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Hepatitis BPhase 3HBRNNCT01369212

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

A Phase 3 study testing Tenofovir and Peginterferon-alfa 2a and tenofovir in people with Hepatitis B, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 21 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatitis B
What is being tested?
Tenofovir and Peginterferon-alfa 2a and tenofovir
Could I receive a placebo?
No, everyone receives an active treatment
How many people
201 participants
Where
21 sitesin 2 countries
Study dates
Nov 2012to 8 Mar 2021
Phase
Phase 3

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
  • 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.
  • 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
Show all 12Show fewer
  • 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

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

21 sites in 2 countries.

21 sites in 2 countries

United States20 sites

  • University of Michigan Health System

    Ann Arbor, Michigan, 48109

  • NIH Clinical Center

    Bethesda, Maryland, 20892

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • University of Texas Southwestern

    Dallas, Texas, 75390

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Queen's Medical Center

    Honolulu, Hawaii, 96813

  • Cedars Sinai Medical Center

    Los Angeles, California, 90048

  • University of California Los Angeles

    Los Angeles, California, 90095

  • University of Minnesota

    Plymouth, Minnesota, 55446

  • Virginia Commonwealth University

    Richmond, Virginia, 23498

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • California Pacific Medical Center

    San Francisco, California, 94115

  • University of California San Francisco

    San Francisco, California, 94143

  • Virginia Mason Medical Center

    Seattle, Washington, 98101

  • University of Washington Medical Center

    Seattle, Washington, 98105

  • Saint Louis University

    St Louis, Missouri, 63104

  • Washington University

    St Louis, Missouri, 63110

Other trials in United States

Canada1 site

  • University of Toronto-Toronto Western Hospital

    Toronto, Ontario, M5T 2S8

Other trials in Canada

About this study

Official title: 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).

Read the 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.

Conditions
Hepatitis B
Being tested
Tenofovir, Peginterferon-alfa 2a and tenofovir
Medical subject headings
Hepatitis B

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TenofovirDrug

    Also called Hepatitis B, Viread

    300 mg daily for 192 weeks (4 years)

  • Peginterferon-alfa 2a and tenofovirDrug

    Also called Hepatitis B, PEGASYS, Viread, 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).

Study groups in NCT01369212
Study groupRoleWhat they receive
TenofovirExperimentalTenofovir 192 weeks
Receives: Drug: Tenofovir
Peginterferon-alfa 2a and tenofovirExperimentalA combination of peginterferon-alfa 2a plus tenofovir for 24 weeks and then tenofovir only for 168 weeks
Receives: Drug: Peginterferon-alfa 2a and tenofovir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Week 240

Secondary outcomes (18)

  1. 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

    Measured: Week 192

  2. Number of Participants With Serious Adverse Events

    Number of participants with at least one serious adverse event between randomization and week 240

    Measured: Up to 240 weeks

  3. Number of Participants With Adverse Events

    Number of participants with at least one adverse event between randomization and week 240

    Measured: up to 240 weeks

  4. 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)

    Measured: week 192

  5. 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

    Measured: week 240

  6. Number of Participants With HBsAg Seroconversion at Week 192

    Number of participants who became with HBsAg negative and developed anti-HBs at week 192

    Measured: week 192

  7. Number of Participants With HBsAg Seroconversion at Week 240

    Number of participants who became HBsAg negative and developed anti-HBs at week 240

    Measured: week 240

  8. 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

    Measured: week 192

  9. 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

    Measured: week 240

  10. 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)

    Measured: week 192

  11. 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

    Measured: week 240

  12. Number of Participants With HBV DNA<1000 IU/mL at Week 192

    Number of participants with HBV DNA <1000 IU/mL at week 192

    Measured: week 192

  13. Number of Participants With HBV DNA<1000 IU/mL at Week 240

    Number of participants with HBV DNA <1000 IU/mL at week 240

    Measured: week 240

  14. Number of Participants With HBV DNA<20 IU/mL at Week 192

    Number of participants with HBV DNA<20 IU/mL at week 192

    Measured: week 192

  15. Number of Participants With HBV DNA<20 IU/mL at Week 240

    Number of participants with HBV DNA<20 IU/mL at week 240

    Measured: week 240

  16. Absence of Detectable Antiviral Drug-Resistant HBV Mutations at Week 192

    Absence of detectable antiviral drug-resistant HBV mutations at Week 192

    Measured: week 192

  17. 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

    Measured: Week 240

  18. 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.

    Measured: week 192

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Jun 2011 (estimated)
  2. Study startNov 2012
  3. Primary completion8 Mar 2021
  4. Study completion8 Mar 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
201 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01369212
Sponsor's protocol ID
DK082864 HBRN Immune Active
Other IDs
U01DK082864, U01DK082843, U01DK082863, U01DK082866, U01DK082867, U01DK082871, U01DK082872, U01DK082874
Acronym
HBRN
Status last verified
Apr 2023
First submitted
6 Jun 2011
Last updated
28 Apr 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Data will be available at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository https://repository.niddk.nih.gov/home/

Publications

  • Terrault NA, Sterling R, Lok AS, Ghany MG, Feld JJ, Cloherty G, Wahed AS, Yang X. Hepatitis B Virus RNA as a Biomarker for Safe Antiviral Discontinuation: A Prospective Study of Nucleos(t)ide Analogue Withdrawal. J Infect Dis. 2025 Jun 2;231(5):1290-1298. doi: 10.1093/infdis/jiae541.

    PubMed 39478672

  • Feld JJ, Wahed AS, Fried M, Ghany MG, Di Bisceglie AM, Perrillo RP, Khalili M, Yang X, Belle SH, Janssen HLA, Terrault N, Lok AS; Hepatitis B Research Network (HBRN). Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial. Am J Gastroenterol. 2023 Jul 1;118(7):1226-1236. doi: 10.14309/ajg.0000000000002176. Epub 2023 Jan 13.

    PubMed 36728214

  • Terrault NA, Lok AS, Wahed AS, Ghany MG, Perrillo RP, Fried MW, Wong DK, Khalili M, Lau DTY, Sterling RK, Di Bisceglie AM, Lisker-Melman M, Cooper SL, Chung RT, Patel K, Roberts LR, Belle SH, Janssen HLA; Hepatitis B Research Network. Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B. Am J Gastroenterol. 2023 Jul 1;118(7):1214-1225. doi: 10.14309/ajg.0000000000002125. Epub 2022 Dec 23.

    PubMed 36599136

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