamics GT=genotype

Official Title
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Phase 3 Open Label Study Evaluating the Efficacy and Safety of Pegylated Interferon Lambda-1a, in Combination With Ribavirin and Daclatasvir, for Treatment of Chronic HCV Infection With Treatment naïve Genotypes 1, 2, 3 or 4 in Subjects Co-infected With HIV

Conditions
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Chronic Hepatitis C Infection

Intervention / Treatment
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* Biological: Pegylated Interferon Lambda-1a
* Drug: Daclatasvir (DCV)
* Drug: Ribasphere (RBV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HCV Genotype-1, -2, -3 or -4 treatment naïve; HCV RNA ≥10,000 IU/mL at screening; HIV-1 infection [(approximately 200 subjects receiving HAART, approximately 100 subjects not receiving highly active antiretroviral therapy (HAART)]; For subjects receiving HAART, HIV RNA must be below <40 copies/mL at screening and <200 copies/mL for at least 8 weeks prior to screening; CD4 cell count at screening must be ≥100 cells/μL if receiving HAART or ≥350 cells/μL if not receiving HAART) Seronegative for Hepatitis B Surface Antigen (HBsAg) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI=weight (kg)/[height (m)]2 at screening; Subjects with compensated cirrhosis are permitted, but the number of subjects will be capped at approximately 30%. If a subject does not have cirrhosis, a liver biopsy within 3 years prior to enrollment is required to demonstrate the absence of cirrhosis. If cirrhosis is present, any prior liver biopsy is sufficient. Fibroscan® or FibroTest are acceptable if performed within 1 year prior to treatment in countries where liver biopsy is not required prior to treatment and where non-invasive imaging tests are approved for staging of liver disease Subjects with mild to moderate hemophilia as defined as: Mild-factor level activity of 6-4% OR Moderate defined as factor level activity of 1-5% Exclusion Criteria: Any evidence of liver disease other than chronic HCV; Subjects infected with human immunodeficiency virus (HIV-2); Diagnosed or suspected hepatocellular carcinoma; Decompensated liver disease; Presence of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within 12 weeks prior to study entry (AIDS-defining opportunistic infections as defined by the CDC, (CDC, JAMA 1993 Feb 10;269(6):729-30) Laboratory values: ANC <1.5 x 109 cells/L (<1.2 x 109 cells/L for Blacks), platelet count <90 x 109 cells/L, hemoglobin <11 g/dL for females, hemoglobin <12 g/dL for males; Subjects (receiving HAART) who had first initiated anti-retroviral therapy within last 8 weeks prior to Day 1; however, if changes are required to a subject's HAART regimen to meet the requirements of the protocol, these changes are allowed at the screening visit. Subjects should wait a minimum of 1 month prior to Day 1 after a repeat of HIV viral load has been confirmed, <40 copies/mL Subjects on Zidovudine (AZT), Didanosine (ddI), or Stavudine (d4T); Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements Subjects with severe hemophilia (defined as <1% factor activity level)

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: GT-2 or -3 HCV Treatment Naïve Subjects<br>Pegylated Interferon Lambda 180 µg solution, injection subcutaneously once weekly for 24 weeks Ribasphere 200 mg tablets (800 mg per day: two 200 mg tablets in the morning and two 200 mg tablets in the evening) by mouth twice daily for 24 weeks Daclatasvir 30 mg, 60 mg, or 90 mg tablets (depending on concomitant HIV regimen) once daily for 12 weeks | Biological: Pegylated Interferon Lambda-1a<br> <br> * Other names: BMS-914143;Drug: Daclatasvir (DCV)<br> <br> * Other names: BMS-790052;Drug: Ribasphere (RBV)<br> <br> |
| Experimental: Cohort B: GT-1 or -4 HCV Treatment Naïve Subjects<br>Pegylated Interferon Lambda 180 µg solution, injection subcutaneously once weekly for 24 or 48 weeks Ribasphere 200 mg tablets, (1000 mg per day: two 200 mg tablets in the morning and three 200 mg tablets in the evening for subjects weighing <75 kg and 1200 mg per day: three 200 mg tablets in morning and three 200 mg tablets in evening for subjects weighing ≥75 kg) by mouth twice daily for 24 or 48 weeks Daclatasvir 30 mg, 60 mg, or 90 mg tablets (depending on concomitant HIV regimen) once daily for 12 weeks | Biological: Pegylated Interferon Lambda-1a<br> <br> * Other names: BMS-914143;Drug: Daclatasvir (DCV)<br> <br> * Other names: BMS-790052;Drug: Ribasphere (RBV)<br> <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 at Post-treatment Week 12 (SVR12) | SVR12 was defined as HCV RNA less than lower limit of quantification (< LLOQ) (25 IU/mL; target detected or not detected) at follow-up week 12. | Follow-up week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Rapid Virologic Response (RVR) and Extended Rapid Virologic Response (eRVR) | RVR is defined as HCV RNA < LLOQ target not detected at Week 4 and eRVR defined as HCV RNA < LLOQ target not detected at Weeks 4 and 12 | Treatment weeks 4 and 12 | 
| Number of Subjects With Sustained Virologic Response at Post-treatment Week 24 (SVR24) | SVR24 was defined as HCV RNA < LLOQ (25 IU/mL; target detected or not detected) at 24 weeks post treatment. | Follow-up week 24 | 
| Number of Participants With Treatment Emergent Cytopenic Abnormalities | All treated participants were monitored for treatment emergent cytopenic abnormalities (anemia as defined by hemoglobin (Hb) < 10 g/dL, and/or neutropenia as defined by absolute neutrophil count (ANC) < 750 mm3 and/or thrombocytopenia as defined by platelets < 50,000/mm3) during the treatment period (Weeks 1, 2, 4, 6, 8, 12, 20, and 24, and at Weeks 28, 32, 36, 40, 44, and 48 for subjects requiring those visits). | After Day 1 to end of treatment; up to Weeks 24 or 48 | 
| Number of Participants With On-treatment IFN-associated Flu-like or Musculoskeletal Symptoms | All treated participants were monitored for IFN-associated Flu-like and Musculoskeletal symptoms. Flu-like symptoms were defined as pyrexia, chills, or pain. Musculoskeletal symptoms were defined as arthralgia, myalgia, or back pain. Subjects were monitored throughout the treatment period during the treatment period (After day 1 up to week 24, or After day 1 up to week 48 for subjects requiring those visits). | After Day 1 to end of treatment; up to Weeks 24 or 48 | 
| Number of Participants Who Died or Experienced Severe Adverse Events (SAEs), Dose Reductions of Lambda or Discontinuation Due to Adverse Events (AEs) | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that. at any dose, results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. | After Day 1 to end of treatment; up to Weeks 24 or 48 | 
| Number of Participants With Treatment-emergent Grade 3/4 Lab Abnormalities | Grade 3/4 treatment-emergent lab abnormalities that occurred in >=5% of subjects in either cohort are reported. The analysis included all treated subjects up to the end of the treatment period (Day 1 to week 24, or Day 1 to week 48 for subjects requiring those visits). Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. AST = Aspartate aminotransferase, ALT = Alanine aminotransferase. | After Day 1 to end of treatment; up to Weeks 24 or 48 | 
| Mean Change in Absolute CD4 T Lymphocyte Count From Baseline to End of Treatment | All treated participants were monitored for change in Absolute CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants is reported in Cells/µL. | Day 1 to end of treatment; up to week 24 or week 48 | 
| Mean Percent Change in Absolute CD4 T Lymphocyte Count From Baseline to End of Treatment | All treated participants were monitored for percent change in CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants. | Day 1 to end of treatment; up to week 24 or week 48 | 
| Mean Change in Total Lymphocyte Count From Baseline to End of Treatment | All treated participants were monitored for change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants is reported in Cells/µL. | Day 1 to end of treatment; up to week 24 or week 48 | 
| Mean Percent Change in Total Lymphocyte Count From Baseline to End of Treatment | All treated participants were monitored for percent change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants. | Day 1 to end of treatment; up to week 24 or week 48 | 
| Mean Change in Platelet Count From Baseline to End of Treatment | All treated participants were monitored for change in Platelet Count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants (units of measurement = x10^9 cells/L). | Day 1 to end of treatment; up to week 24 or week 48 | 
| Mean Percent Change in Platelet Count From Baseline to End of Treatment | All treated participants were monitored for percent change in Platelet Count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants. | Day 1 to end of treatment; up to week 24 or week 48 |