| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic genotype 1 Hepatitis C infection |
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| 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 | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
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| 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 is to demonstrate superior efficacy of telaprevir in combination with Peg-IFN alfa-2a and RBV compared to standard treatment in subjects with chronic HCV genotype 1 infection who failed prior treatment with Peg-IFN plus RBV. The aim is to reach this primary objective separately for both strata of treatment failures: non-responders (defined as subjects who did not reach undetectable levels) or relapsers (defined as subjects with detectable HCV RNA during the follow-up period after previous undetectable HCV RNA at end of treatment). This will be evaluated by comparing the proportion of subjects achieving SVR who were treated with either of 2 regimens of telaprevir (with and without delayed start) combined with Peg-IFN alfa-2a and RBV, versus proportion of subjects achieving SVR, treated with standard treatment (Peg-IFN alfa-2a and RBV). SVR is defined as having undetectable plasma HCV RNA levels (< 10 IU/mL) 24 weeks after last planned intake of study medication. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate:
− effect of delayed start of telaprevir on efficacy (SVR and secondary parameters) of telaprevir in combination with Peg-IFN alfa-2a and RBV;
− efficacy of 2 telaprevir-based regimens versus standard treatment for 2 subgroups within non-responders, namely (1) null-responders and (2) partial responders;
− safety and tolerability of telaprevir in combination with Peg-IFN alfa-2a and RBV;
− changes from baseline in HCV NS3 protease domain;
− pharmacokinetics of telaprevir, Peg-IFN alfa-2a, and RBV, and the pharmacokinetic-pharmacodynamic relationship with virologic response, safety and tolerability parameters. Influence of covariates such as gender, age, body weight on pharmacokinetics of telaprevir will also be studied. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A substudy of VX-950-TiDP24-C216 to evaluate the pharmacokinetic profile of telaprevir and its R-diastereomer VRT-127394 in combination with pegylated interferon alfa-2a (Pegasys®) and ribavirin (Copegus®).
Final, 11 May 2008
Objectives:
The objective of this substudy is to obtain full steady-state pharmacokinetic profiles of telaprevir in plasma during treatment with 750 mg telaprevir q8h in combination with standard treatment with Peg-IFN alfa-2a (Pegasys) and RBV (Copegus). |
|
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria are eligible for this trial:
1. Subject is male or female, 18 to 70 years of age, inclusive.
2. Subject has chronic hepatitis C infection genotype 1 with HCV RNA level ≥ 1000 IU/mL. Genotype must be confirmed during screening. Chronic infection status must be confirmed by diagnosis of HCV > 6 months before the screening period.
3. Subject failed at least 1 prior course of Peg-IFN/RBV therapy, defined as:
− Subject had an undetectable HCV RNA level (by branched-chain DNA [bDNA], reverse transcription-polymerase chain reaction [RT-PCR], or transcription mediated amplification [TMA]-based assay) at the end (6 weeks or less after the last dose of medication) of a prior course of at least 42 weeks of Peg-IFN/RBV therapy but did not achieve SVR (viral relapser); or
− Subject never had an undetectable HCV RNA level (by bDNA, RT-PCR, or TMA-based assay) during or at the end of a prior course of at least 12 weeks of Peg-IFN/RBV therapy (null-responder and partial responder).
Subject must have received 80% or more of the intended dose of Peg-IFN/RBV.
The following information related to the virologic response to the last course of Peg-IFN/RBV therapy (that qualifies as an adequate course as defined above) must be available in the medical records of the subject:
- start and end date of the previous treatment course;
- HCV RNA results at start of treatment (all subjects), at 12 weeks after start of treatment (null and partial responders), at end of treatment (all subjects), and during follow-up (relapsers);
Note: the following time window is allowed for the Week 12 assessment time point: Week 11 to Week 16
- HCV RNA assay used and limit of detection.
4. Subject must have received the last dose of Peg-IFN or RBV at least 12 weeks before the screening visit.
5. Subject is judged to be in good health (besides HCV infection) in the opinion of the investigator, on the basis of medical history and physical examination (including vital signs and screening electrocardiogram [ECG]), with any chronic medical conditions under stable medical control.
6. Subject must have had a liver biopsy within 18 months prior to the screening visit and the biopsy report should be available, or he/she should agree to have a biopsy performed within the screening period.
Note: If a biopsy more than 18 months prior to screening has already demonstrated histological cirrhosis (Metavir F4; Ishak score ≥ 5), the biopsy does not need to be repeated if the biopsy report can be provided.
Note: If a biopsy was performed > 18 months but ≤ 21 months prior to screening, the biopsy does not need to be repeated if information supportive of the absence of progression of fibrosis since the time of the previous biopsy is provided by the investigator (e.g., recent fibrotest/fiboscan consistent with previous results) and if the biopsy report can be provided.
7. Subjects with cirrhosis should have serum alpha-fetoprotein (AFP) ≤ 50 ng/mL and normal abdominal ultrasound. If AFP > 50 ng/mL or ultrasound abnormal, subjects must have a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan to exclude hepatocellular carcinoma.
8. If heterosexually active, a female subject of childbearing potential and a non-vasectomized male subject who has a female partner of childbearing potential must agree to the use of 2 effective methods of contraception from screening onwards until 6 months (female subject) or 7 months (male subject) after the last dose of RBV.
Note: Hormonal contraceptives may not be reliable when taking telaprevir. Therefore, to be eligible for this trial, subjects should use 2 other effective birth control methods during telaprevir/placebo treatment and for 2 months after the last intake of telaprevir/placebo. As of 2 months after completion of telaprevir/placebo treatment, hormonal contraceptives can again be used as one of the 2 required effective methods of birth control.
Note: The use of birth control methods does not apply if the male partners have been vasectomized minimally 1 month prior to screening or if the female partners have had a bilateral oophorectomy, a total hysterectomy, or tubal ligation, or if they have been post-menopausal for at least 2 years.
9. Subject is willing and able to refrain from the concomitant use of any medications, substances, or foods noted under Section 5.3.11, from 14 days prior to the first day of study medication dosing through the end of treatment.
10. Subject is able to read and understand, and is willing to sign the Informed Consent Form (ICF) voluntarily before first trial-related activity and abide by the trial restrictions.
11. Subjects should agree not to participate in other clinical trials for the duration of his/her participation in this trial.
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| E.4 | Principal exclusion criteria |
Subjects meeting one or more of following criteria cannot be selected:
1. Subject is a previous non-responder that is classified as a viral breakthrough case i.e., subject had undetectable HCV RNA level during prior course of Peg-IFN/RBV therapy but regained detectable HCV RNA before therapy ended.
2. Subject is infected with HCV genotype 1 exhibiting more than one subtype.
3. Subject has HCV genotype 1 and exhibits co-infection with any other genotype.
4. Subject discontinued prior course(s) of Peg-IFN/RBV therapy due to tolerance issue instead of lack of response.
5. Subject has any contraindication to administration of Peg-IFN alfa-2a or RBV, including but not limited to any of following:
− hypersensitivity to Peg-IFN alfa-2a, RBV, or any of their components;
− hemoglobinopathies;
− history or clinical evidence of significant or unstable cardiac disease and/or clinically significant ECG abnormalities;
− abnormal thyroid function that cannot be controlled effectively by medication;
− poorly controlled diabetes mellitus as evidenced by hemoglobin A1c (HbA1c) ≥ 8.5% at screening;
− creatinine clearance ≤ 50 mL/min at screening;
− antinuclear antibody (ANA) titer ≥ 1:640 at screening, evidence of
autoimmune-mediated disease and/or evidence of autoimmune hepatitis.
6. Subject has a pre-existing psychiatric condition that could interfere with subject’s participation in and completion of the trial, including but not limited to:
− severe depression or hospitalization for depression;
− schizophrenia, bipolar illness, severe anxiety, or personality disorder;
− a period of disability or impairment due to a psychiatric disease within the past 5 years.
7. Subject has history of decompensated liver disease: history of ascites, hepatic
encephalopathy, or bleeding esophageal varices, and/or any of the following screening laboratory results:
− International Normalized Ratio (INR) of ≥ 1.5;
− Serum albumin < 3.3 g/dL;
− Serum total bilirubin > 1.8 times ULN, unless isolated and for subjects with Gilbert’s Syndrome.
8. Subject shows evidence of significant liver disease in addition to hepatitis C, which may include but is not limited to, drug or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, Nonalcoholic Steatohepatitis (NASH), or primary biliary cirrhosis.
9. Subject has active malignant disease or history of malignant disease within past 5 years
10. Subject has history of seizure disorders.
11. Subject has history of organ transplant that requires chronic immunosuppression
12. Subject has a medical condition that requires use of systemic corticosteroids
13. Diabetic or hypertensive subject with clinically significant ocular exam findings, e.g., retinopathy, cotton wool spots, and optic nerve disorder.
14. Subject has history or other clinical evidence of chronic pulmonary disease associated with functional impairment.
15. Subject has hemophilia.
16. Subject has evidence of serious or severe bacterial or fungal infection(s), including active tuberculosis.
17. Subject has human immunodeficiency virus (HIV) or hepatitis B virus (HBV) co-infection.
18. Subject has history of acute or chronic pancreatitis.
19. Suspicion exists of alcohol, barbiturate, amphetamine recreational or narcotic drug use, current or within 2 years prior to screening visit, that in investigator’s opinion would compromise the subject’s safety and/or compliance with study procedures.
20. Subject or female partner is pregnant, planning to become pregnant, or breastfeeding.
21. Subject has hypersensitivity to tartrazine (yellow dye #5).
22. Subject has a Grade 3 laboratory abnormality as defined by grading scale for the severity of AEs in hepatitis C clinical trials (see Section 7.3, Addendum 3), with the following exceptions:
- Grade 3 elevations in transaminsases (alanine aminotransferase [ALT]; aspartate aminotransferase [AST]). However, ALT/AST levels at screening should not exceed 10 times ULN.
- Grade 3 elevations in gamma-glutamyltransferase (GGT). However, subjects with grade 3 GGT elevations will only be allowed to enter trial if there is no evidence of current alcohol abuse and there are no other clinically relevant laboratory abnormalities, as judged by the investigator.
OR
subject has screening laboratory values of following variables that do not meet the acceptable values defined below:
Laboratory variable Acceptable values
Absolute neutrophil count ≥ 1,200/mm3
Platelet count ≥ 90,000/mm3
Hemoglobin ≥ 12 g/dL for females
≥ 13 g/dL for males
Uric acid Within normal range
TSH Within normal range, or adequately controlled thyroid function on treatment
23. Subject previously participated in:
• any investigational trial including direct acting anti-HCV antiviral agents or protease inhibitors;
• any clinical trial within 12 weeks before drug administration or participation in more than 2 trials in the last 12 months (exclusive of the current trial).
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to demonstrate the superior efficacy of telaprevir in combination with Peg-IFN alfa-2a and RBV compared to standard treatment in subjects with chronic HCV genotype 1 infection who failed prior treatment with Peg- FN plus RBV. The aim is to reach this primary objective separately for both strata of treatment failures: non-responders (defined as subjects who did not reach undetectable levels) or relapsers (defined as subjects with detectable HCV RNA during the follow-up period after previous undetectable HCV RNA at end of treatment). This will be evaluated by comparing the proportion of subjects achieving SVR who were treated with either of 2 regimens of telaprevir (with and without delayed start) combined with Peg-IFN alfa-2a and RBV, versus the proportion of subjects achieving SVR who were treated with standard treatment (Peg-IFN alfa-2a and RBV). SVR is defined as having undetectable plasma HCV RNA levels (< 10 IU/mL) 24 weeks after the last planned intake of study medication. |
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| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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