A Randomized Study to Evaluate the Safety, Tolerability and Antiviral Activity of ABT-450, ABT-333 and ABT-072

Hepatitis C Clinical Trial

— Champion2  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01074008
• Other study ID #: M11-602
• Status: Completed
• Phase: Phase 2
• First received: February 22, 2010
• Last updated: December 29, 2014
• Start date: March 2010
• Est. completion date: January 2012

Study information

• Verified date: December 2014
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: January 2012
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C Infection
• HCV
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C Genotype 1
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• ABT-450
50 mg capsules co-administered with ritonavir
• ABT-072
50 mg tablet
• ABT-333
400 mg tablet
• Ritonavir
100 mg capsules co-administered with ABT-450
• Peginterferon alpha-2a
Syringe, 180 µg/0.5 mL for subcutaneous injections
• Ribavirin
200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day

Other:
• Placebo
Matching placebo for ABT-450/r, ABT-072, or ABT-333 monotherapy at each dose level

Locations

Country	Name	City	State
Puerto Rico	Site Reference ID/Investigator# 23363	Ponce
United States	Site Reference ID/Investigator# 23370	Anaheim	California
United States	Site Reference ID/Investigator# 23371	Aurora	Colorado
United States	Site Reference ID/Investigator# 23391	Baltimore	Maryland
United States	Site Reference ID/Investigator# 23372	Baton Rouge	Louisiana
United States	Site Reference ID/Investigator# 23375	Chapel Hill	North Carolina
United States	Site Reference ID/Investigator# 23373	Chicago	Illinois
United States	Site Reference ID/Investigator# 24908	Chicago	Illinois
United States	Site Reference ID/Investigator# 23376	Dallas	Texas
United States	Site Reference ID/Investigator# 23377	Detroit	Michigan
United States	Site Reference ID/Investigator# 23385	Durham	North Carolina
United States	Site Reference ID/Investigator# 24891	Houston	Texas
United States	Site Reference ID/Investigator# 23381	Indianapolis	Indiana
United States	Site Reference ID/Investigator# 23387	La Jolla	California
United States	Site Reference ID/Investigator# 23388	Los Angeles	California
United States	Site Reference ID/Investigator# 23383	Madison	Wisconsin
United States	Site Reference ID/Investigator# 24710	New Orleans	Louisiana
United States	Site Reference ID/Investigator# 23379	New York	New York
United States	Site Reference ID/Investigator# 35842	New York	New York
United States	Site Reference ID/Investigator# 23369	Orlando	Florida
United States	Site Reference ID/Investigator# 26362	Orlando	Florida
United States	Site Reference ID/Investigator# 23392	Phoenix	Arizona
United States	Site Reference ID/Investigator# 24715	Salt Lake City	Utah
United States	Site Reference ID/Investigator# 23382	San Antonio	Texas
United States	Site Reference ID/Investigator# 25463	Seattle	Washington
United States	Site Reference ID/Investigator# 24909	St. Paul	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie (prior sponsor, Abbott)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-450 in Non-structural Viral Protein 3 (NS3)	Baseline samples were analyzed for resistance-associated amino acid variants using population and clonal sequencing and were compared with the appropriate reference sequence (1a-H77 or 1b-Con1). Phenotypic resistance to ABT-450 at baseline was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the appropriate reference replicon (1a-H77 or 1b-Con1). Available samples at Day 4 with HCV RNA = 1000 IU/mL were analyzed for resistance-associated variants using population and clonal sequencing and were compared with the baseline sequences to assess amino acid changes. Phenotypic resistance to ABT-450 at Day 4 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 amino acid positions and phenotypic resistance are presented.	Baseline and Day 4	No
Other	Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-072 in Non-structural Viral Protein 5B (NS5B)	Baseline samples were analyzed for resistance-associated amino acid variants using population and clonal sequencing and were compared with the appropriate reference sequence (1a-H77 or 1b-Con1). Phenotypic resistance to ABT-072 at baseline was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the appropriate reference replicon (1a-H77 or 1b-Con1). Available samples at Day 4 with HCV RNA = 1000 IU/mL were analyzed for the presence of resistance-associated variants using population and clonal sequencing and were compared with the baseline sequences to assess amino acid changes. Phenotypic resistance to ABT-072 at Day 4 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 amino acid positions and phenotypic resistance are presented.	Baseline and Day 4	No
Other	Number of Participants With Resistance-Associated Variants and Phenotypic Resistance to ABT-333 in Non-structural Viral Protein 5B (NS5B)	Baseline samples were analyzed for resistance-associated amino acid variants using population and clonal sequencing and were compared with the appropriate reference sequence (1a-H77 or 1b-Con1). Phenotypic resistance to ABT-333 at baseline was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the appropriate reference replicon (1a-H77 or 1b-Con1). Available samples at Day 4 with HCV RNA = 1000 IU/mL were analyzed for the presence of resistance-associated variants using population and clonal sequencing and were compared with the baseline sequences to assess amino acid changes. Phenotypic resistance to ABT-333 at Day 4 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 amino acid positions and phenotypic resistance are presented.	Baseline and Day 4	No
Other	Change From Baseline in Hepatitis C Virus Patient-reported Outcomes (HCV-PRO) Total Score	The Hepatitis C Virus Patient-report Outcomes (HCV-PRO, formerly known as HCV Quality of Life) survey was used to assess disease-specific function and well-being on a scale from 0 to 100; a higher score indicated relatively good function and well-being of treated participants. Data presented are the summaries across all participants, for each treatment arm, regardless of dose. Data are reported as the group mean change from baseline ± standard deviation.	Baseline up to Post-treatment Week 24	No
Other	Change From Baseline in ED-5D Visual Analog Scale (ED-5D VAS) Score	The ED-5D VAS was a self-rating survey used to capture the current health status of a participant and ranged from 0 (the worst imaginable health state) to 100 (best imaginable health state). Data presented are the summaries across all participants, for each treatment arm, regardless of dose. Data are presented as the group mean change from baseline ± standard deviation.	Baseline and Post-treatment Week 24	No
Other	Change From Baseline in EQ-5D (3 Level) Health Index Score	The EQ-5D was a health state questionnaire used to measure five health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The combination of responses from all five dimensions were derived into an index score ranging from 0 to 1; a higher score indicated a more preferable health utility value from the societal perspectives. Data presented are the summaries across all participants, for each treatment arm, regardless of dose. Data are presented as the group mean change from baseline ± standard deviation.	Baseline and Post-treatment Week 24	No
Other	Change From Baseline in SF-36 Physical Component Summary (PCS)	The Physical Component Summary (PCS) of the SF-36 was used to measure the overall physical health status of a participant. The aggregated score of the SF-36 PCS score was standardized using a linear T-score transformation with a mean of 50 and a standard deviation of 10; a higher score indicated better physical function and well-being. Data presented are the summaries across all participants, for each treatment arm, regardless of dose. Data are presented as the group mean change from baseline ± standard deviation.	Baseline and Post-treatment Week 24	No
Other	Change From Baseline in SF-36 Mental Component Summary (MCS)	The Mental Component Summary (MCS) of the SF-36 was used to measure the overall mental health status of participants. The aggregated score of the SF-36 MPS was standardized using a linear T-score transformation with a mean of 50 and a standard deviation of 10; a higher score indicated better mental function and well-being. Data presented are the summaries across all participants, for each treatment arm, regardless of dose. Data are presented as the group mean change from baseline ± standard deviation.	Baseline and Post-treatment Week 24	No
Primary	Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-450/r, ABT-333, or ABT-072 Monotherapy Treatment	Plasma HCV RNA levels (reported as log10 IU/mL) were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification of 25 IU/mL. The baseline value was the HCV RNA level before the first dose of study drug on Day 1. The maximal change during monotherapy was the difference from baseline to the lowest log10 HCV RNA level anytime after the first dose of study drug on Day 1 through the last log10 HCV RNA level before the first dose of study drug on Day 4. Data are reported as the mean ± standard deviation.	Prior to dosing on Day 1 to before the morning dose on Day 4	No
Primary	Maximum Plasma Concentration (Cmax) of ABT-450	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Time to Maximum Plasma Concentration (Tmax) of ABT-450	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-450	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Maximum Plasma Concentration (Cmax) of Ritonavir	Blood samples were collected 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). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Time to Maximum Plasma Concentration (Tmax) of Ritonavir	Blood samples were collected 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). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of Ritonavir	Blood samples were collected 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). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Maximum Plasma Concentration (Cmax) of ABT-072	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Time to Maximum Plasma Concentration (Tmax) of ABT-072	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-072	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Maximum Plasma Concentration (Cmax) of ABT-333	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Time to Maximum Plasma Concentration (Tmax) of ABT-333	Blood samples were collected 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). The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	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)	No
Primary	Area Under the Plasma Concentration-time Curve From 0 to 12 Hours (AUC12) Post-dose of ABT-333	Blood samples were collected immediately prior to morning dose (time 0 hours) and at 2, 4, 8, and 12 hours after the morning dose on Day 1. The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC12 of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation.	Immediately prior to morning dose (time 0 hours) and at 2, 4, 8, and 12 hours after the morning dose on Day 1	No
Secondary	Percentage of Participants With Rapid Virologic Response (RVR) at Week 4	Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL. Rapid virologic response was defined as HCV RNA level < LLOQ (< 25 IU/mL) at Week 4. Data are reported as the percentage of participants with RVR.	Week 4	No
Secondary	Percentage of Participants With Partial Early Virologic Response (EVR) at Week 12	Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification of 25 IU/mL. Partial early virologic response (EVR) was defined as HCV RNA levels that decreased > 2 log10 IU/mL at Week 12 as compared to baseline. The baseline value was the last measurement before the first dose on Day 1. Data are reported as the percentage of participants with partial EVR.	Baseline and Week 12	No
Secondary	Percentage of Participants With Complete Early Virologic Response (cEVR) at Week 12	Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL. Complete EVR was defined as HCV RNA levels < LLOQ (< 25 IU/mL) at Week 12. Data are reported as the percentage of participants with cEVR.	Week 12	No

External Links

•   Link