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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C Infection
• Intervention / Treatment: Drug: Ribavirin; Drug: ABT-267; Drug: ABT-333; Drug: ABT-450; Drug: Ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Bakersfield, California, United States, 93301
      • Site Reference ID/Investigator# 68002
  • Florida
    • Orlando, Florida, United States, 32809
      • Site Reference ID/Investigator# 67383
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Site Reference ID/Investigator# 67382
  • New York
    • Poughkeepsie, New York, United States, 12601
      • Site Reference ID/Investigator# 67385

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ABT-267 1.5 mg, then ABT-267, ABT-450/r, ABT-333, plus RBV; 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: Ribavirin; Tablet; Drug: ABT-267; Tablet; Other Names: ombitasvir; Drug: ABT-333; Tablet; Other Names: dasabuvir; Drug: ABT-450; Tablet; Drug: Ritonavir; Capsule
Experimental: ABT-267 25 mg, then ABT-267, ABT-450/r, ABT-333, plus RBV; 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: Ribavirin; Tablet; Drug: ABT-267; Tablet; Other Names: ombitasvir; Drug: ABT-333; Tablet; Other Names: dasabuvir; Drug: ABT-450; Tablet; Drug: Ritonavir; Capsule

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resistance-Associated Variants and Phenotypic Resistance	Baseline (pre-dose on Day 1) samples were analyzed for resistance-associated amino acid (AA) variants using population sequencing. Phenotypic resistance to ABT-267 at Baseline was assessed by calculating the fold difference in the the half maximal effective concentration (EC50) compared with the EC50 for the appropriate reference replicon (1a-H77 or 1b-Con1). Day 3 samples were analyzed using population sequencing and were compared with the baseline and appropriate prototypic reference sequences to assess AA changes. Phenotypic resistance at Day 3 was assessed by calculating the fold difference in the EC50 compared with the EC50 for the corresponding Baseline sample. The number of participants with variants at resistance-associated AA positions and phenotypic resistance at Baseline and Day 3 are presented.	Day 1 Pre-dose (Baseline) and Day 3 Pre-dose

Collaborators and Investigators

• Sponsor: AbbVie (prior sponsor, Abbott)
• Investigators: Study Director: Andrew L Campbell, MD, AbbVie

Publications and helpful links

General Publications

• Mensing S, Polepally AR, Konig D, Khatri A, Liu W, Podsadecki TJ, Awni WM, Menon RM, Dutta S. Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies. AAPS J. 2016 Jan;18(1):270-80. doi: 10.1208/s12248-015-9846-1. Epub 2015 Nov 23.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: January 27, 2012
• First Submitted That Met QC Criteria: March 23, 2012
• First Posted (Estimate): March 27, 2012

Study Record Updates

• Last Update Posted (Actual): July 2, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Hepatitis C,Genotype 1
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ribavirin; Ritonavir
• Other Study ID Numbers: M13-386