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
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
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.
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.
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.