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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir
* Drug: Peginterferon-alfa 2a and tenofovir


Participation Criteria
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Eligibility Criteria
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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: 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir<br>Tenofovir 192 weeks | Drug: Tenofovir<br>* 300 mg daily for 192 weeks (4 years)<br>* Other names: Viread;|
| Experimental: Peginterferon-alfa 2a and tenofovir<br>A combination of peginterferon-alfa 2a plus tenofovir for 24 weeks and then tenofovir only for 168 weeks | Drug: Peginterferon-alfa 2a and tenofovir<br>* 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).<br>* Other names: tenofovir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Week 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Week 192 | 
| Number of Participants With Serious Adverse Events | Number of participants with at least one serious adverse event between randomization and week 240 | Up to 240 weeks | 
| Number of Participants With Adverse Events | Number of participants with at least one adverse event between randomization and week 240 | up to 240 weeks | 
| 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) | week 192 | 
| 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 | week 240 | 
| Number of Participants With HBsAg Seroconversion at Week 192 | Number of participants who became with HBsAg negative and developed anti-HBs at week 192 | week 192 | 
| Number of Participants With HBsAg Seroconversion at Week 240 | Number of participants who became HBsAg negative and developed anti-HBs at week 240 | week 240 | 
| 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 | week 192 | 
| 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 | week 240 | 
| 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) | week 192 | 
| 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 | week 240 | 
| Number of Participants With HBV DNA<1000 IU/mL at Week 192 | Number of participants with HBV DNA <1000 IU/mL at week 192 | week 192 | 
| Number of Participants With HBV DNA<1000 IU/mL at Week 240 | Number of participants with HBV DNA <1000 IU/mL at week 240 | week 240 | 
| Number of Participants With HBV DNA<20 IU/mL at Week 192 | Number of participants with HBV DNA<20 IU/mL at week 192 | week 192 | 
| Number of Participants With HBV DNA<20 IU/mL at Week 240 | Number of participants with HBV DNA<20 IU/mL at week 240 | week 240 | 
| Absence of Detectable Antiviral Drug-Resistant HBV Mutations at Week 192 | Absence of detectable antiviral drug-resistant HBV mutations at Week 192 | week 192 | 
| 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 | Week 240 | 
| 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. | week 192 |