Efficacy & Safety of Tenofovir Disoproxil Fumarate (TDF) Plus Peginterferon α-2a (Peg-IFN) Versus TDF or Peg-IFN Monotherapy in Chronic Hepatitis B

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (Peg-IFN) combination therapy for 48 weeks versus standard of care TDF monotherapy or Peg-IFN monotherapy for 48 weeks in non-cirrhotic adults with chronic hepatitis B virus (HBV) as determined by loss of hepatitis B surface antigen (HBsAg). The study will consist of 2 phases for participants in the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups. Following an initial 48 weeks of treatment, participants in these groups will be monitored for 24 weeks for signs of worsening HBV, and those meeting TDF retreatment and flare management criteria will be eligible to receive TDF monotherapy during a retreatment phase, up to Week 120.

Official Title
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A Phase 4, Randomized, Open-label, Active-Controlled, Superiority Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Combination With Peginterferon α-2a (Pegasys®) Versus Standard of Care Tenofovir Disoproxil Fumarate Monotherapy or Peginterferon α-2a Monotherapy for 48 Weeks in Non-Cirrhotic Subjects With HBeAg-Positive or HBeAg-Negative Chronic Hepatitis B (CHB)

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: TDF
* Drug: Peg-IFN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (age 18-75) with chronic HBV (positive for serum hepatitis B surface antigen (HBsAg) or HBV DNA for at least 6 months) prior to baseline Anti-HBV treatment-naive adults; adults who have taken oral anti-HBV nucleoside therapy with the last dose ≥ 24 weeks prior to screening are also eligible. Positive or negative for hepatitis B e antigen (HBeAg) HBV DNA ≥ 20,000 IU/ml (HBeAg-positive participants) and ≥ 2,000 IU/ml (HBeAg-negative participants) Alanine aminotransferase (ALT) > 54 U/L and ≤ 400 U/L for men and > 36 U/L and ≤ 300 U/L for women Creatinine clearance ≥ 70 mL/min Negative serum pregnancy test for females of childbearing potential Sexually active females of childbearing potential must agree to use a protocol-recommended method of contraception throughout the study and for 30 days following the last dose of study medication Lactating females must agree to discontinue nursing before initiation of study investigational medicinal product Exclusion Criteria: Known bridging fibrosis or cirrhosis and/or decompensated liver disease Evidence of hepatocellular carcinoma Significant kidney, heart, lung, neurological, autoimmune disease, or bone disease (eg, osteomalacia,chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures) Absolute neutrophil count < 1,500/mm^3, platelet < 100,000/mm^3, hemoglobin < 10 g/dL (female) or < 11 g/dL (male) History of severe depression or severe psychiatric disease Thyroid dysfunction Coinfection with HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV) Pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: TDF+Peg-IFN 48 Weeks<br>TDF plus Peg-IFN for 48 weeks | Drug: TDF<br>* TDF 300 mg tablets administered orally once daily<br>* Other names: Viread®;Drug: Peg-IFN<br>* Peg-IFN 180 µg administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Experimental: TDF 48 Weeks + Peg-IFN 16 Weeks<br>TDF plus Peg-IFN for 16 weeks, followed by TDF alone for an additional 32 weeks | Drug: TDF<br>* TDF 300 mg tablets administered orally once daily<br>* Other names: Viread®;Drug: Peg-IFN<br>* Peg-IFN 180 µg administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Active Comparator: TDF 120 Weeks<br>TDF monotherapy for 120 weeks | Drug: TDF<br>* TDF 300 mg tablets administered orally once daily<br>* Other names: Viread®;|
| Active Comparator: Peg-IFN 48 Weeks<br>Peg-IFN monotherapy for 48 weeks | Drug: Peg-IFN<br>* Peg-IFN 180 µg administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With 48 Weeks of TDF Plus Peg-IFN Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone | Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate. The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis. | Baseline; Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With TDF (48 Weeks) Plus Peg-IFN (16 Weeks) Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone | Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate. The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis. | Baseline; Week 72 | 
| Percentage of Participants With HBsAg Loss at Weeks 96 and 120 | Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate. The analysis visit window for Week 96 comprised study Week 90 through Week 102, so results up to Week 102 are included in this analysis. The analysis visit window for Week 120 comprised study Week 114 through Week 126, so results up to Week 126 are included in this analysis. | Baseline; Weeks 96 and 120 | 
| Percentage of Participants With HBsAg Seroconversion at Weeks 72, 96, and 120 | HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. Proportions are based on a Kaplan-Meier estimate. The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis. The analysis visit window for Week 96 comprised Week 90 through Week 102, so results up to Week 102 are included in this analysis. The analysis visit window for Week 120 comprised Week 114 through Week 120. | Baseline; Weeks 72, 96, and 120 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 72 | Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit. For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 72, and in the Retreated column for participants who did enter the retreatment phase by Week 72. | Baseline; Week 72 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 96 | Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit. For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 96, and in the Retreated column for participants who did enter the retreatment phase by Week 96. | Baseline; Week 96 | 
| Percentage of Participants With HBeAg Loss and Seroconversion at Week 120 | Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit. For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 120, and in the Retreated column for participants who did enter the retreatment phase by Week 120. | Baseline; Week 120 | 
| Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 72 | For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 72, and in the Retreated column for participants who did enter the retreatment phase by Week 72. | Week 72 | 
| Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 96 | For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 96, and in the Retreated column for participants who did enter the retreatment phase by Week 96. | Week 96 | 
| Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 120 | For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 120, and in the Retreated column for participants who did enter the retreatment phase by Week 120. | Week 120 | 
| Percentage of Participants With Normal ALT at Week 72 | Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT). For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 72, and in the Retreated column for participants who did enter the retreatment phase by Week 72. | Week 72 | 
| Percentage of Participants With Normal ALT at Week 96 | Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT). For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 96, and in the Retreated column for participants who did enter the retreatment phase by Week 96. | Week 96 | 
| Percentage of Participants With Normal ALT at Week 120 | Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT). For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the Not Retreated column for participants who had not entered the retreatment phase by Week 120, and in the Retreated column for participants who did enter the retreatment phase by Week 120. | Week 120 | 
| Percentage of Participants Who Required Retreatment | Participants in the TDF 120 week group were not eligible to enter the retreatment phase and are not presented. | Up to 120 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Hepatitis B, Hep B, Non cirrhotic, Tenofovir disoproxil fumarate (TDF), Peginterferon α-2a (Peg-IFN)