Multiple Ascending Dose Study of BMS-929075 in Hepatitis C Virus (HCV) Infected Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine the change from baseline in HCV Ribonucleic acid (RNA) on Day 4 following three days of dosing with BMS-929075 in chronically genotype subtype 1a and 1b HCV infected subjects

Official Title
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Double-Blinded, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Antiviral Activity, Safety, Tolerability, and Pharmacokinetics of BMS-929075 in Treatment Naive Subjects Infected With Hepatitis C Virus Genotype 1

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: BMS-929075
* Drug: BMS-929075
* Drug: BMS-929075
* Drug: BMS-929075
* Drug: Placebo matching BMS-929075
* Drug: Placebo matching BMS-929075


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, ages 18 to 65 years, inclusive Subjects who are naive to HCV treatment, defined as no previous exposure to an Interferon (IFN), Ribavirin (RBV); or any HCV-specific direct acting antiviral or experimental therapy HCV genotype 1a or 1b only HCV RNA viral load of ≥ 100,000 IU/mL Have one of the following: i) Documented Fibrotest score of ≤ 0.72 and AST to platelet ratio index (APRI) ≤ 2; or ii) Documented liver biopsy within 12 months preceding Day 1 showing absence of cirrhosis Body Mass Index (BMI) of 18.0 to 35.0 kg/m2, inclusive Exclusion Criteria: Any significant acute or chronic medical illness History of adrenal gland disease, including but not limited to adrenal insufficiency or Cushing's syndrome Current or recent (within 3 months of study drug administration) gastrointestinal disease Any major surgery within 4 weeks of study drug administration Any gastrointestinal surgery that could impact upon the absorption of study drug Positive for hepatitis B surface antigen (HBsAg) Positive for Human Immunodeficiency Virus (HIV) -1 and/or -2 antibodies Smoking > 10 cigarettes per day Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) > 5x upper limit of normal (ULN) Total Bilirubin ≥ 1.5x ULN Hemoglobin < 10 g/dL Platelets < 75,000 cell/μL ALC (absolute lymphocyte count) < 1000 cell/μL Creatinine clearance (as estimated by method of Cockcroft and Gault) less than 60 mL/min

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 |
| --- | --- |
| Experimental: Arm 1: BMS-929075 (≤ 25 mg) OR Placebo matching BMS-929075<br> | Drug: BMS-929075<br>* Oral Suspension, ≤ 25 mg, Once daily, 3 days<br>Drug: Placebo matching BMS-929075<br>* Oral Suspension, 0 mg, Once daily, 3 days<br>|
| Experimental: Arm 2: BMS-929075 (≤ 100 mg) OR Placebo matching BMS-929075<br> | Drug: BMS-929075<br>* Oral Suspension, ≤ 100 mg, Once daily, 3 days<br>Drug: Placebo matching BMS-929075<br>* Oral Suspension, 0 mg, Once daily, 3 days<br>|
| Experimental: Arm 3: BMS-929075 (≤ 400 mg) OR Placebo matching BMS-929075<br> | Drug: BMS-929075<br>* Oral Suspension, ≤ 400 mg, Once daily, 3 days<br>Drug: Placebo matching BMS-929075<br>* Oral Suspension, 0 mg, Once daily, 3 days<br>|
| Experimental: Arm 4: BMS-929075 (≤ 800 mg) OR Placebo matching BMS-929075<br> | Drug: BMS-929075<br>* Oral Suspension, (≤ 800 mg, Once daily) OR (≤ 400 mg, Twice daily), 3 days<br>Drug: Placebo matching BMS-929075<br>* Oral Suspension, 0 mg, (Once daily for ≤ 800 mg group) OR (Twice daily for ≤ 400 mg group), 3 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV RNA level on Day 4 |  | Within 4 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum decrease from baseline in plasma HCV RNA levels during the period from Day 1 to Day 28 |  | Days 1-28 | 
| Time course of the change from baseline in plasma HCV RNA levels and the time of maximum decrease during the period of Day 1 through Day 28 |  | Days 1-28 | 
| Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests |  | Days 1-28 (with SAE from screening to Day 30) | 
| Maximum observed plasma concentration (Cmax) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Minimum observed plasma concentration (Cmin) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Trough observed plasma concentration (Ctrough) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Time of maximum observed plasma concentration (Tmax) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Plasma half-life (T-HALF) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| Protein Binding (PB) of BMS-929075 derived from plasma concentration versus time |  | Day 3 (0h and 2h) | 
| Fraction of free drug in plasma (fu) of BMS-929075 derived from plasma concentration versus time |  | Day 1 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h), Day 2, and Day 3 (0h, 0.5h, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,24h, 36h, 48h and 72h) | 
| The relationship between antiviral activity and measures of exposure to BMS-929075 |  | Days 1-6 |