| 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 | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019752 |
| E.1.2 | Term | Hepatitis C virus (HCV) |
|
| 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 objective of the trial is to evaluate the efficacy of 6 different regimens of TMC435 in combination with PegIFNα-2a and RBV (i.e., SoC), defined as the proportion of subjects with undetectable HCV RNA (< 10 IU/mL) 24 weeks after the planned end of treatment (SVR24), compared to the control group receiving SoC in combination with TMC435-matched placebo. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To evaluate and compare the antiviral activity of TMC435 when administered in different regimens versus control (SoC) over the trial period;
- To evaluate and compare the antiviral activity of TMC435 when administered in different regimens versus control (SoC) over the trial period in the different subpopulations (prior null responders/partial responders/relapsers);
- To evaluate and compare the safety and tolerability of the TMC435-containing regimens versus SoC over the trial period;
- To determine the frequency/kinetics and viral genetics of virologic failures;
- To evaluate the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship for efficacy and safety of TMC435;
- To collect Medical Resource Utilization information, and to evaluate Quality of Life
(QoL) and the level of fatigue over the trial period. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria are eligible for this trial:
1. Male or female subject aged between 18 and 70 years, extremes included;
2. Documented chronic hepatitis C infection as evidenced by all of the following:
- a liver biopsy demonstrating chronic viral hepatitis within 2 years of screening;
- anti-HCV positive;
- HCV RNA positive (if only inflammation is present on liver biopsy, HCV RNA presence
should be documented for at least 6 months prior to baseline).
Note: If no biopsy is available, one will be performed on a separate day during screening. For subjects with cirrhosis diagnosed by prior biopsy (evidence of which should be available in the source documents) and no evidence of hepatocellular carcinoma (confirmed by alpha-fetoprotein [AFP] level < 50 ng/mL and ultrasound at screening), another biopsy is not required.
3. Genotype 1 HCV infection (confirmed at screening);
4. Plasma HCV RNA of > 10,000 IU/mL at screening (as assessed by standard quantitative in vitro nucleic acid amplification assay);
Note: Retesting of HCV RNA to reassess eligibility will be allowed only once using an
unscheduled visit during the screening period.
5. At least 1 prior documented course of PegIFNα-2a/RBV or PegIFNα-2b/RBV therapy for at least 12 consecutive weeks which has not been discontinued due to intolerability to PegIFNα-2a/b and RBV therapy;
Note: Subjects who were treated with (Peg)IFN monotherapy are not allowed.
6. Body weight between 40 and 125 kg;
7. Subject (male with partner of childbearing potential or female of childbearing potential) agrees to use 2 separate forms of highly effective contraception methods (1 of the methods needs to be a barrier method, e.g., condom or diaphragm) from screening throughout the duration of study treatment and for 7 months after the last dose of RBV, or is non-heterosexually active, vasectomized (male subject) or has a vasectomized partner (female subject), or is a female (subject or partner of male subject) of non-childbearing potential;
8. Informed consent signed voluntarily before the first trial-related activity;
9. Being able to comply with the protocol requirements. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting 1 or more of the following criteria cannot be selected:
1. Decompensated liver disease defined as history or presence of ascites, hepatic encephalopathy, esophageal bleeding, or gastric varices.
2. Any other liver disease of non-HCV etiology; this may include but is not limited to hepatitis A or B, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, non-alcoholic steatohepatitis (NASH) or primary biliary cirrhosis;
3. Infection/co-infection with non-genotype 1 HCV;
4. Co-infection with HIV type 1 or type 2 (HIV-1 or HIV-2) (positive HIV-1 or HIV-2 antibodies test at screening) or hepatitis B virus infection (hepatitis B surface antigen
[HbsAg]);
5. History of invasive malignancy diagnosed or treated within 5 years prior to screening (locally treated non-invasive basal cell skin carcinoma is permitted; cervical carcinoma in situ is allowed if treated prior to screening);
6. Evidence of hepatocellular carcinoma (e.g., AFP > 50 ng/mL);
7. Medical conditions that are exclusion criteria for PegIFNα-2a or RBV treatment (please refer to the manufacturer’s prescribing information for details):
− Presence or history of psychiatric disorders including but not limited to severe depression, anxiety disorders, psychotic disorders, a history of hospitalization for
any psychiatric disorder or a suicide attempt;
− Uncontrolled/unstable cardiac disorders (e.g., congestive heart failure, supraventricular arrhythmias);
− Uncontrolled/unstable chronic pulmonary disorders (e.g., chronic obstructive
pulmonary disease);
− Severe bacterial, viral or fungal infections including acute tuberculosis;
− Uncontrolled/unstable thyroid disease (hypo- or hyperthyroidism);
− Uncontrolled/unstable diabetes mellitus (e.g., glycated hemoglobin [HbA1c] ≥ 7%,
diabetic retinopathy);
− Renal impairment (e.g., serum creatinine >1.5 x ULN or creatinine clearance
< 50 mL/min);
− Anti-nuclear Antibody (ANA) titer ≥ 1:320;
− Autoimmune disease (e.g., Graves’ disease);
− Hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
8. Any active clinically significant disease other than hepatitis C (e.g., chronic pancreatitis) or findings during screening of medical history, physical examination, laboratory testing or ECG recordings that, in the investigator’s opinion, would compromise the subject’s safety or the outcome of the trial;
9. Having had an organ transplant (other than cornea or hair transplant or skin graft);
10. Having any of the following laboratory abnormalities:
− AST and/or ALT > 10 x ULN;
− Laboratory evidence of significantly decreased hepatic function or decompensation
(i.e., international normalized ratio [INR] > 1.5, or albumin < 30 g/L, or bilirubin > 1.5 x upper limit of laboratory normal range [ULN]);
− Laboratory abnormalities that are exclusion criteria for PegIFNα-2a or RBV treatment (please refer to the manufacturer’s prescribing information for details):
a. Platelet count < 90,000/mm³;
b. Absolute neutrophil count (ANC) < 1500 cells/mm³;
c. Hemoglobin < 12 g/dL for females and < 13 g/dL for males;
− Any other grade 3 or grade 4 laboratory abnormality according to the World Health
Organization (WHO) Toxicity Grading Scale.
11. History or evidence of current use of alcohol, barbiturates, amphetamines, 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 drug/alcohol misuse must be at least 1 year before the first administration of study medication);
12. Female subject who is pregnant, planning on becoming pregnant, or breast- eeding or partner of male subject who is pregnant or planning on becoming pregnant;
13. Concurrent participation in a clinical trial with another investigational drug or device within 30 days of the screening visit;
14. Known allergy or hypersensitivity to any of the components of the investigational medication or to any of the components of PegIFNα-2a s.c. solution or RBV tablets.
15. Having previously received treatment with TMC435 or any other direct-acting anti-HCV agent (e.g., NS5B polymerase, NS3/4A protease, or NS5A inhibitor). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Compare the efficacy, tolerability, and safety of different regimens with TMC435 plus PegIFNα-2a and RBV versus PegIFNα-2a and RBV alone (i.e., SoC) in adult subjects with genotype 1 HCV infection who have failed at least 1 prior course of PegIFN/RBV therapy. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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
| No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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