E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic hepatitis C infection |
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E.1.1.1 | Medical condition in easily understood language |
Chronic hepatitis C infection |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019752 |
E.1.2 | Term | Hepatitis C virus (HCV) |
E.1.2 | System Organ Class | 100000004848 |
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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 |
to determine the efficacy of telaprevir administered as 750 mg every 8 hours (q8h) in combination with pegylated interferon (Peg-IFN)-alfa-2a and ribavirin (RBV) in genotype 1 chronic HCV infected liver transplant patients as measured by sustained virologic response (SVR12planned). SVR12planned is defined as
having an undetectable HCV ribonucleic acid (RNA) level 12 weeks after the last planned dose of study medication. |
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E.2.2 | Secondary objectives of the trial |
- to compare the SVR rate from this study to a historical control SVR rate derived from the literature in subjects treated with Peg-IFN and RBV;
- to evaluate HCV RNA levels and responses over time, on treatment and during follow-up;
- to evaluate changes in liver graft biopsy histology comparing the last pre-treatment biopsy to the 24-week post-treatment biopsy;
- to evaluate safety and tolerability of telaprevir in combination with Peg-IFN-alfa-2a, RBV, and tacrolimus (TAC) or cyclosporin A (CsA);
- to evaluate the pharmacokinetics (PK) of telaprevir and concentrations of TAC or CsA;
- to evaluate dose titration requirements for TAC and CsA;
- to evaluate the incidence of liver graft rejection;
- to evaluate relapse rates and virologic failure rates;
- to evaluate changes from baseline in the amino acid sequence of HCV NS3-4A protease. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 to 70 years old.
2. First time liver transplant recipient
3. One of the following based on clinical history or by documented HCV RNA and treatment history:
a) Treatment-naïve subject
OR
- Relapser:
- Partial responder: ;
- Null responder:.
4. > 6 months to 10 years post-liver transplant.
5. Subject must be on a stable TAC or CsA containing immunosuppressive regimen, combination with MMF is allowed
6. Subject must agree to have a liver graft biopsy: >1 year of liver transplantation within 6 months prior to screening, 6-12 months of transplantation within 3 months,
7. The last pre-treatment liver graft biopsy report must reveal fibrosis stage (Metavir) F0-F3.
8. Subject is judged to be in moderately good health
9. 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. Male subjects must also agree not to donate sperm during the study and for 7 months after the last intake of RBV.
10. Subject or female partner is not pregnant, planning to become pregnant, or breastfeeding.
11. Subject is willing and able to refrain from the concomitant use of medications as described in the section “Disallowed Medication”
12. Subject is able to read and understand, and is willing to sign the Informed Consent Form (ICF) voluntarily.
13. Subject should agree not to participate in other clinical studies for the duration of his/her participation in this study, except for non-interventional or observational studies.
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E.4 | Principal exclusion criteria |
1. Subject is infected or co-infected with non-genotype 1 HCV.
2. Subject received treatment with a direct acting antiviral for hepatitis C.
3. Subject received HCV treatment following liver transplantation.
4. Subject has histological evidence of rejection on the most recent liver graft biopsy
5. Subject has a contraindication to the administration of Peg-IFN-alfa or RBV,
6. Subject has a pre-existing psychiatric condition that could interfere with the subject’s participation in and completion of the study,:
7. Following transplantation, subject has history of decompensated liver disease:
8. Subject’s liver graft biopsy used to meet study eligibility criteria and/or clinical condition shows evidence of liver disease in addition to hepatitis C,
9. Subject has active malignant disease or history of malignant disease within the past 5 years (with the exception of treated basal cell carcinoma or hepatocellular carcinoma (HCC) cured by liver transplant).
10. Family history of congenital QT prolongation or sudden death. History of congenital QT prolongation, drug-induced QT prolongation or Torsade de Pointes, nonsustained or sustained ventricular tachycardia, or baseline QTcF >450 msec.
11. Subject has history of seizure disorders unrelated to calcineurin toxicity.
12. Uncontrolled diabetes or hypertension post transplantwithin 3 months prior to the screening visit.
13. Subject has history or other evidence of clinically significant retinopathy or ophthalmological disorder,
14. Subject has history or other clinical evidence of chronic pulmonary disease
15. Subject has active hemophilia or other bleeding disorder.
16. Subject has evidence of serious or severe bacterial or fungal infection(s), including active tuberculosis.
17. Subject has HIV or HBV co-infection.
18. Subject has a history of acute or chronic pancreatitis post transplant with exception of gallstone or post ERCP pancreatitis.
19. Knowledge of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, current or within 2 years prior to the screening visit that in the investigator’s opinion would compromise the subject’s safety and/or compliance with study procedures.
20. Subject has a confirmed Grade 4 laboratory abnormality as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE grading table”) or any other clinically relevant abnormalities in the opinion of the investigator. Subjects with Grade 4 elevations of gamma- glutamyltransferase (GGT) will be allowed to enter the study if there are no other clinically relevant laboratory abnormalities as judged by the investigator.
The screening laboratory values of the following variables should meet the acceptable values defined below:
- absolute neutrophil count (ANC) ≥ 1,000/mm3;
- platelet count ≥ 75,000/mm3;
- hemoglobin ≥ 11g/dL;
- estimated creatinine clearance (Cockroft-Gault) > 60 mL/min at screening;
- potassium and magnesium within normal range;
- Grade ≤ 1 uric acid;
- Thyroxin stimulating hormone (TSH) and free thyroxine (T4) within normal range, or hyperthyroid and adequately controlled with thyroid treatment, or TSH or free T4 abnormal but considered to be clinically insignificant as judged by the investigator.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients achieving undetectable plasma HCV ribonucleic acid (RNA) levels. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after the last planned dose of study drugs |
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E.5.2 | Secondary end point(s) |
- Proportion of patients having undetectable plasma HCV ribonucleic acid (RNA levels)
- Proportion of patients having undetectable plasma HCV ribonucleic acid (RNA levels)
- Proportion of patients having undetectable plasma HCV ribonucleic acid (RNA levels)
- Proportion of patients having detectable plasma HCV ribonucleic acid (RNA levels) of <25IU/mL
- Proportion of patients having confirmed detectable HCV ribonucleic acid (RNA levels)
- Proportion of patients having confirmed detectable HCV ribonucleic acid (RNA levels)
- Proportion of patients having confirmed detectable HCV RNA during the follow-up period after previous HCV RNA < 25 IU/mL at
planned end of treatment
- Proportion of patients having an increase > 1 log in HCV RNA level from the lowest level reached, or a value of HCV RNA > 100 IU/mL in subjects whose HCV RNA has previously become < 25 IU/mL during treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 24 weeks after last planned dose of study drugs
- actual end of study drugs
- week 48 of study drugs
- week 48 of study drugs
- follow-up period after previous undetectable HCV RNA levels at actual end of study drugs
- follow-up period after previous undetectable HCV RNA levels at week 48
- follow up period after previous undetectable HCV RNA levels at week 48
- from day 1 till week 48
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 | No |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |