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

National Institutes of Health (NIH)

Status and phase

Completed

Phase 3

Conditions

Hepatitis B

Treatments

Drug: Peginterferon-alfa 2a and tenofovir

Drug: Tenofovir

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01369212

M01RR000040 (U.S. NIH Grant/Contract)

P30DK050306 (U.S. NIH Grant/Contract)

U01DK082866 (U.S. NIH Grant/Contract)

U01DK082867 (U.S. NIH Grant/Contract)

A-DK-3002-001 (Other Grant/Funding Number)

U01DK082874 (U.S. NIH Grant/Contract)

U01DK082863 (U.S. NIH Grant/Contract)

U01DK082927 (U.S. NIH Grant/Contract)

UL1TR001111 (U.S. NIH Grant/Contract)

UL1TR000058 (U.S. NIH Grant/Contract)

UL1RR024986 (U.S. NIH Grant/Contract)

U01DK082871 (U.S. NIH Grant/Contract)

U01DK082944 (U.S. NIH Grant/Contract)

U01DK082943 (U.S. NIH Grant/Contract)

U01DK082872 (U.S. NIH Grant/Contract)

U01DK082919 (U.S. NIH Grant/Contract)

UL1TR000004 (U.S. NIH Grant/Contract)

U01DK082843 (U.S. NIH Grant/Contract)

U01DK082864 (U.S. NIH Grant/Contract)

DK082864 HBRN Immune Active

U01DK082923 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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).

Full 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.

Enrollment

201 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.