Study to Assess the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ABT-267 in HCV Infected Subjects

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and antiviral activity of multiple, ascending doses of ABT-267 (also known as ombitasvir) administered as two-day monotherapy followed by ABT-267 in combination therapy with other direct-acting antiviral agents (DAAs) ABT-450 with ritonavir (ABT-450/r) and ABT-333 (also known as dasabuvir) plus ribavirin (RBV) in patients with chronic Hepatitis C virus (HCV) infection without cirrhosis.

Detailed Description
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An open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of ABT-267 as monotherapy for 2 days, followed by ABT-267, ABT-450 with ritonavir (ABT-450/r) and ABT-333 plus ribavirin (RBV) combination therapy for 12 weeks in treatment-naïve, non-cirrhotic patients with chronic hepatitis C virus (HCV) infection. The study included post-treatment follow-up for 48 weeks.

Official Title
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An Open-Label, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ABT-267 in HCV Infected Subjects

Conditions
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Chronic Hepatitis C Infection

Intervention / Treatment
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* Drug: ABT-267
* Drug: ABT-450
* Drug: ABT-333
* Drug: Ritonavir
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the age of 18 and 70 years, inclusive, at time of enrollment. Subject has never received antiviral treatment for hepatitis C virus (HCV) infection. Body mass index (BMI) is ≥ 18 to < 38 kg/m^2. BMI is calculated as weight measured in kilograms (kg) divided by the square of height measured in meters (m). Chronic HCV genotype 1-infection for at least 6 months prior to study enrollment. Subject has plasma HCV RNA level > 10,000 IU/mL at screening Exclusion Criteria: History of severe, life-threatening or other significant sensitivity to any drug. Females who are or plan to become pregnant or breastfeeding or males whose partner is pregnant or planning to become pregnant. Recent history of drug or alcohol abuse that could preclude adherence to the protocol. Positive test result for hepatitis B surface antigen or anti-human immunodeficiency virus (HIV) antibodies. Any current or past clinical evidence of cirrhosis (e.g., ascites, esophageal varices), or a liver biopsy or FibroTest/aspartate aminotransferase to platelet ratio (APRI) or FibroScan® showing cirrhosis or extensive bridging fibrosis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-267 1.5 mg, then ABT-267, ABT-450/r, ABT-333, plus RBV<br>ABT-267 (1.5 mg once daily) as monotherapy for 2 days, then ABT-267 (1.5 mg once daily), ABT-450/r (150 mg/ 100 mg once daily) and ABT-333 (400 mg twice daily), plus weight-based RBV (dosed 1,000 or 1,200 mg daily divided twice a day) combination therapy for 12 weeks | Drug: ABT-267<br>* Tablet<br>* Other names: ombitasvir;Drug: ABT-450<br>* Tablet<br>Drug: ABT-333<br>* Tablet<br>* Other names: dasabuvir;Drug: Ritonavir<br>* Capsule<br>Drug: Ribavirin<br>* Tablet<br>|
| Experimental: ABT-267 25 mg, then ABT-267, ABT-450/r, ABT-333, plus RBV<br>ABT-267 (25 mg once daily) as monotherapy for 2 days, then ABT-267 (25 mg once daily), ABT-450/r (150 mg/ 100 mg once daily) and ABT-333 (400 mg twice daily), plus weight-based RBV (dosed 1,000 or 1,200 mg daily divided twice a day) combination therapy for 12 weeks | Drug: ABT-267<br>* Tablet<br>* Other names: ombitasvir;Drug: ABT-450<br>* Tablet<br>Drug: ABT-333<br>* Tablet<br>* Other names: dasabuvir;Drug: Ritonavir<br>* Capsule<br>Drug: Ribavirin<br>* Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of ABT-267 Following Monotherapy on Day 1 | Blood samples were collected pre-dose (time 0) and at 2, 4, and 6 hours post-dose on Day 1 and pre-dose on Day 2 (ABT-267 monotherapy). The samples were analyzed for ABT-267 using validated analytical methods. Maximum plasma concentration (Cmax; measured in ng/mL) was estimated using noncompartmental analyses. | Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) | 
| Time of Maximum Plasma Concentration (Tmax) of ABT-267 Following Monotherapy on Day 1 | Blood samples were collected pre-dose (time 0) and at 2, 4, and 6 hours post-dose on Day 1 and pre-dose on Day 2 (ABT-267 monotherapy). The samples were analyzed for ABT-267 using validated analytical methods. Time of maximum plasma concentration (Tmax; measured in hours) was estimated using noncompartmental analyses. | Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC[24]) of ABT-267 Following Monotherapy on Day 1 | Blood samples were collected pre-dose (time 0) and at 2, 4, and 6 hours post-dose on Day 1 and pre-dose on Day 2 (ABT-267 monotherapy). The samples were analyzed for ABT-267 using validated analytical methods. Area under the plasma concentration-time curve from time 0 to 24 hours (AUC[24]; measured in ng multiplied by hour/mL) was estimated using noncompartmental analyses. | Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) | 
| Plasma Concentration of ABT-267 Pre-dose (Ctrough) on Day 2 and Day 3 | Blood samples were collected pre-dose on Day 2 (prior to second dose of ABT-267 monotherapy) and pre-dose on Day 3 (prior to first dose of combination therapy). The samples were analyzed for ABT-267 using validated analytical methods. Pre-dose plasma concentrations on Day 2 and Day 3 (Ctrough, measured in ng/mL) are reported. | Day 2 (pre-dose) and Day 3 (pre-dose) | 
| Number of Participants With Adverse Events (AEs) | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each AE to the use of direct-acting antiviral agents (DAAs), and rated the severity of each event as either: Mild: The AE was transient and easily tolerated by the participant; Moderate: The AE caused the participant discomfort and interrupted usual activities; Severe: The AE caused considerable interference with the participant's usual activities and could have been incapacitating or life-threatening. A serious adverse event was any event that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, resulted in a congenital anomaly or persistent or significant disability or was any other important medical event requiring medical or surgical intervention. | All AEs were collected from the time of study drug administration to 30 days after last dose of study drug (16 weeks). | 
| Mean Maximal Decrease From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) During ABT-267 Monotherapy | The baseline value was the last measurement before the first dose of ABT-267 monotherapy (Day 1). The maximal decrease during monotherapy was the change from baseline to the lowest log10 IU/mL HCV RNA level any time from the first dose of ABT-267 on Day 1 to the last log10 HCV RNA level before the first dose of ABT-267 combination therapy (Study Day 3). | Pre-dose on Days 1, 2, and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 12 Weeks and 24 Weeks After Combination Therapy | The percentage of participants with sustained virologic response (plasma Hepatitis C virus ribonucleic acid [HCV RNA] level less than the lower limit of quantitation [< LLOQ]) 12 and 24 weeks after the last dose of combination study drug. The LLOQ for the assay was 25 IU/mL. | 12 and 24 weeks after last dose of combination study drug | 
| Percentage of Participants With Rapid Virologic Response | The percentage of participants with virologic response (plasma HCV RNA less than the lower limit of quantitation [< LLOQ]) after 4 weeks of combination therapy. | 4 weeks | 
| Percentage of Participants With End-of-Treatment Response | The percentage of participants with virologic response (plasma HCV RNA less than the lower limit of quantitation [< LLOQ]) at the end of combination therapy (12 weeks). | 12 weeks | 
| Percentage of Participants With Extended Rapid Virologic Response | The percentage of participants with virologic response (plasma HCV RNA less than the lower limit of quantitation [< LLOQ]) at Weeks 4 through 12 of combination therapy. | Weeks 4 to 12 | 
| Mean Change in Viral Load From Baseline to Pre-dose on Day 2 and Day 3 of ABT-267 Monotherapy | The relationship between ABT-267 dose, ABT-267 concentration, and response was analyzed as the change in viral load (measured as log10 IU/mL) from baseline (pre-dose on Day 1) to pre-dose on Days 2 and 3. Plasma concentrations of ABT-267 pre-dose on Days 2 and 3 are presented above in 4. Primary Outcome: Plasma Concentration of ABT-267 Pre-dose (Ctrough) on Day 2 and Day 3. | Predose on Days 1, 2, and 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C,Genotype 1