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TMC649128HPC1002 - a Trial inGenotype 1 Hepatitis C Virus (HCV) - Infected Participants to Determine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of TMC649128, Alone and Combined With Pegylated Interferon + Ribavirin

This study has been terminated.
(Antiviral activity was considered insufficient to warrant further clinical development of TMC649128.)
Sponsor:
Information provided by (Responsible Party):
Tibotec BVBA
ClinicalTrials.gov Identifier:
NCT01391117
First received: June 13, 2011
Last updated: October 25, 2012
Last verified: October 2012
  Purpose

The purpose of this study is to determine in genotype 1 Hepatitis C Virus (HCV)-infected participants, the safety, tolerability, pharmacokinetics (how the drug is absorbed in the body, how it is distributed within the body and removed from the body over time) and antiviral activity of repeated doses of TMC649128 given as monotherapy and given in combination with pegylated interferon + ribavirin. We assess the pharmacokinetic/pharmacodynamic (how the study medication affects the body) (PK/PD) relationship for antiviral activity, active metabolite and safety of TMC649128 and its metabolites. We determine the short term safety and tolerability of the co-administration of TMC649128 and pegylated interferon + ribavirin during multiple dosing for 14 days in treatment-naive genotype 1 HCV-infected participants. We explore the effect of pegylated interferon + ribavirin on the pharmacokinetics of TMC649128 during the multiple dosing for 14 days in treatment-naive genotype 1 HCV-infected participants. We also assess in a preliminary way the short term antiviral effect of the combination of TMC649128 with pegylated interferon + ribavirin during a 14-day dosing period in treatment-naive genotype 1 HCV-infected participants.


Condition Intervention Phase
Hepatitis C Virus
Drug: placebo.
Drug: TMC649128.
Drug: placebo
Drug: TMC649128
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase Ib, Double-Blind, Randomized, Placebo-Controlled Trial in Genotype 1 HCV-Infected Subjects to Determine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Repeated Doses of TMC649128 Given as Monotherapy and Given in Combination With Pegylated Interferon + Ribavirin

Resource links provided by NLM:


Further study details as provided by Tibotec BVBA:

Primary Outcome Measures:
  • Change in the steady-state plasma concentrations of TMC649128. [ Time Frame: From baseline up to Day 80 per panel (panel 1 + panel 2 + panel 3). ] [ Designated as safety issue: No ]
  • Change in the steady-state plasma concentrations of TMC649128 following co-administration with pegylated interferon + ribavirin. [ Time Frame: From baseline up to day 84 (panel 4). ] [ Designated as safety issue: No ]
  • Viral load decreases and/or changes of viral load from baseline (HCV RNA copies/ml) (PK/PD). [ Time Frame: For monotherapy from baseline up to Day 80 per panel (panel 1 + panel 2 + panel 3) and for combination therapy from baseline up to day 84 (panel 4). ] [ Designated as safety issue: No ]
  • Number of participants with adverse events as a measure of safety and tolerability - TMC649128 as monotherapy and when co-administered with pegylated interferon + ribavirin. [ Time Frame: For monotherapy from baseline up to Day 80 per panel (panel 1 + panel 2 + panel 3) and for combination therapy from baseline up to day 84 (panel 4). ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antiviral activity (HCV RNA levels) of TMC649128 as monotherapy and when co-administered with pegylated interferon + ribavirin. [ Time Frame: For monotherapy from baseline up to Day 80 per panel (panel 1 + panel 2 + panel 3) and for combination therapy from baseline up to day 84 (panel 4) ] [ Designated as safety issue: No ]
  • Antiviral activity (viral breakthrough) of TMC649128 as monotherapy and when co-administered with pegylated interferon + ribavirin. [ Time Frame: For monotherapy from baseline up to Day 80 per panel (panel 1 + panel 2 + panel 3) and for combination therapy from baseline up to day 84 (panel 4). ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: June 2011
Study Completion Date: November 2011
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 010
TMC649128 panel 4 arm 2: 10 participants receive PegIFN a-2a/RBV in combination with TMC649128 administered q12h or q24h for 14 days. Actual dose and dose regimen (12h or 24h) is to be selected based on panels 1 2 and 3.
Drug: TMC649128
panel 4, arm 2: 10 participants receive PegIFN a-2a/RBV in combination with TMC649128, administered q12h or q24h, for 14 days. Actual dose and dose regimen (12h or 24h) is to be selected based on panels 1, 2 and 3.
Experimental: 001
TMC649128. panel 1: 8 participants receive a q24h regimen at 1000 mg of TMC649128.
Drug: TMC649128.
panel 1: 8 participants receive a q24h regimen at 1000 mg of TMC649128.
Placebo Comparator: 002
placebo. panel 1: 2 participants receive placebo at a q24h regimen.
Drug: placebo.
panel 1: 2 participants receive placebo at a q24h regimen.
Experimental: 003
TMC649128. panel 2 arm 1: 8 participants receive a q12h regimen of TMC649128 at a selected dose based on results of panel 1.
Drug: TMC649128.
panel 2, arm 1: 8 participants receive a q12h regimen of TMC649128 at a selected dose based on results of panel 1.
Placebo Comparator: 004
placebo. panel 2 arm 1: 2 participants receive placebo at a q12h regimen.
Drug: placebo.
panel 2, arm 1: 2 participants receive placebo at a q12h regimen.
Experimental: 005
TMC649128. panel 2 arm 2: 8 participants receive a q24h regimen TMC649128 at a dose based on results of panel 1.
Drug: TMC649128.
panel 2, arm 2: 8 participants receive a q24h regimen TMC649128 at a dose based on results of panel 1.
Placebo Comparator: 006
placebo. panel 2 arm 2: 2 participants receive placebo at a q24h regimen.
Drug: placebo.
panel 2, arm 2: 2 participants receive placebo at a q24h regimen.
Experimental: 007
TMC649128 panel 3: 8 participants receive TMC649128. Actual dose and dose regimen (q12h or q24h) to be selected based on the results of the panels 1 and 2.
Drug: TMC649128
panel 3: 8 participants receive TMC649128. Actual dose and dose regimen (q12h or q24h) to be selected based on the results of the panels 1 and 2.
Placebo Comparator: 008
placebo. panel 3: 2 participants receive placebo. Actual dose and dose regimen (q12h or q24h) to be selected based on the results of the panels 1 and 2.
Drug: placebo.
panel 3: 2 participants receive placebo. Actual dose and dose regimen (q12h or q24h) to be selected based on the results of the panels 1 and 2.
Placebo Comparator: 009
placebo panel 4 arm 1: 10 participants receive PegIFN a-2a/RBV in combination with placebo administered q12h or q24h for 14 days. Actual dose and dose regimen (12h or 24h) is to be selected based on panels 1 2 and 3.
Drug: placebo
panel 4, arm 1: 10 participants receive PegIFN a-2a/RBV in combination with placebo, administered q12h or q24h, for 14 days. Actual dose and dose regimen (12h or 24h) is to be selected based on panels 1, 2 and 3.

Detailed Description:

TMC649128 is a nucleoside inhibitor (NI) of hepatitis C virus (HCV) polymerase in development for the treatment of chronic hepatitis C infection. Treatment-naive genotype 1 HCV-infected participants are participants who have never received (pegylated) interferon ([Peg]IFN), ribavirin (RBV) or any other approved or investigational treatment for chronic HCV infection. Treatment-experienced genotype 1 HCV-infected participants are defined as previous non-responder and relapse subjects to previous treatment regimens (IFN/RBV or PegIFN/RBV), who have never received a HCV polymerase inhibitor and HCV protease inhibitor treatment was stopped since at least one year. This study is a Phase Ib, double-blind, randomized, placebo-controlled trial in genotype 1 HCV-infected participants to determine the safety, tolerability, pharmacokinetics and antiviral activity of repeated doses of TMC649128 given as monotherapy and given in combination with pegylated interferon + ribavirin. This trial consists of 2 phases. In the first phase TMC649128 will be given as monotherapy during 10 days at different doses and dosing regimens. In the second phase TMC649128 will be administered at one selected dose regimen in combination with PegIFN a-2a/RBV for 14 days.; All dosages of TMC649128 or placebo are given orally under fed conditions.; The monotherapy phase includes 3 panels (panel 1-3) and the combination therapy phase includes 1 panel (panel 4). In panel 1, subjects are randomly assigned to receive TMC649128 at 1000 mg q24h (every 24h) (n=8) or placebo (n=2) q24h on Days 1-10. In panel 2 subjects are randomized into Arm 1 and Arm 2 and within each arm, subjects are randomly assigned to receive TMC649128 or placebo as follows: In arm 1 volunteers receive TMC649128 at a selected dose (n=8) or placebo (n=2) q12h on Days 1-10. In arm 2 volunteers receive TMC649128 at a selected dose (n=8) or placebo (n=2) q24h on Days 1-10. Panel 3: TMC649128 at a selected dose (n=8) or placebo (n=2) q12h (every 12h) OR q24h on Days 1-10 where the assignment is determined by randomization; Panel 4 volunteers are randomized into Arm 1 and Arm 2. In panel 4, arm 1, 10 volunteers receive placebo (q12h OR q24h, dosing regimen matched to Arm 2 of Panel 4) + PegIFN a-2a/RBV on Days 1-14. In Panel 4, arm 2, 10 volunteers receive TMC649128 at a selected dose (q12h OR q24h) + PegIFN a-2a/RBV on Days 1-14.; The actual dose of Panel 1 is derived from data obtained from the currently ongoing MC649128HPC1001 trial. The actual dose in Panel 2 will depend on the results of Panel 1 (total daily dose of TMC649128 administered in both arms of Panel 2 will be the same. The dose of TMC649128 of the q24h regimen in Arm 2 will be higher than the q24h dose administered in Panel 1 [1000 mg q24h]). The actual doses and dose regimens in Panels 3 and 4 will depend on the results of Panels 1 and 2 (data review meetings). Selection of doses and dose regimens in Panels 2, 3 and 4 will also depend on the data obtained from trial TMC649128HPC1001. Dosing will stay within the exposure limits. The intended doses for Panels 2 and 3 are 2000 mg or 3000 mg q12h or q24h, but may be adapted based on previous clinical data. If needed and based on the outcome of the Panel 1 results, subjects in Panel 3 may eventually receive a lower dose than in Panel 1. See detailed study description.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Documented chronic (> 6 months) genotype 1a or 1b Hepatitis C virus (HCV) infection
  • Treatment-naive volunteer, meaning never received (Peg)IFN, RBV or any other approved or investigational treatment for chronic HCV infection (Panels 1, 2, 3 or 4) OR volunteer is a documented prior non-responder or relapser subject to previous treatment regimens (IFN/RBV or pegylated IFN/RBV) but has stopped this treatment at least 6 months before screening
  • volunteer has never received a HCV polymerase inhibitor and HCV protease inhibitor treatment was stopped since at least one year (Panels 1, 2 or 3)
  • Volunteer with HCV plasma RNA levels of > 100,000 IU/mL at screening
  • Body Mass Index of 18.0 to 35.0 kg/m2
  • Healthy based on a medical evaluation including medical history, physical examination, blood tests, vital signs, and electrocardiogram.

Exclusion Criteria:

  • Evidence of liver cirrhosis
  • Historical liver biopsy graded as liver cirrhosis or evidence for the presence of oesophageal varices or a transient elastography (Fibroscan) result of more than 14.6 kPa within 2 years prior to screening
  • Evidence of decompensated liver disease defined as prior history or current evidence of ascites, hepatic encephalopathy, bleeding oesophageal or gastric varices
  • Evidence of renal dysfunction, documented by an estimated creatinine clearance below 70 mL/min
  • Evidence of any other cause of significant liver disease in addition to hepatitis C, this may include but is not limited to hepatitis B, drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson's disease, non-alcoholic steatohepatitis, or primary biliary cirrhosis
  • Volunteer with diagnosed or suspected hepatocellular carcinoma
  • Volunteer receiving or having received any treatment for HCV during the 6 months before screening
  • Volunteer coinfected with Human Immunodeficiency Virus-1 (HIV-1) or HIV-2, or hepatitis A or B virus infection, or clinically active tuberculosis at study screening.
  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: NCT01391117

Locations
Netherlands
Zuidlaren, Netherlands
Poland
Krakow, Poland
Kraków, Poland
Warszawa, Poland
Sponsors and Collaborators
Tibotec BVBA
Investigators
Study Director: Tibotec-Virco Virology BVBA Clinical Trial Tibotec BVBA
  More Information

No publications provided

Responsible Party: Tibotec BVBA
ClinicalTrials.gov Identifier: NCT01391117     History of Changes
Obsolete Identifiers: NCT01532557
Other Study ID Numbers: CR017992, TMC649128HPC1002
Study First Received: June 13, 2011
Last Updated: October 25, 2012
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Tibotec BVBA:
TMC649128
HCV
TMC649128HPC1002
Hepatitis C
Hep C

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

ClinicalTrials.gov processed this record on November 25, 2014