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Tenofovir DF With or Without Peginterferon for Chronic Hepatitis B

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Chronic Hepatitis B e Antigen Negative; Chronic Hepatitis B e Antigen Positive

Intervention: Peginterferon and Tenofovir (Drug)

Phase: Phase 3

Status: Recruiting

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

Official(s) and/or principal investigator(s):
Marc G Ghany, M.D., Principal Investigator, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall contact:
Elenita Rivera, R.N., Phone: (301) 496-3531, Email: erivera@cc.nih.gov

Summary

Background:

- There are two forms of chronic hepatitis B. The difference between the forms is whether or

not a viral protein called hepatitis B e antigen is present in the blood. Standard approaches to treating both forms of chronic hepatitis B involve different drugs. One drug is called peginterferon, another is called tenofovir DF. These drugs are often given separately and used for different forms of the disease. However, researchers want to see if combining peginterferon and tenofovir DF will be a more effective treatment than tenofovir DF alone. Objectives:

- To see whether combining tenofovir DF and peginterferon, or using tenofovir DF alone, is a

more effective treatment of chronic hepatitis B. Eligibility:

- Individuals at least 18 years of age who have chronic hepatitis B and are in the Hepatitis

B Research Network Cohort study. Design:

- Participants will be screened with a physical exam and medical history. Blood, urine,

and liver tissue samples will be collected. Bone and liver imaging studies will also be performed.

- Participants will be divided into two groups. One group will have tenofovir DF alone

for 192 weeks (about 4 years). The other group will have tenofovir DF and peginterferon for 24 weeks (about 6 months), and then tenofovir DF alone for 168 weeks (about 3. 5 years).

- Participants will take the study drugs on the schedule determined by their study

doctors. They will keep a diary to record their doses and any side effects.

- Participants will have three study visits 4 weeks apart after the starting the

treatment. At these visits, they will have a physical exam and provide blood samples. They may also provide urine samples and have imaging studies.

- After the first three study visits, participants will continue to have study visits

every 12 weeks until the treatment ends at week 192. These visits will have many of the same tests as the first three visits. At some of these visits, they may fill out questionnaires about their quality of life.

- Participants who do not respond to the study drugs may have their medications changed.

They may also be asked to stop treatment.

Clinical Details

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

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

Primary outcome: HBsAg loss at the end of 48-weeks post-treatment follow-up (week 240)

Secondary outcome:

ALT normalization

Cumulative HBsAg loss

HBsAg seroconversion

HBeAg loss

ALT corresponding to approx 1.25XULN

HBV DNA & lt; 1000 IU/mL

HBV DNA & lt; 20 IU/m

Absence antiviral drug-resistance HBV mu

Sustained HBV DNA less than 1000 IU/mL

Rate treatment discontinuation due to AE

Rates of AE and SAE

HBV DNA & lt; 1000IU/mL & amp; ALT approx 1.25XULN

Rate of treatment failure

Detailed description: 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 micrograms/g 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 180-192) to assess improvement in histology. Emtricitabine/tenofovir coformulated as Truvada, approved for treating HIV but not for treating HBV infection, will be offered to participants with primary nonresponse, partial virological response or confirmed virologic breakthrough.

Eligibility

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

Criteria:

- INCLUSION CRITERIA:

1. Enrolled in the Hepatitis B Research Network (HBRN) Cohort Study or completed the necessary components of the Cohort baseline evaluation by the end of the baseline visit for this study. 2. At least 18 years of age at the time of randomization (day 0). 3. Chronic HBV 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 plus absence of detectable anti-HBc IgM in serum within 8 weeks prior to randomization. 3. HBsAg positive within 8 weeks prior to randomization and HBV DNA greater than or equal to 1,000 IU/mL on 2 occasions at least 24 weeks apart (can include result from screening visit within 8 weeks of randomization). 4. HBsAg positive within 8 weeks prior to randomization plus evidence of chronic hepatitis B infection as indicated by a liver biopsy within 144 weeks of randomization 4. HBeAg positive or negative. 5. Serum HBV DNA greater than or equal to 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). 6. At least two elevated serum ALT levels (> 45 U/L for males and > 30 U/L for females) at least 4 weeks, and no more than 32 weeks apart with the second being within 8 weeks of randomization. 7. Compensated liver disease, with total bilirubin less than or equal to 2 mg/dL (except if Gilbert s syndrome), direct bilirubin less than or equal to 0. 5 mg/dL, INR less than or equal to 1. 5, and serum albumin greater than or equal to 3. 5 g/dL 8. No evidence of HCC based upon alpha-fetoprotein (AFP) less than or equal to 20ng/mL within 8 weeks prior to randomization: 1. Participants who meet AASLD criteria for HCC surveillance must have negative liver imaging by ultrasound (US), computerized tomography (CT) or magnetic resonance imaging (MR) within 28 weeks of randomization as part of standard of care. 2. Participants with AFP > 20 ng/mL must be evaluated clinically with additional imaging and shown not to have HCC on CT or MRI. 9. Liver biopsy that shows findings consistent with chronic hepatitis B with the Modified Ishak histology activity index (HAI) greater than or equal to 3 (necroinflammatory component only) or Ishak fibrosis score greater than or equal to 1 or both, as assessed by the local consortium pathologist on review of a liver biopsy done within 144 weeks of randomization. Slides must be available for review by the local consortium pathologist and meet adequacy requirements. If the participant had received previous treatment for hepatitis B, the biopsy must have been done after discontinuation of treatment. 10. 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. 11. Provide informed consent and agree to adhere to the requirements of the study. EXCLUSION CRITERIA: 1. Serum ALT > 450 U/L for males and > 300 U/L for females (participants are eligible for re-screening if ALT levels fall to the range of eligibility). 2. Treatment with interferon or nucleos(t)ide analogues for hepatitis B within 48 weeks of randomization. 3. More than 48 weeks of therapy with nucleos(t)ide analogues for hepatitis B at any time in the past. 4. History of hepatic decompensation including, but not limited to, ascites, variceal bleeding, or hepatic encephalopathy. 5. Known allergy or intolerance to any of the study medications. 6. Females who are pregnant or breastfeeding. 7. Previous organ transplantation including engrafted bone marrow transplant. 8. Any other concomitant liver disease, including hemochromatosis or hepatitis C or D. Non-alcoholic fatty liver disease (NAFLD) with steatosis and/or mild to moderate steatohepatitis is acceptable but NALFD with severe steatohepatitis is exclusionary. 9. Positive anti-HIV (test to be completed within 8 weeks prior to randomization). 10. Renal insufficiency with calculated (by MDRD method) creatinine clearance < 60 mL/min within 8 weeks prior to randomization. 11. 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) within 8 weeks prior to randomization. 12. History of alcohol or drug abuse within 48 weeks of randomization. 13. Pre-existing psychiatric condition(s), including, but not limited to: 1. Current moderate or severe depression as determined by the study physician. 2. History of depression requiring hospitalization within past 10 years. 3. History of suicidal or homicidal attempt within the past 10 years. 4. History of severe psychiatric disorders including, but not limited to, schizophrenia, psychosis, bipolar disorder as determined by a study physician. 14. 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, as determined by a study physician. 15. Any medical condition that would, in the opinion of a study physician be predicted to be exacerbated by therapy or that would limit study participation. 16. Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study. 17. Evidence of active or suspected malignancy, or a history of malignancy within the last 144 weeks prior to randomization (except adequately treated carcinoma in situ or basal cell carcinoma of the skin). 18. Expected need for ongoing use of any antivirals with activity against HBV during the course of the study. 19. Participation in any other clinical trial involving investigational drugs within 30 days of randomization or intention to participate in another clinical trial involving investigational drugs during participation in this study. 20. Any other condition that in the opinion of a study physician would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.

Locations and Contacts

Elenita Rivera, R.N., Phone: (301) 496-3531, Email: erivera@cc.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL), Phone: 800-411-1222, Ext: TTY8664111010, Email: prpl@mail.cc.nih.gov

Mayo Clinic, Rochester, Rochester, Minnesota 55905, United States; Recruiting

Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007 Apr;45(4):1056-75. Review.

Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112-25. Epub 2006 Jun 5. Review.

Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. Erratum in: Hepatology. 2007 Jun;45(6):1347.

Starting date: March 2013
Last updated: April 30, 2015

Page last updated: August 23, 2015

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