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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AbbVie ( AbbVie (prior sponsor, Abbott) )
ClinicalTrials.gov Identifier:
NCT01563536
First received: January 27, 2012
Last updated: December 29, 2014
Last verified: December 2014
  Purpose

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.


Condition Intervention Phase
Chronic Hepatitis C Infection
Drug: ABT-267
Drug: ABT-450
Drug: ABT-333
Drug: Ritonavir
Drug: Ribavirin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ABT-267 in HCV Infected Subjects

Resource links provided by NLM:


Further study details as provided by AbbVie:

Primary Outcome Measures:
  • Maximum Plasma Concentration (Cmax) of ABT-267 Following Monotherapy on Day 1 [ Time Frame: Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) ] [ Designated as safety issue: No ]
    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.

  • Time of Maximum Plasma Concentration (Tmax) of ABT-267 Following Monotherapy on Day 1 [ Time Frame: Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) ] [ Designated as safety issue: No ]
    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.

  • Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC[24]) of ABT-267 Following Monotherapy on Day 1 [ Time Frame: Day 1 (pre-dose [time 0] and at 2, 4, and 6 hours post-dose) and Day 2 (pre-dose) ] [ Designated as safety issue: No ]
    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.

  • Plasma Concentration of ABT-267 Pre-dose (Ctrough) on Day 2 and Day 3 [ Time Frame: Day 2 (pre-dose) and Day 3 (pre-dose) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Adverse Events (AEs) [ Time Frame: All AEs were collected from the time of study drug administration to 30 days after last dose of study drug (16 weeks). ] [ Designated as safety issue: Yes ]

    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.


  • Mean Maximal Decrease From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) During ABT-267 Monotherapy [ Time Frame: Pre-dose on Days 1, 2, and 3 ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Percentage of Participants With Sustained Virologic Response 12 Weeks and 24 Weeks After Combination Therapy [ Time Frame: 12 and 24 weeks after last dose of combination study drug ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Rapid Virologic Response [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    The percentage of participants with virologic response (plasma HCV RNA less than the lower limit of quantitation [< LLOQ]) after 4 weeks of combination therapy.

  • Percentage of Participants With End-of-Treatment Response [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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).

  • Percentage of Participants With Extended Rapid Virologic Response [ Time Frame: Weeks 4 to 12 ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Viral Load From Baseline to Pre-dose on Day 2 and Day 3 of ABT-267 Monotherapy [ Time Frame: Predose on Days 1, 2, and 3 ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Resistance-Associated Variants and Phenotypic Resistance [ Time Frame: Day 1 Pre-dose (Baseline) and Day 3 Pre-dose ] [ Designated as safety issue: No ]
    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.


Enrollment: 12
Study Start Date: February 2012
Study Completion Date: June 2013
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: ABT-267
Tablet
Other Name: ombitasvir
Drug: ABT-450
Tablet
Drug: ABT-333
Tablet
Other Name: dasabuvir
Drug: Ritonavir
Capsule
Drug: Ribavirin
Tablet
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: ABT-267
Tablet
Other Name: ombitasvir
Drug: ABT-450
Tablet
Drug: ABT-333
Tablet
Other Name: dasabuvir
Drug: Ritonavir
Capsule
Drug: Ribavirin
Tablet

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01563536

Locations
United States, California
Site Reference ID/Investigator# 68002
Bakersfield, California, United States, 93301
United States, Florida
Site Reference ID/Investigator# 67383
Orlando, Florida, United States, 32809
United States, Maryland
Site Reference ID/Investigator# 67382
Annapolis, Maryland, United States, 21401
United States, New York
Site Reference ID/Investigator# 67385
Poughkeepsie, New York, United States, 12601
Sponsors and Collaborators
AbbVie (prior sponsor, Abbott)
Investigators
Study Director: Andrew L Campbell, MD AbbVie
  More Information

Additional Information:
No publications provided

Responsible Party: AbbVie ( AbbVie (prior sponsor, Abbott) )
ClinicalTrials.gov Identifier: NCT01563536     History of Changes
Other Study ID Numbers: M13-386
Study First Received: January 27, 2012
Results First Received: December 29, 2014
Last Updated: December 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by AbbVie:
Hepatitis C,Genotype 1

Additional relevant MeSH terms:
Hepatitis C
Hepatitis C, Chronic
Hepatitis, Chronic
Digestive System Diseases
Flaviviridae Infections
Hepatitis
Hepatitis, Viral, Human
Liver Diseases
RNA Virus Infections
Virus Diseases

ClinicalTrials.gov processed this record on April 23, 2015