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

Condition(s) targeted: Hepatitis B

Intervention: Tenofovir (Drug); Combination of peginterferon alfa 2a and tenofovir (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Official(s) and/or principal investigator(s):
Averell Sherker, MD, Study Chair, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Edward Doo, MD, Study Chair, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Anna Lok, MD, Principal Investigator, Affiliation: University of Michigan

Overall contact:
Jennifer A Dobberstein, MS, Phone: 412-624-5555, Email: jad183@pitt.edu

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 sustained HBsAg loss in serum one year after stopping all antiviral therapy (sustained off-treatment response).

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Hepatitis B surface antigen (HBsAg) loss

Secondary outcome:

Cumulative HBsAg loss

Cumulative HBsAg loss

Serious Adverse Events

Adverse events

Hepatitis B e antigen (HBeAg) loss

Hepatitis B e antigen (HBeAg) loss

HBeAg loss

HBsAg seroconversion

HBsAg seroconversion

HBsAg seroconversion

HBeAg seroconversion

HBeAg seroconversion

HBeAg seroconversion

Normalization of Alanine Transaminase(ALT) levels

Normalization of Alanine Transaminase(ALT) levels

Normalization of Alanine Transaminase(ALT) levels

Proportion with HBV DNA ≤1000 IU/mL

Proportion with HBV DNA ≤1000 IU/mL

Proportion with HBV DNA ≤1000 IU/mL

Proportion with HBV DNA <20 IU/mL

Proportion with HBV DNA <20 IU/mL

Proportion with HBV DNA <20 IU/mL

Absence of detectable antiviral drug-resistance HBV mutations

Stable or improved Ishak fibrosis score compared to pre-treatment

Improved necroinflammation defined by HAI reduction of ≥2 points (compared to pre-treatment).

Sustained HBV DNA <1000 IU/ml AND "mild" histology defined as HAI ≤3 AND improvement in Ishak fibrosis score by ≥ 1

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 DF 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). A liver biopsy will be obtained at the end-of-treatment (week 192) to assess improvement in histology. Emtricitabine/tenofovir coformulated as Truvada, approved for treatment of HIV but not for treatment of HBV infection, will be offered to patients with primary nonresponse, partial virological response or confirmed virologic breakthrough.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion criteria:

- Participant is enrolled in the HBRN Cohort Study (NCT01263587) and has completed the

baseline evaluation

- 18 years or older

- Chronic hepatitis B infection as evidenced by either of the following:

1. HBsAg positive result at screening (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 plus absence of detectable anti-HBc IgM in serum at screening (within 8 weeks prior to randomization).

- Hepatitis B e antigen positive or negative

- Serum HBV DNA ≥1000 IU/mL on 2 occasions at least 4 weeks, and no more than 24 weeks,

apart with the second being within 8 weeks of randomization

- Two elevated serum ALT levels 4 weeks apart, and no more than 24 weeks apart, with

the second being within 8 weeks of randomization

- Treatment Naive for the last 48 weeks

- Compensated liver disease

- No evidence of HCC

- Liver biopsy (done as standard of care) that shows findings consistent with chronic

hepatitis B with histology activity index (HAI) ≥5 (necroinflammatory component only) or Ishak fibrosis score ≥2 or both, as assessed by the local study pathologist on review of a liver biopsy done within 96 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 IU/L for males and ≥300 IU/L for females

- History of hepatic decompensation including but not limited to ascites, variceal

bleeding, or hepatic encephalopathy

- Liver biopsy with ≥3+/4 iron in hepatocytes by Prussian blue stain

- 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 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 MDRD method) creatinine clearance <50 mL/min,

at the screening visit

- Platelet count <90,000 /mm3, hemoglobin <13 g/dl (males) or <12 g/dl (females),

absolute neutrophil count <1500 /mm3 (<1000/mm3 for African-Americans) during the screening visit

- 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 and 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.

Jennifer A Dobberstein, MS, Phone: 412-624-5555, Email: jad183@pitt.edu

University of California Los Angeles, Los Angeles, California 90095, United States; Not yet recruiting
Steven Han, MD, Phone: 310-206-0645, Email: steven.han@ucla.edu

Cedars Sinai Medical Center, Los Angeles, California 90048, United States; Not yet recruiting
Tram Tran, MD, Phone: 310-423-1971, Email: tram.tran@cshs.org

University of California San Francisco, San Francisco, California 94143, United States; Recruiting
Norah Terrault, Phone: 415-476-2227, Email: norah.terrault@ucsf.edu

California Pacific Medical Center, San Francisco, California 94115, United States; Recruiting
Stewart Cooper, MD, Phone: 415-600-1548, Email: coopersl@sutterhealth.org

Queen's Medical Center - Liver Center, Honolulu, Hawaii 96813, United States; Recruiting
Naoky Tsai, MD, Phone: 808-691-7609, Email: naoky@hawaii.edu

NIH Clinical Center, Bethesda, Maryland 20892, United States; Not yet recruiting
Marc Ghany, MD, Phone: 301-402-5115, Email: marcg@intra.niddk.nih.gov

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States; Not yet recruiting
Darryl Lau, MD, Phone: 617-362-1098, Email: dlau@bidmc.harvard.edu

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Not yet recruiting
Ray Chung, MD, Phone: 617-724-7562, Email: rtchung@partners.org

University of Michigan Health System, Ann Arbor, Michigan 48109, United States; Recruiting
Anna Lok, MD, Phone: 734-936-7511, Email: aslok@med.umich.edu

University of Minnesota, Plymouth, Minnesota 55446, United States; Not yet recruiting
Coleman Smith, MD, Phone: 612-871-1145, Ext: 2908, Email: smith146@umn.edu

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
W. Ray Kim, MD, Phone: 507-538-0254, Email: kim.woong@mayo.edu

Saint Louis University, St. Louis, Missouri 63104, United States; Recruiting
Adrian Di Bisceglie, MD, Phone: 314-577-8551, Email: dibiscam@slu.edu

Washington University, St. Louis, Missouri 63110, United States; Recruiting
Mauricio Lisker-Melman, MD, Phone: 314-747-3969, Email: mlisker@dom.wustl.edu

University of North Carolina, Chapel Hill, North Carolina 27599, United States; Recruiting
Micheal Fried, MD, Phone: 919-966-2516, Email: mfried@med.unc.edu

Duke University Medical Center, Durham, North Carolina 27710, United States; Recruiting
Keyur Patel, MD, Phone: 919-681-4044, Email: keyur.patel@duke.edu

University of Toronto-Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada; Recruiting
David Wong, MD, Phone: 416-603-5800, Ext: 5118, Email: dave.wong.uhn@gmail.com

Baylor University Medical Center, Dallas, Texas 75246, United States; Not yet recruiting
Robert Perrillo, MD, Phone: 214-820-2956, Email: roberper@baylorhealth.edu

University of Texas Southwestern, Dallas, Texas 75390, United States; Not yet recruiting
William Lee, MD, Phone: 214-645-6110, Email: william.lee@utsouthwestern.edu

Virginia Commonwealth University, Richmond, Virginia 23498, United States; Recruiting
Richard Sterling, MD, Phone: 804-828-4060, Email: rksterli@vcu.edu

University of Washington Medical Center, Seattle, Washington 98105, United States; Not yet recruiting
Robert Caithers, MD, Phone: 206-598-4956, Email: doctorc@u.washington.edu

Virginia Mason Medical Center, Seattle, Washington 98101, United States; Not yet recruiting
Kris Kowdley, MD, Phone: 206-223-2319, Email: kkowdley@benaroyaresearch.org

Hepatitis B Research Network

Starting date: October 2012
Last updated: December 20, 2012