Clinical trial NCT01074008: A Randomized Study to Evaluate the Safety, Tolerability and Antiviral Activity of ABT-450, ABT-333 and ABT-072
Official title: A Blinded, Randomized, Placebo-controlled, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Multiple Doses of ABT-450 With Ritonavir (ABT-450/r), ABT-333 or ABT-072 Each Administered Alone and in Combination With Peginterferon α-2a and Ribavirin (PegIFN/RBV) in Treatment-Naïve Subjects With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C
HCV
Chronic Hepatitis C Infection
Hepatitis C Genotype 1
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2010-02-24
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of multiple oral doses of ABT-450/ritonavir (r), ABT-333 (also known as dasabuvir), or ABT-072 in hepatitis C virus (HCV), genotype 1-infected, treatment-naïve adults.

Detailed description: This was a Phase 2a, randomized, blinded, placebo-controlled, dose-ranging study in chronically, hepatitis C virus (HCV) genotype 1-infected participants designed to explore the safety, tolerability, pharmacokinetics, antiviral activity, as well as the evolution and persistence to resistance of ABT-450/r, ABT-333, or ABT-072. Participants were treated with ABT-450/r, ABT-333, or ABT-072 monotherapy for 3 days, followed by 81 days (12 weeks minus 3 days of monotherapy) of ABT-450/r, ABT-333, or ABT-072 combined with pegylated interferon/ribavirin (pegIFN/RBV), followed by 36 weeks of pegIFN/RBV alone. Participants randomized to an ABT-450/r treatment group who achieved rapid virologic response (RVR) and had HCV ribonucleic acid (RNA) levels \< 25 IU/mL at all subsequent visits were eligible to stop pegIFN/RBV therapy on or after Week 24.

Eligibility criteria: Inclusion Criteria:

* Chronic hepatitis C virus (HCV), genotype 1 infection (HCV ribonucleic acid level greater than or equal to 100,000 IU/mL) at screening
* Liver biopsy within 3 years with histology consistent with HCV-induced liver damage, with no evidence of cirrhosis or liver pathology due to any cause other than chronic HCV
* Treatment naïve male or female between the ages of 18 and 65
* Females must be post-menopausal for more than 2 years or surgically sterile
* Negative screen for drugs and alcohol
* Negative hepatitis B surface antigen (HBsAg) and anti-human immunodeficiency virus antibodies (anti-HIV Ab)
* No use of cytochrome P450 3A (CYP3A) and cytochrome P450 2C8 (CYP2C8) enzyme inducers or inhibitors within 1 month of dosing
* Be in a condition of general good health, as perceived by the investigator, other than HCV infection

Exclusion Criteria:

* Significant sensitivity to any drug
* Use of herbal supplements within 2 weeks prior to study drug dosing
* History of major depression within 2 years
* Prior treatment with any investigational or commercially available anti-HCV agents
* Abnormal laboratory tests

Primary outcomes:
measure: Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-450/r, ABT-333, or ABT-072 Monotherapy Treatment
timeFrame: Prior to dosing on Day 1 to before the morning dose on Day 4
measure: Maximum Plasma Concentration (Cmax) of ABT-450
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Time to Maximum Plasma Concentration (Tmax) of ABT-450
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-450
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Maximum Plasma Concentration (Cmax) of Ritonavir
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Time to Maximum Plasma Concentration (Tmax) of Ritonavir
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of Ritonavir
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Maximum Plasma Concentration (Cmax) of ABT-072
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Time to Maximum Plasma Concentration (Tmax) of ABT-072
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-072
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Maximum Plasma Concentration (Cmax) of ABT-333
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Time to Maximum Plasma Concentration (Tmax) of ABT-333
timeFrame: Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose)
measure: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours (AUC12) Post-dose of ABT-333
timeFrame: Immediately prior to morning dose (time 0 hours) and at 2, 4, 8, and 12 hours after the morning dose on Day 1
Secondary outcomes:
measure: Percentage of Participants With Rapid Virologic Response (RVR) at Week 4
timeFrame: Week 4
measure: Percentage of Participants With Partial Early Virologic Response (EVR) at Week 12
timeFrame: Baseline and Week 12
measure: Percentage of Participants With Complete Early Virologic Response (cEVR) at Week 12
timeFrame: Week 12
Other outcomes:
measure: Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-450 in Non-structural Viral Protein 3 (NS3)
timeFrame: Baseline and Day 4
measure: Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-072 in Non-structural Viral Protein 5B (NS5B)
timeFrame: Baseline and Day 4
measure: Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-333 in Non-structural Viral Protein 5B (NS5B)
timeFrame: Baseline and Day 4
measure: Change From Baseline in Hepatitis C Virus Patient-reported Outcomes (HCV-PRO) Total Score
timeFrame: Baseline up to Post-treatment Week 24
measure: Change From Baseline in ED-5D Visual Analog Scale (ED-5D VAS) Score
timeFrame: Baseline and Post-treatment Week 24
measure: Change From Baseline in EQ-5D (3 Level) Health Index Score
timeFrame: Baseline and Post-treatment Week 24
measure: Change From Baseline in SF-36 Physical Component Summary (PCS)
timeFrame: Baseline and Post-treatment Week 24
measure: Change From Baseline in SF-36 Mental Component Summary (MCS)
timeFrame: Baseline and Post-treatment Week 24
Locations:
city: Phoenix
country: United States
facility: Site Reference ID/Investigator# 23392
state: Arizona
city: Anaheim
country: United States
facility: Site Reference ID/Investigator# 23370
state: California
city: La Jolla
country: United States
facility: Site Reference ID/Investigator# 23387
state: California
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 23388
state: California
city: Aurora
country: United States
facility: Site Reference ID/Investigator# 23371
state: Colorado
city: Orlando
country: United States
facility: Site Reference ID/Investigator# 23369
state: Florida
city: Orlando
country: United States
facility: Site Reference ID/Investigator# 26362
state: Florida
city: Chicago
country: United States
facility: Site Reference ID/Investigator# 23373
state: Illinois
city: Chicago
country: United States
facility: Site Reference ID/Investigator# 24908
state: Illinois
city: Indianapolis
country: United States
facility: Site Reference ID/Investigator# 23381
state: Indiana
city: Baton Rouge
country: United States
facility: Site Reference ID/Investigator# 23372
state: Louisiana
city: New Orleans
country: United States
facility: Site Reference ID/Investigator# 24710
state: Louisiana
city: Baltimore
country: United States
facility: Site Reference ID/Investigator# 23391
state: Maryland
city: Detroit
country: United States
facility: Site Reference ID/Investigator# 23377
state: Michigan
city: St. Paul
country: United States
facility: Site Reference ID/Investigator# 24909
state: Minnesota
city: New York
country: United States
facility: Site Reference ID/Investigator# 35842
state: New York
city: New York
country: United States
facility: Site Reference ID/Investigator# 23379
state: New York
city: Chapel Hill
country: United States
facility: Site Reference ID/Investigator# 23375
state: North Carolina
city: Durham
country: United States
facility: Site Reference ID/Investigator# 23385
state: North Carolina
city: Dallas
country: United States
facility: Site Reference ID/Investigator# 23376
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 24891
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 23382
state: Texas
city: Salt Lake City
country: United States
facility: Site Reference ID/Investigator# 24715
state: Utah
city: Seattle
country: United States
facility: Site Reference ID/Investigator# 25463
state: Washington
city: Madison
country: United States
facility: Site Reference ID/Investigator# 23383
state: Wisconsin
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 23363
Study officials:
affiliation: AbbVie
name: Daniel Cohen
role: STUDY_DIRECTOR
References:
citation: Pilot-Matias T, Tripathi R, Cohen D, Gaultier I, Dekhtyar T, Lu L, Reisch T, Irvin M, Hopkins T, Pithawalla R, Middleton T, Ng T, McDaniel K, Or YS, Menon R, Kempf D, Molla A, Collins C. In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450. Antimicrob Agents Chemother. 2015 Feb;59(2):988-97. doi: 10.1128/AAC.04227-14. Epub 2014 Dec 1.