A Study Evaluating AL-3778 in Combination With Peginterferon Alpha-2a in Chronic Hepatitis B Subjects

Study Overview
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Brief Summary
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This is a Phase 2a, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, efficacy, and pharmacokinetics (PK) of AL-3778 in combination with Peg-IFN in subjects with Hepatitis B e antigen (HBeAg) positive CHB virus infection who are treatment-naïve. The study will consist of a screening phase , a double-blind treatment phase followed by treatment with Peg-IFN alone, and a post-treatment follow-up phase. Approximately 30 subjects to complete the study. Eligible subjects will be randomized into 2 treatment arms in a 2:1 ratio (active:placebo) to receive one of the following treatments: Arm A: Peg-IFN plus AL-3778 (N=20) Arm B: Peg-IFN plus matching placebo (N=10)

Official Title
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A Phase 2a, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety, Efficacy, and Pharmacokinetics of AL-3778 in Combination With Peginterferon Alpha-2a in Treatment Naïve Chronic Hepatitis B Subjects Who Are HBeAg-positive

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: AL-3778
* Drug: Peginterferon Alfa-2A
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A female subject must be of non-childbearing potential Subjects must have CHB infection, documented by serologic profile consistent for CHB infection at screening: serum HBsAg positive (for >6 months) serum IgM anti-HBc negative Subjects are treatment-naïve and are serum HBeAg positive with: serum HBV DNA >=20,000 IU /mL at screening HBsAg >250 IU/mL at screening ≥2× upper limit of normal (ULN) ALT and ≤5× ULN at screening Exclusion Criteria: Positive test for hepatitis A virus immunoglobulin, hepatitis delta antibody (Ab), hepatitis C Ab, human immunodeficiency virus (HIV) Ab and/or evidence of clinically relevant active infection that would interfere with study conduct or its interpretation would also lead to exclusion. Positive test for anti-HBs antibodies and anti-HBe antibodies. Subjects must have low levels of liver fibrosis that is classified as Metavir F0-F2 Any history or current evidence of hepatic decompensation Subjects must have absence of hepatocellular carcinoma Subject with evidence of retinopathy on retinal fundus photographs Exclusions related to interferon use for the purposes of this study Subjects with one or more of the following laboratory abnormalities at screening serum creatinine elevation >1.0× ULN hemoglobin <11 g/dL [males], <10.5 g/dL [females] platelet count <125× 109 cells/L absolute neutrophil count <1.0× 109 cells/L total bilirubin >1.0× ULN; unless known Gilbert's Disease or Dubin-Johnson Syndrome Subjects having received an investigational agent or investigational vaccine, or having received a biological product within 12 weeks or 5 half-lives (whichever is longer) prior to baseline (first intake of study drugs).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Peg-IFN plus AL-3778<br> | Drug: AL-3778<br>* AL-3778 tablets<br>Drug: Peginterferon Alfa-2A<br>* Peginterferon Alfa-2A for subcutaneous injection<br>|
| Placebo Comparator: Peg-IFN plus matching placebo<br> | Drug: Peginterferon Alfa-2A<br>* Peginterferon Alfa-2A for subcutaneous injection<br>Drug: Placebo Oral Tablet<br>* Placebo to Match AL-3778 tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change (measured in log10 IU/mL) in serum HBsAg from baseline at Week 24. |  | Day 1 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of AEs |  | Screening to Week 72 | 
| Incidence and severity of laboratory abnormalities |  | Screening to Week 72 | 
| Incidence of serious adverse events (SAEs). |  | Screening to Week 72 | 
| Incidence and severity of AEs leading to study drug discontinuation. |  | Screening to Week 72 | 
| Changes in serum HBV DNA over time |  | Day 1 to Week 72 | 
| Proportion of subjects with ALT normalization |  | Day 1 to Week 72 | 
| Incidence and severity of hepatic flares on treatment |  | Day 1 to Week 48 | 
| Incidence and severity of hepatic flares off-treatment. |  | Week 48 to week 72 | 
| Proportions of subjects with HBeAg loss and/or seroconversion. |  | Day 1 to Week 72 | 
| Proportions of subjects with HBsAg loss and/or seroconversion. |  | Day 1 to Week 72 | 
| Changes in serum HBsAg and serum HBeAg levels over time. |  | Day 1 to Week 72 | 
| Proportion of subjects experiencing a viral breakthrough on treatment. |  | Day 1 to Week 48 | 
| Assess emergence of treatment-associated mutations during study treatment and follow-up with a focus on subjects with treatment failure |  | Day 1 to Week 72 | 
| Individually derived Bayesian estimates of AL-3778 Steady state plasma concentration (C0h) |  | Week 2 | 
| Individually derived Bayesian estimates of AL-3778 area under the plasma concentration curve vs time (AUC0-12h) |  | Week 2 | 
| AL-3778 maximum observed plasma concentration (Cmax) |  | Week 2 | 
| AL-3778 Steady state plasma concentration (C0h) |  | Week 2 | 
| AL-3778 area under the plasma concentration curve vs time (AUC0-12h) |  | Week 2 |