A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Multiple Doses of ABT-333 Alone and in Combination With Pegylated Interferon (pegIFN) and Ribavirin (RBV) in Subjects With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection

Chronic Hepatitis C Virus Infection Clinical Trial

Official title:

A Blinded, Randomized, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Multiple Doses of ABT-333 Alone and in Combination With Pegylated Interferon (pegIFN) and Ribavirin (RBV) in Subjects With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00851890
• Other study ID #: M10-380
• Status: Completed
• Phase: Phase 2
• Start date: March 2009
• Est. completion date: July 2009

Study information

• Verified date: December 2014
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to assess the safety, tolerability, pharmacokinetics and antiviral activity of ABT-333 (also known as dasabuvir) in treatment-naïve, hepatitis C virus (HCV)-infected participants.

Description:

This was a Phase 2a, blinded, randomized, placebo-controlled clinical trial in hepatitis C virus (HCV)-infected adults with 2 planned sequential evaluations, Part 1 and Part 2. The study evaluated the safety, tolerability, antiviral activity, and pharmacokinetics of ABT-333 or placebo monotherapy, followed by 26 days of ABT-333 or placebo with pegylated interferon a-2a (pegIFN) and ribavirin (RBV) combination therapy. Review of safety and efficacy in Part 1 of the study showed similar response rates across ABT-333 doses so Part 2 of the study was not performed. The study also assessed emergence of resistant HCV in conjunction with kinetics of viral load decay and rebound in treatment-naïve, HCV-infected participants.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Participant has provided written consent.

• If female, participant is postmenopausal or surgically sterile.

• If male, must be practicing two effective methods of birth control.

• Participant is hepatitis C virus (HCV) genotype 1 with HCV ribonucleic acid levels >50,000 IU/mL.

• Participants must demonstrate chronic hepatitis C infection for at least 6 months prior to study enrollment.

• Participants must have a liver biopsy with histology consistent with HCV-induced liver damage, and with no evidence of cirrhosis or liver pathology due to any cause other than chronic HCV.

• Condition of general good health other then HCV infection.

• Participants with a history of thyroid disease must have a thyroid stimulating hormone (TSH) value in the normal range.

Exclusion Criteria:

• No prior history of receiving therapy for HCV infection.

• Positive test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus antibody (HIV Ab).

• Pregnant or breastfeeding females or male partners of women who are pregnant.

• History of seizures or cancer.

• History of major depressive disorder within 2 years.

• Any current or past history of cirrhosis.

• Any cause of liver disease other than chronic HCV infection.

Related Conditions & MeSH terms

• Chronic Hepatitis C Virus Infection
• Communicable Diseases
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic
• Infection
• Virus Diseases

Intervention

Drug:
• ABT-333
50 mg capsules

Other:
• Placebo for ABT-333
Capsule

Drug:
• Pegylated interferon
Syringe, 180 µg/0.5 mL for subcutaneous injections administered weekly
• Ribavirin
200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day

Locations

Country	Name	City	State
Puerto Rico	Site Reference ID/Investigator# 16182	Santurce
United States	Site Reference ID/Investigator# 16103	Anaheim	California
United States	Site Reference ID/Investigator# 16105	Baton Rouge	Louisiana
United States	Site Reference ID/Investigator# 16106	Chapel Hill	North Carolina
United States	Site Reference ID/Investigator# 16107	Dallas	Texas
United States	Site Reference ID/Investigator# 16124	Los Angeles	California
United States	Site Reference ID/Investigator# 16102	Orlando	Florida
United States	Site Reference ID/Investigator# 16123	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie (prior sponsor, Abbott)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (1)

Mensing S, Polepally AR, König 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Monotherapy Treatment	Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during monotherapy was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time 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 3. Data are reported as the least squares mean change from nadir ± standard error.	Prior to the first dose on Day 1 to before first dose on Day 3
Primary	Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28	Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during treatment was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time after the first dose of study drug on Day 1 through the last log10 HCV RNA level on Day 28. Data are reported as the least squares mean change from nadir ± standard error.	Prior to the first dose on Day 1 through Day 28
Primary	Maximum Plasma Concentration (Cmax) of ABT-333	Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.	Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Primary	Time to Maximum Plasma Concentration (Tmax) of ABT-333	Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.	Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Primary	Area Under the Plasma Concentration-time Curve From 0 to 12 Hours Post-dose (AUC12) of ABT-333	Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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) measures 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.	Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Primary	Serum Concentrations of Pegylated Interferon (pegIFN)	Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of pegIFN (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.	Prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28
Primary	Plasma Concentrations of Ribavirin (RBV)	Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of RBV (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.	Prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28
Primary	Number of Participants Having Treatment-emergent Adverse Events (AEs)	An AE was any untoward medical occurrence that did not have a causal relationship with treatment. An Adverse Drug Reaction (ADR) was any noxious and undesired reaction related to the experimental drug or experiment. A serious adverse event (SAE) was an AE that resulted in death, was life-threatening, resulted in or prolonged hospitalization, resulted in congenital anomaly, was persistent or caused significant disability/incapacity, spontaneous or elective abortion, or required intervention to prevent a serious outcome. AEs were rated for severity as either: Mild - transient and easily tolerated; Moderate - caused discomfort and interrupted usual activities; Severe - caused considerable interference with usual activities, may be incapacitating or life-threatening.; AEs related to direct-acting antiviral agents (DAAs) were assessed as being either probably or possibly related by the investigator.	AEs were collected from the time of study drug administration to 30 days after last dose of study drug (8 Weeks)
Secondary	Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28 or Final Visit	Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (reported as log10 IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1 and the Day 28 or Final Visit value was the last HCV RNA measurement during the study. Data are reported as the least squares mean change from baseline ± standard error.	Day 28 and Final Visit
Secondary	Percentage of Participants With at Least a 2 log10 Maximal Decrease in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Treatment	Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. Data are reported as the percentage of participants.	Prior to the first dose on Day 1 and Day 28
Secondary	Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels = 25 IU/mL (the Lower Limit of Quantitation [LLOQ]) at Day 28 or Final Visit	Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of quantification (LLOQ) was defined as HCV RNA levels = 25 IU/mL. Data are reported as the percentage of participants.	Day 28 or Final Visit
Secondary	Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels = 10 IU/mL (Lower Limit of Detection [LLOD]) at Day 28 or Final Visit	Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of detection (LLOD) was defined as a HCV RNA level equal to 10 IU/mL. Data are reported as the percentage of participants.	Day 28 or Final Visit
Secondary	Number of Participants With Resistance-Associated Variants in Non-structural Viral Protein 5B (NS5B) Through Day 28	Samples from Days 1, 5, 10, 17, 24 and 28 were analyzed for the presence of resistance-associated amino acids using population sequencing and compared to the baseline non-structural viral protein 5B (NS5B) sequence to assess amino acid changes. The amino acid sequence of NS5B before the first dose of ABT-333 on Day 1 was defined as the baseline sequence. The number of participants with variants at resistance-associated amino acid positions in the post-baseline samples are presented.	Days 1, 5, 10, 17, 24 and 28
Secondary	Number of Participants With Maximal Phenotypic Resistance to ABT-333 >10 Fold Relative to Baseline Through Day 28	Phenotypic resistance to ABT-333 was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the corresponding baseline sample, and the maximal fold change in EC50 from baseline over the Day 5-28 period. The resistance sample drawn before the first dose of ABT-333 on Day 1 was defined as the baseline sample. The number of participants with phenotypic resistance in the post-baseline samples are presented.	Days 1 through 28

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