Dose Ranging Study of Pegylated Interferon Lambda in Patients With Hepatitis B and Positive for the Hepatitis B e Antigen

Study Overview
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Brief Summary
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At least 1 dose of pegIFNλ will be identified which is safe, well tolerated, and efficacious for the treatment of chronic hepatitis B virus infection (CHB) Amendment 7, Part B Sub Study: The primary purpose of this amendment is to obtain preliminary data on the safety of pegylated interferon Lambda (Lambda) when administered in combination with Entecavir(ETV) to patients with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B(CHB) infection employing a sequential therapy approach

Detailed Description
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Part B sub study is Open Label

Official Title
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Dose-Ranging Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Pegylated Interferon Lambda (BMS-914143) Monotherapy in Interferon-Naive Patients With Chronic Hepatitis B Virus Infection Who Are HBeAg-positive

Conditions
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Hepatitis B Virus

Intervention / Treatment
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* Drug: pegIFN
* Drug: pegIFNα-2a
* Drug: PegIFN lambda
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infection with the hepatitis B virus (HBV) and positive for the hepatitis B e antigen Between the ages of 18 and 70 Have not been previously treated with an interferon HBV nucleos(t)ide-naive Exclusion Criteria: Not infected with the hepatitis C virus (HCV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV) Do not have a serious liver, psychiatric, blood, thyroid, lung, heart or eye disease Able to tolerate oral medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Arm 1: pegIFN (180 μg)<br> | Drug: pegIFN<br>* Syringe, Subcutaneous, 180 μg, Once Weekly, 48 weeks<br>|
| Active Comparator: Part A Arm 2: pegIFNα-2a<br> | Drug: pegIFNα-2a<br>* Syringe, Subcutaneous 180 μg, Once Weekly, 48 Weeks<br>* Other names: Pegasys;|
| Experimental: Part B: pegIFN lambda + Entecavir<br> | Drug: PegIFN lambda<br>* Syringe, Subcutaneous, 180 µg, Once weekly, 48 weeks<br>* Other names: BMS-914143;Drug: Entecavir<br>* Tablet, Oral, 0.5 mg, Once daily, 12 weeks initial monotherapy followed by 48 weeks of combination therapy with PegIFN lambda<br>* Other names: Baraclude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Proportion of subjects who achieve Hepatitis B e antigen (HBeAg) seroconversion |  | 24 weeks post-dosing (Week 72) | 
| Part A: Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events |  | Week 24 | 
| Part A: Number and percent of subjects with serious adverse events (SAEs) and discontinuations due to adverse events |  | 24 weeks post-dosing (Week 72) | 
| Part B: Safety and tolerability of Lambda/ETV regimen as measured by the frequency of SAEs and discontinuations due to AEs |  | Up to 84 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Proportion of subjects who achieve an hepatitis B virus Deoxyribonucleic acid levels (HBV DNA) < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - High Pure System (HPS) assay |  | Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | 
| Part A: Mean change from baseline in log10 HBV DNA levels over time (Proportion of subjects with Alanine amino transferase (ALT) normalization (≤ 1 x upper limit of normal (ULN)) |  | Baseline (Day 1), Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | 
| Part A: Proportion of subjects with ALT normalization (≤ 1 x ULN) |  | Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | 
| Part A: Hepatitis E antigen (HBeAg) loss |  | Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | 
| Part A: HBeAg seroconversion |  | Weeks 24, 48, 96, 120, 144, 168 and 192 | 
| Part A: Mean change from baseline in log10 quantitative HBeAg levels over time |  | Baseline (Day 1), Weeks 24, 48, 96, 120, 144, 168 and 192 | 
| Part A: Number and percent of subjects with adverse events (AEs) or laboratory abnormalities |  | Up to Week 24 | 
| Part A: Number and percent of subjects with adverse events (AEs) or laboratory abnormalities |  | Up to Week 72 | 
| Part A: Pharmacokinetic (PK) parameter Maximum observed concentration (Cmax) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part A: Pharmacokinetic (PK) parameter Time of maximum observed concentration (Tmax) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part A: Pharmacokinetic (PK) parameter Trough serum concentration pre-dose (C0) of Pegylated interferon lambda (pegIFNλ) will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part A: PK parameter serum concentration 168 hours post observed dose [Cmin] (C0 will be used as an estimate of Cmin if sample is not collected) of pegIFNλ will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part A: PK parameter Area under the concentration-time curve in 1 dosing interval from time 0 to 168 hours post observed dose [AUC(TAU)] of pegIFNλ will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part A: PK parameter Accumulation index (AI) ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose (only conducted if data warrant) of pegIFNλ will be derived from serum concentration versus time data |  | Day 1 (including intense PK), Weeks 2, 4, 12 (including intense PK), 16, 24, 40, 48 | 
| Part B: HBeAg seroconversion rate at 24 weeks off treatment |  | Week 84 | 
| Part B: Antiviral activity of Lambda/ETV regimen, as determined by the proportion of subjects who achieve an HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche COBAS® TaqMan - HPS assay |  | Weeks 4, 8, 12, 24, 36, 60, and 84 | 
| Part B: Mean change from baseline in HBV DNA over time in subjects treated with Lambda/ETV |  | Weeks 4, 8, 12, 24, 36, 60, and 84 | 
| Part B: HBeAg loss and seroconversion in subjects treated with Lambda/ETV regimen |  | Weeks 12, 24, 36, 60 and 84 | 
| Part B: HBeAg levels over time in subjects treated with Lambda/ETV regimen |  | Weeks 4, 8, 12, 24, 36, 60, and 84 | 
| Part B: biochemical response rates in subjects treated with Lambda/ETV regimen |  | Weeks 4, 8, 12, 24, 36, 60, and 84 | 
| Part B: Pharmacokinetic (PK) parameter Maximum observed concentration (Cmax) of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: Pharmacokinetic (PK) parameter Time of maximum observed concentration (Tmax) of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: Pharmacokinetic (PK) parameter Trough serum concentration pre-dose (C0) of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: PK parameter Area under the concentration-time curve in 1 dosing interval from time 0 to 168 hours post observed dose [AUC(TAU)] of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: PK parameter serum concentration 168 hours post observed dose [Cmin] (C0 will be used as an estimate of Cmin if sample is not collected) of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: PK parameter Accumulation index (AI) ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose (only conducted if data warrant) of Lambda/ETV regimen will be derived from serum concentration versus time data |  | Baseline (Day 1), Weeks 4, 12, 16, 24, 52, 60 | 
| Part B: Rate of resistance to ETV during treatment with the Lambda/ETV regimen |  | Up to Week 84 |