Combination Therapy of Pegylated Interferon Alfa-2a and Tenofovir Versus Tenofovir Monotherapy in Chronic Hepatitis B (HBRN)

Combination Therapy of Pegylated Interferon Alfa-2a and Tenofovir Versus Tenofovir Monotherapy in HBeAg-positive and HBeAg-negative Chronic Hepatitis B

This clinical trial compares the efficacy of peginterferon plus tenofovir for 24 weeks followed by monotherapy with tenofovir for a further 3.5 years to the efficacy of tenofovir alone given for 4 years in patients with chronic hepatitis B. The primary measure of outcome will be HBsAg loss in serum at 48 weeks after stopping all antiviral therapy (sustained off-treatment response).

Study Overview

• Status: Completed
• Conditions: Hepatitis B
• Intervention / Treatment: Drug: Tenofovir; Drug: Peginterferon-alfa 2a and tenofovir

Detailed Description

The objective of this study is to compare the long-term efficacy of treatment with combination therapy with peginterferon plus tenofovir versus tenofovir monotherapy in the treatment of chronic hepatitis B.

This is a randomized (1:1) parallel group design trial comparing (i) tenofovir disoproxil fumarate (TDF) 300 mg daily for 192 weeks (4 years) and (ii) peginterferon alfa-2a 180 µg weekly for 24 weeks plus Tenofovir DF 300 mg daily for 192 weeks (4 years). Enrolled participants will be stratified by HBeAg status (positive/negative), genotype (A vs. all others) and cirrhosis (present vs. absent). After 192 weeks of treatment, participants meeting criteria for treatment discontinuation will stop treatment and be followed for 48 weeks (total duration of treatment and follow up is 240 weeks). Emtricitabine/tenofovir coformulated as Truvada, approved for treatment of HIV but not for treatment of hepatitis B virus (HBV) infection, will be offered to patients with primary nonresponse, partial virological response or confirmed virologic breakthrough.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • University of Toronto-Toronto Western Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH Clinical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23498
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98105
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Participant is enrolled in the HBRN Cohort Study (NCT01263587) or completed the necessary components of the cohort baseline evaluation by the end of the baseline visit for this study
• 18 years or older

• Chronic hepatitis B infection as evidenced by at least one of the following:

  1. HBsAg positive result within 8 weeks prior to randomization and another time at least 24 weeks prior to randomization with no HBsAg negative result in between.
  2. HBsAg positive within 8 weeks prior to randomization and HBV DNA ≥1000 IU/mL on 2 occasions at least 24 weeks apart (can include result from screening visit within 8 weeks of randomization)
• Hepatitis B e antigen positive or negative
• Serum HBV DNA ≥1000 IU/mL on 2 occasions at least 4 weeks apart within the 32 weeks prior to randomization (can include result from screening visit within 8 weeks of randomization)
• At least 2 elevated serum alanine aminotransferase (ALT) levels (> 30 U/L for males, >20 U/L for females) 4 weeks apart, and no more than 32 weeks apart, with the second being within 8 weeks of randomization
• Compensated liver disease
• No evidence of hepatocellular carcinoma (HCC)
• Liver biopsy done that shows findings consistent with chronic hepatitis B with histology activity index (HAI) ≥3 (necroinflammatory component only) or Ishak fibrosis score ≥1 or both, as assessed by the local study pathologist on review of a liver biopsy done within 144 weeks of randomization
• Females of child bearing potential must agree to use an adequate method of contraception throughout the study and must have a negative pregnancy test immediately prior to the start of treatment

Exclusion criteria:

• Serum ALT ≥450 U/L for males and ≥300 U/L for females
• Treatment with interferon or nucleos(t)ide analogues for hepatitis B within 48 weeks of randomization
• More than 48 weeks of therapy with nucleos(t)ide analogues for hepatitis B at any time in the past
• History of hepatic decompensation including but not limited to ascites, variceal bleeding, or hepatic encephalopathy
• Known allergy or intolerance to any of the study medications
• Females who are pregnant or breastfeeding
• Previous organ transplantation including engrafted bone marrow transplant
• Any other concomitant liver disease, including hemochromatosis, hepatitis C or D; Participants with severe steatohepatitis will be excluded (participants with non-alcoholic fatty liver disease [NAFLD] with steatosis only and/or mild to moderate steatohepatitis are acceptable)
• Positive anti-HIV
• Renal insufficiency with calculated (by Modification of Diet in Renal Disease (MDRD) method) creatinine clearance <60 mL/min within 8 weeks prior to randomization
• Platelet count <90,000 /mm3, hemoglobin <13 g/dL (males) or <12 g/dL (females), absolute neutrophil count <1500 /mm^3 (<1000/mm^3 for African-Americans) within 8 weeks prior to randomization
• History of active alcohol or drug abuse within 48 weeks of screening.
• Pre-existing psychiatric condition(s), including but not limited to: Current moderate or severe depression as determined by the study physician, history of depression requiring hospitalization within past 10 years, history of suicidal or homicidal attempt within the past 10 years, or history of severe psychiatric disorders including but not limited to schizophrenia, psychosis, bipolar disorder
• History of immune-mediated disease, or cerebrovascular, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease, poorly controlled diabetes or uncontrolled seizure disorder
• Any medical condition that would be predicted to be exacerbated by therapy or that would limit study participation
• Any medical condition requiring or likely to require chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study
• Evidence of active or suspected malignancy, or a history of malignancy within the last 144 weeks (except adequately treated carcinoma in situ or basal cell carcinoma of the skin)
• Need for ongoing use of any antivirals with activity against HBV during the course of the study
• Any other condition that in the opinion of the investigator would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.
• Participation in any other clinical trial involving investigational drugs within 30 days of randomization or intention to participate in another clinical trial during this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenofovir; Tenofovir 192 weeks	Drug: Tenofovir; 300 mg daily for 192 weeks (4 years); Other Names: Viread; Hepatitis B
Experimental: Peginterferon-alfa 2a and tenofovir; A combination of peginterferon-alfa 2a plus tenofovir for 24 weeks and then tenofovir only for 168 weeks	Drug: Peginterferon-alfa 2a and tenofovir; A combination of peginterferon-alfa 2a 180 µg weekly plus tenofovir 300 mg daily for 24 weeks and then only tenofovir 300 mg daily for 168 weeks (3.5 years).; Other Names: Viread; PEGASYS; tenofovir; Hepatitis B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants With Hepatitis B Surface Antigen (HBsAg) Loss by Week 240	Estimated percent of participants who became HBsAg negative by week 240 from randomization	Week 240

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Percent of Participants With HBsAg Loss at Week 192	Cumulative percentage of participants with HBsAg loss at week 192 estimated using Kaplan-Meier method	Week 192
Number of Participants With Serious Adverse Events	Number of participants with at least one serious adverse event between randomization and week 240	Up to 240 weeks
Number of Participants With Adverse Events	Number of participants with at least one adverse event between randomization and week 240	up to 240 weeks
Number of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 192	Number of participants who became Hepatitis B e antigen (HBeAg) negative at week 192 among HBeAg positive participants at randomization (baseline)	week 192
Number of Participants With HBeAg Loss at Week 240	Number of participants who became HBeAg negative at week 240 among HBeAg positive participants at baseline	week 240
Number of Participants With HBsAg Seroconversion at Week 192	Number of participants who became with HBsAg negative and developed anti-HBs at week 192	week 192
Number of Participants With HBsAg Seroconversion at Week 240	Number of participants who became HBsAg negative and developed anti-HBs at week 240	week 240
Number of Participants With HBeAg Seroconversion at Week 192	Number of participants who became HBeAg negative and developed anti-HBe at week 192 among HBeAg positive participants at baseline	week 192
Number of Participants With HBeAg Seroconversion at Week 240	Number of participants who became HBeAg negative and developed anti-HBe at week 240 among HBeAg positive participants at baseline	week 240
Number of Participants With Normal Alanine Transaminase (ALT) Levels at Week 192	Number of participants with normal alanine transaminase (ALT) levels at week 192 (Normal ALT for males ≤30 U/L, for females ≤20 U/L)	week 192
Number of Participants With Normal Alanine Transaminase (ALT) Levels at Week 240	Number of participants with normal alanine transaminase (ALT) levels [males ≤30 U/L, for females ≤20 U/L] at week 240	week 240
Number of Participants With HBV DNA<1000 IU/mL at Week 192	Number of participants with HBV DNA <1000 IU/mL at week 192	week 192
Number of Participants With HBV DNA<1000 IU/mL at Week 240	Number of participants with HBV DNA <1000 IU/mL at week 240	week 240
Number of Participants With HBV DNA<20 IU/mL at Week 192	Number of participants with HBV DNA<20 IU/mL at week 192	week 192
Number of Participants With HBV DNA<20 IU/mL at Week 240	Number of participants with HBV DNA<20 IU/mL at week 240	week 240
Absence of Detectable Antiviral Drug-Resistant HBV Mutations at Week 192	Absence of detectable antiviral drug-resistant HBV mutations at Week 192	week 192
Cumulative Percent of Participants With HBsAg Loss at Week 240	Cumulative percent of participants with HBsAg loss at week 240 estimated using Kaplan-Meier method	Week 240
Number of Participants With Alanine Transaminase(ALT) Levels <= 38 U/L for Males and <=25 for Females at Week 192	Number of participants with alanine transaminase(ALT) levels <= 38 U/L for males and <=25 for females at week 192. The cut-offs 38 and 25 are approximately 1.25 times the upper limit of normal (30 U/L for males and 20 U/L for females) respectively.	week 192

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: University of Pittsburgh; National Center for Research Resources (NCRR)
• Investigators: Study Chair: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Study Chair: Edward Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Principal Investigator: Anna Lok, MD, University of Michigan

Publications and helpful links

Helpful Links

• Hepatitis B Research Network

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): March 8, 2021
• Study Completion (Actual): March 8, 2021

Study Registration Dates

• First Submitted: June 6, 2011
• First Submitted That Met QC Criteria: June 7, 2011
• First Posted (Estimate): June 8, 2011

Study Record Updates

• Last Update Posted (Actual): April 28, 2023
• Last Update Submitted That Met QC Criteria: April 25, 2023
• Last Verified: April 1, 2023

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, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Peginterferon alfa-2a
• Other Study ID Numbers: DK082864 HBRN Immune Active; UL1RR024986 (U.S. NIH Grant/Contract); UL1TR001111 (U.S. NIH Grant/Contract); U01DK082864 (U.S. NIH Grant/Contract); U01DK082874 (U.S. NIH Grant/Contract); U01DK082944 (U.S. NIH Grant/Contract); U01DK082843 (U.S. NIH Grant/Contract); U01DK082871 (U.S. NIH Grant/Contract); UL1TR000004 (U.S. NIH Grant/Contract); A-DK-3002-001 (Other Grant/Funding Number: Interagency agreement with NIDDK); U01DK082863 (U.S. NIH Grant/Contract); U01DK082866 (U.S. NIH Grant/Contract); U01DK082867 (U.S. NIH Grant/Contract); U01DK082872 (U.S. NIH Grant/Contract); U01DK082919 (U.S. NIH Grant/Contract); U01DK082923 (U.S. NIH Grant/Contract); U01DK082927 (U.S. NIH Grant/Contract); U01DK082943 (U.S. NIH Grant/Contract); UL1TR000058 (U.S. NIH Grant/Contract); P30DK050306 (U.S. NIH Grant/Contract); M01RR000040 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository https://repository.niddk.nih.gov/home/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No