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

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

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

Study Overview

• Status: Completed
• Conditions: Hepatitis B Virus
• Intervention / Treatment: Drug: pegIFN; Drug: pegIFNα-2a; Drug: PegIFN lambda; Drug: Entecavir

Detailed Description

Part B sub study is Open Label

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Local Institution
    • Liverpool, New South Wales, Australia, 2170
      • Local Institution
    • Westmead Nsw, New South Wales, Australia, 2145
      • Local Institution
  • Victoria
    • Clayton Vic, Victoria, Australia, 3168
      • Local Institution
    • Heidelberg Vic, Victoria, Australia, 3084
      • Local Institution
    • Melbourne, Victoria, Australia, 3004
      • Local Institution
  • Western Australia
    • Fremantle, Western Australia, Australia, 6160
      • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Heritage Medical Research Clinic, University of Calgary
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Local Institution
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital University Health Network
• France
  • Clichy Cedex, France, 92118
    • Local Institution
  • Nice Cedex 03, France, 06202
    • Local Institution
  • Paris Cedex 12, France, 75571
    • Local Institution
  • Rennes Cedex 9, France, 35033
    • Local Institution
• Germany
  • Frankfurt, Germany, 60590
    • Local Institution
  • Freiburg, Germany, 79106
    • Local Institution
  • Hamburg, Germany, 20246
    • Local Institution
  • Hannover, Germany, 30625
    • Local Institution
  • Tuebingen, Germany, 72076
    • Local Institution
• Hong Kong
  • Hong Kong, Hong Kong, 852
    • Local Institution
  • Shatin, Hong Kong, 30-32
    • Local Institution
  • Tai Po, Hong Kong, 852
    • Local Institution
• Italy
  • Firenze, Italy, 50012
    • Local Institution
  • Roma, Italy, 00161
    • Local Institution
• Korea, Republic of
  • Chuncheon, Korea, Republic of, 200-704
    • Local Institution
  • Gyeonggi-Do, Korea, Republic of, 480-717
    • Local Institution
  • Seoul, Korea, Republic of, 120-752
    • Local Institution
  • Seoul, Korea, Republic of, 135-710
    • Local Institution
  • Seoul, Korea, Republic of, 138-736
    • Local Institution
  • Seoul, Korea, Republic of, 135-720
    • Local Institution
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Local Institution
• Singapore
  • Singapore, Singapore, 169608
    • Local Institution
  • Singapore, Singapore, 119228
    • Local Institution
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Local Institution
  • Taichung, Taiwan, 404
    • Local Institution
  • Tainan, Taiwan, 704
    • Local Institution
  • Taipei, Taiwan, 100
    • Local Institution
  • Taipei, Taiwan, 114
    • Local Institution
  • Taoyuan, Taiwan, 333
    • Local Institution
• United States
  • California
    • Anaheim, California, United States, 92801
      • Advanced Clinical Research Institute
    • Garden Grove, California, United States, 92844
      • SC Clinical Research, Inc.
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center
    • San Diego, California, United States, 92105
      • Research and Education, Inc.
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Associates, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Colombia, Maryland, United States, 21045
      • Gastro Center of Maryland
  • New York
    • Flushing, New York, United States, 11355
      • Medical Procare, PLLC
    • Flushing, New York, United States, 11355
      • Office Of Sing Chan Md
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Phillips S, Mistry S, Riva A, Cooksley H, Hadzhiolova-Lebeau T, Plavova S, Katzarov K, Simonova M, Zeuzem S, Woffendin C, Chen PJ, Peng CY, Chang TT, Lueth S, De Knegt R, Choi MS, Wedemeyer H, Dao M, Kim CW, Chu HC, Wind-Rotolo M, Williams R, Cooney E, Chokshi S. Peg-Interferon Lambda Treatment Induces Robust Innate and Adaptive Immunity in Chronic Hepatitis B Patients. Front Immunol. 2017 May 29;8:621. doi: 10.3389/fimmu.2017.00621. eCollection 2017.
• Chan HLY, Ahn SH, Chang TT, Peng CY, Wong D, Coffin CS, Lim SG, Chen PJ, Janssen HLA, Marcellin P, Serfaty L, Zeuzem S, Cohen D, Critelli L, Xu D, Wind-Rotolo M, Cooney E; LIRA-B Study Team. Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B). J Hepatol. 2016 May;64(5):1011-1019. doi: 10.1016/j.jhep.2015.12.018. Epub 2015 Dec 29.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: September 16, 2010
• First Submitted That Met QC Criteria: September 16, 2010
• First Posted (ESTIMATE): September 17, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 9, 2015
• Last Update Submitted That Met QC Criteria: September 23, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Anti-Infective Agents; Antiviral Agents; Entecavir
• Other Study ID Numbers: AI452-005; 2010-020387-38 (EUDRACT_NUMBER)