Combination Therapy of Pegylated Interferon Alfa-2a and Tenofovir Versus Tenofovir Monotherapy in Chronic Hepatitis B
NCT ID: NCT01369212
Last Updated: 2023-04-28
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
201 participants
INTERVENTIONAL
2012-11-30
2021-03-08
Brief Summary
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Detailed Description
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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
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Tenofovir
Tenofovir 192 weeks
Tenofovir
300 mg daily for 192 weeks (4 years)
Peginterferon-alfa 2a and tenofovir
A combination of peginterferon-alfa 2a plus tenofovir for 24 weeks and then tenofovir only for 168 weeks
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).
Interventions
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Tenofovir
300 mg daily for 192 weeks (4 years)
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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University of Pittsburgh
OTHER
National Center for Research Resources (NCRR)
NIH
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH
Responsible Party
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Principal Investigators
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Averell Sherker, MD
Role: STUDY_CHAIR
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Edward Doo, MD
Role: STUDY_CHAIR
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Anna Lok, MD
Role: PRINCIPAL_INVESTIGATOR
University of Michigan
Locations
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Cedars Sinai Medical Center
Los Angeles, California, United States
University of California Los Angeles
Los Angeles, California, United States
California Pacific Medical Center
San Francisco, California, United States
University of California San Francisco
San Francisco, California, United States
Queen's Medical Center
Honolulu, Hawaii, United States
NIH Clinical Center
Bethesda, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
University of Michigan Health System
Ann Arbor, Michigan, United States
University of Minnesota
Plymouth, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Saint Louis University
St Louis, Missouri, United States
Washington University
St Louis, Missouri, United States
University of North Carolina
Chapel Hill, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Baylor University Medical Center
Dallas, Texas, United States
University of Texas Southwestern
Dallas, Texas, United States
Virginia Commonwealth University
Richmond, Virginia, United States
Virginia Mason Medical Center
Seattle, Washington, United States
University of Washington Medical Center
Seattle, Washington, United States
University of Toronto-Toronto Western Hospital
Toronto, Ontario, Canada
Countries
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References
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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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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A-DK-3002-001
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
DK082864 HBRN Immune Active
Identifier Type: -
Identifier Source: org_study_id
NCT01821794
Identifier Type: -
Identifier Source: nct_alias
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