| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this trial are the following:
- to determine the dose dependency of the antiviral effect of TMC435350 during 1 week of monotherapy in treatment-naïve HCV-infected subjects;
- to determine the dose dependency of the antiviral effect of TMC435350 during combined tritherapy with PegIFNα-2a and RBV in treatment-naïve HCV-infected subjects. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are the following:
- to determine the safety, tolerability and pharmacokinetic profile of TMC435350 during 1 week of monotherapy, and during combined tritherapy with PegIFNα-2a and RBV, in treatment-naïve HCV-infected subjects;
- to determine the 4-week efficacy and safety of 2 selected doses of TMC435350 given in combination with PegIFNα-2a and RBV in treatment-experienced (prior non-responders to IFN-based therapy/relapsers, who did not discontinue anti-HCV therapy due to AEs) HCV-infected subjects;
- to determine the frequency, kinetics, and genetics of viral breakthrough of HCV during monotherapy and combination therapy; genetics of viral breakthrough will also be determined during SoC treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for this trial:
1. Aged between 18 and 70 years, extremes included;
2. Documented chronic (diagnosis of hepatitis C > 6 months before the screening period) genotype 1a or 1b HCV infection (as assessed by line probe assay); treatment-naïve subjects or prior non-responding subjects/relapsers to previous treatment regimens (IFN/RBV or pegylated IFN/RBV), who did not discontinue anti-HVC therapy due to AEs; genotype 1 HCV patients with hemophilia or with stable methadone use may be enrolled; (subtyping in genotype 1a and 1b patients will also be done);
3. ICF signed voluntarily before the first trial related activity;
4. Able to comply with the protocol requirements and having good accessible veins;
5. HCV plasma viral load of ≥ 10,000 IU/mL at screening (as assessed by the Taqman assay);
6. Bodyweight as defined by a Quetelet Index (Body Mass Index [BMI], weight in kg divided by the square of height in meters) between 18 and 32 kg/m², extremes included. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting one or more of the following criteria cannot be selected:
1. Evidence of Child Pugh B or C liver disease or Metavir score 5 or 6 at screening; history or evidence of cirrhosis or decompensated liver disease defined as prior or current history of ascites, hepatic encephalopathy, bleeding esophageal or gastric varices. 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. Subjects with diagnosed or suspected hepatocellular carcinoma;
2. Subjects receiving or having received polymerase inhibitor or protease inhibitor treatment for HCV during the 6 months before screening;
3. Male subjects with female partners of childbearing potential not agreeing to use a reliable birth control method for 90 days after the last dosing of TMC435350 in the trial or as prescribed in the leaflet of the medication as administered in the SoC treatment period (when taking PegIFNα-2a in combination with RBV, all subjects must use effective birth control methods during treatment and for 7 months afterwards);
4. Female, except if postmenopausal for over 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation);
5. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which in the Investigator’s opinion would compromise the subject’s safety and/or compliance with the trial procedures (period of non-drug/alcoholic misuse must at least be 1 month before the first administration of study medication).
6. A positive urine drug test at screening. Urine will be tested to check the current use of amphetamines, cocaine, and opioids (with the exclusion of methadone).
7. Subjects with at least one of the following laboratory abnormalities as defined by the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (see
Section 8.2, Addendum 2) at screening:
- Bilirubin ≥ 1.5x upper limit of laboratory normal range (ULN);
- Platelet count < 80,000/mm3;
- White blood cell (WBC) count < 2,000 cells/mm3;
- Any other lab toxicity found to be clinically significant by the Investigator.
8. Subjects coinfected with HIV-1 or HIV-2, or hepatitis A or B virus infection (confirmed by hepatitis A antibody immunoglobulin [IgM], or hepatitis B surface antigen [HBsAg]) at screening;
9. Subjects with a pathologically prolonged QTc value (> 500 ms) at screening, or any active clinically significant disease (e.g., tuberculosis, cardiac dysfunction), or medical history or physical examination findings during screening that, in the Investigator’s opinion, would compromise the outcome of the trial;
10. Subjects having uncontrolled/unstable diabetes, epilepsy, a manifest psychiatric disease;
11. Non-stable methadone use or subjects having any other unstable disease;
12. Subjects enrolled in another clinical trial within 90 days prior to screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Determine the dose dependency of antiviral effect of TMC435350 in treatment-naïve subjects during one week of monotherapy and during combined tritherapy with PegIFNα-2a and RBV. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| unblinding after data review meeting |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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