Phase I Safety and Tolerability Study of Birinapant in Chronic Hepatitis B

Study Overview
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Brief Summary
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This study evaluates the addition of birinapant in subjects with chronic Hepatitis B who are currently receiving anti-viral therapy with either tenofovir or entecavir. Patients will receive either birinapant or placebo in addition to their anti-viral therapy.

Official Title
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Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose, Safety, Tolerability and Pharmacokinetics Study of Birinapant in Subjects With Chronic Hepatitis B

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Antiviral Therapy (tenofovir or entecavir)
* Drug: Birinapant
* Drug: Placebo (for birinapant)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented history of chronic Hepatitis B infection currently being treated with tenofovir or entecavir for at least 3 months Measurable titer of HBsAg HBV DNA level < 2 log copies/mL or 10² copies/mL No more than Child-Pugh score of 5 plus a valid FibroScan® of at least 10 readings with a median score of <7 and interquartile range of < 30% Adequate liver function, aspartate AST and ALT ≤2 x ULN Adequate renal function as evidenced by creatinine ≤2 mg/dL Exclusion Criteria: Participation in any interventional study within 4 weeks prior to Screening Known HIV infection, Hepatitis C, or other significant hepatic disorder including cirrhosis (Child-Pugh Class B or C) Serious illness or autoimmune disease or other known liver disease Uncontrolled hypertension Impaired cardiac function, uncontrolled cardiac arrhythmias despite medications, or clinically significant cardiac disease Currently breast feeding, pregnant or planning on becoming pregnant Known allergy or hypersensitivity to any of the formulation components of birinapant or placebo, including citric acid History of cranial nerve palsy Current treatment with anti-TNF therapies or has received treatment with anti-TNF therapies within the last 6 months Use of non-steroidal anti-inflammatory drugs

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antiviral Therapy & Birinapant<br>Antiviral therapy (tenofovir 300 mg or entecavir 0.5 mg) taken once daily by mouth, and birinapant administered as a 30 minute IV infusion once weekly for four weeks. | Drug: Antiviral Therapy (tenofovir or entecavir)<br> <br> Drug: Birinapant<br> <br> |
| Placebo Comparator: Antiviral Therapy & Placebo<br>Antiviral therapy (tenofovir 300 mg or entecavir 0.5 mg) taken once daily by mouth, and placebo (for birinapant) administered as a 30 minute infusion once weekly for four weeks. | Drug: Antiviral Therapy (tenofovir or entecavir)<br> <br> Drug: Placebo (for birinapant)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | From Screening through end of study, up to 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of birinapant (in plasma): maximum concentration (Cmax), time of maximum concentration (Tmax), area under the curve (AUC) extrapolated to time infinity, AUC from dosing to last quantifiable concentration |  | Day -1 through Day 26 | 
| Pharmacokinetics of birinapant (in plasma): terminal elimination half-life (t1/2), clearance (CL), terminal disposition rate constant,volume of distribution (Vdss) |  | Day -1 through Day 26 | 
| Pharmacokinetics of oral antiviral medication (tenofovir or entecavir): Cmax, Tmax, AUC from dosing to last quantifiable concentration, t1/2, CL, terminal disposition rate constant, Vdss |  | Day -1, Day 1 and Day 22 | 
| Hepatitis B markers (Determine levels of HBsAg, HBeAg, HBV DNA, and HBsAb) | Determine levels of HBsAg, HBeAg, HBV DNA, and HBsAb | Screening through Day 29 | 
| Pharmacodynamic effect of birinapant on cIAP1 and cIAP2 levels in peripheral blood mononuclear cells (PBMC) and levels of cluster of differentiation 4 and 8 (CD4+, CD+8) lymphocytes |  | Screening through Day 29 |