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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

Primary Purpose

Chronic Hepatitis C Virus Infection

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

ABT-333

Placebo for ABT-333

Pegylated interferon

Ribavirin

About this trial

This is an interventional treatment trial for Chronic Hepatitis C Virus Infection

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

ABT-333 (300 mg) twice daily (BID) + pegIFN/RBV

ABT-333 (600 mg) twice daily (BID) + pegIFN/RBV

ABT-333 (1200 mg) once daily (QD) + pegIFN/RBV

Placebo + pegIFN/RBV

Arm Description

Hepatitis C virus (HCV) positive, treatment-naive participants received 300 mg ABT-333 BID for 2 days followed by 300 mg ABT-333 BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.

Hepatitis C virus (HCV) positive, treatment-naive participants received 600 mg ABT-333 BID for 2 days followed by 600 mg ABT-333 BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.

Hepatitis C virus (HCV) positive, treatment-naive participants received 1200 mg ABT-333 QD for 2 days followed by 1200 mg ABT-333 QD with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.

Hepatitis C virus (HCV) positive, treatment-naïve participants received matching placebo once daily (QD) or twice daily (BID) for 2 days followed by placebo QD or BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT00851890

First Posted

February 24, 2009

Last Updated

June 1, 2018

Sponsor

AbbVie (prior sponsor, Abbott)

1. Study Identification

Unique Protocol Identification Number

NCT00851890

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2014

Overall Recruitment Status

Completed

Study Start Date

March 2009 (undefined)

Primary Completion Date

July 2009 (Actual)

Study Completion Date

July 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AbbVie (prior sponsor, Abbott)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Hepatitis C Virus Infection

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ABT-333 (300 mg) twice daily (BID) + pegIFN/RBV

Arm Type

Experimental

Arm Description

Arm Title

ABT-333 (600 mg) twice daily (BID) + pegIFN/RBV

Arm Type

Experimental

Arm Description

Arm Title

ABT-333 (1200 mg) once daily (QD) + pegIFN/RBV

Arm Type

Experimental

Arm Description

Arm Title

Placebo + pegIFN/RBV

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

ABT-333

Other Intervention Name(s)

dasabuvir

Intervention Description

50 mg capsules

Intervention Type

Other

Intervention Name(s)

Placebo for ABT-333

Intervention Description

Capsule

Intervention Type

Drug

Intervention Name(s)

Pegylated interferon

Intervention Description

Syringe, 180 µg/0.5 mL for subcutaneous injections administered weekly

Intervention Type

Drug

Intervention Name(s)

Ribavirin

Intervention Description

200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day

Primary Outcome Measure Information:

Title

Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Monotherapy Treatment

Description

Time Frame

Prior to the first dose on Day 1 to before first dose on Day 3

Title

Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28

Description

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.

Time Frame

Prior to the first dose on Day 1 through Day 28

Title

Maximum Plasma Concentration (Cmax) of ABT-333

Description

Time Frame

Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2

Title

Time to Maximum Plasma Concentration (Tmax) of ABT-333

Description

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.

Time Frame

Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2

Title

Area Under the Plasma Concentration-time Curve From 0 to 12 Hours Post-dose (AUC12) of ABT-333

Description

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.

Time Frame

Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2

Title

Serum Concentrations of Pegylated Interferon (pegIFN)

Description

Time Frame

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

Title

Plasma Concentrations of Ribavirin (RBV)

Description

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.

Time Frame

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

Title

Number of Participants Having Treatment-emergent Adverse Events (AEs)

Description

Time Frame

AEs were collected from the time of study drug administration to 30 days after last dose of study drug (8 Weeks)

Secondary Outcome Measure Information:

Title

Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28 or Final Visit

Description

Time Frame

Day 28 and Final Visit

Title

Percentage of Participants With at Least a 2 log10 Maximal Decrease in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Treatment

Description

Time Frame

Prior to the first dose on Day 1 and Day 28

Title

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

Description

Time Frame

Day 28 or Final Visit

Title

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

Description

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.

Time Frame

Day 28 or Final Visit

Title

Number of Participants With Resistance-Associated Variants in Non-structural Viral Protein 5B (NS5B) Through Day 28

Description

Time Frame

Days 1, 5, 10, 17, 24 and 28

Title

Number of Participants With Maximal Phenotypic Resistance to ABT-333 >10 Fold Relative to Baseline Through Day 28

Description

Time Frame

Days 1 through 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Cohen, MD

Organizational Affiliation

AbbVie

Official's Role

Study Director

Facility Information:

Facility Name

Site Reference ID/Investigator# 16103

City

Anaheim

State/Province

California

ZIP/Postal Code

92801

Country

United States

Facility Name

Site Reference ID/Investigator# 16124

City

Los Angeles

State/Province

California

ZIP/Postal Code

90048

Country

United States

Facility Name

Site Reference ID/Investigator# 16102

City

Orlando

State/Province

Florida

ZIP/Postal Code

32803

Country

United States

Facility Name

Site Reference ID/Investigator# 16105

City

Baton Rouge

State/Province

Louisiana

ZIP/Postal Code

70808

Country

United States

Facility Name

Site Reference ID/Investigator# 16106

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599-7584

Country

United States

Facility Name

Site Reference ID/Investigator# 16107

City

Dallas

State/Province

Texas

ZIP/Postal Code

75203

Country

United States

Facility Name

Site Reference ID/Investigator# 16123

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78215

Country

United States

Facility Name

Site Reference ID/Investigator# 16182

City

Santurce

ZIP/Postal Code

00909

Country

Puerto Rico

12. IPD Sharing Statement

Citations:

PubMed Identifier

26597291

Citation

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.

Results Reference

background

Links:

URL

http://rxabbvie.com

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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

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial