E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 15.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008912 |
E.1.2 | Term | Chronic hepatitis C |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 assess efficacy of daclatasvir and TMC435 with and without ribavirin, as determined by the proportion of subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12. |
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E.2.2 | Secondary objectives of the trial |
• To assess safety, as measured by the frequency of SAEs and discontinuations due to AEs;
• To assess the relationship between efficacy and the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene;
• To assess the efficacy as determined by:
− HCV RNA < LOQ at each of the following time points: Weeks 1, 2, 4, 6, 8 (and 12), EOT, post-treatment Week 24 (SVR24), and post-treatment Week 36 (genotype 1b for 12 week arms);
− HCV RNA undetectable at each of the following time points: Weeks 1, 2, 4, 6, 8 (and 12), EOT, post-treatment Week 12, post treatment Week 24, and post-treatment Week 36 (genotype 1b for 12 week arms). |
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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 |
See section 5.5 of the study Protocol (Pharmacokinetic Assessments)
A pharmacokinetics sub-study of approximately 36 subjects at specified sites will be included to evaluate the pharmacokinetics of DCV and TMC435. In addition, an additional HCV RNA level at Day 3 will be collected in a subset of approximately 15 subjects at specified sites. |
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E.3 | Principal inclusion criteria |
• HCV Genotype 1a or 1b;
• Males and females, ≥ 18 years of age;
• HCV RNA ≥ 10,000 IU/mL;
• Subjects with compensated cirrhosis are permitted.
• Advanced fibrosis (F3/F4) is capped at approximately 35% of the total treated population with a minimum of 20% F4 subjects.
• If no cirrhosis, a liver biopsy within 3 years prior to enrollment is required
• If cirrhosis is present, any prior liver biopsy is sufficient |
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E.4 | Principal exclusion criteria |
Target Disease Exceptions
• Liver or any other transplant (other than cornea and hair):
• Evidence of a medical condition contributing to chronic liver disease other than HCV;
• Current or known history of cancer, (except situ carcinoma or adequately tx basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
• Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy;
• Subjects infected with HIV or HBV;
• Gastrointestinal disease impacting absorption of study drug;
• Uncontrolled diabetes or hypertension;
Medication related
• Prior treatment of HCV with HCV direct acting agent (DAA);
• Any criteria that would exclude the subject from receiving RBV.
Exclusion Laboratory results:
• ANC < 1.5 billion cells/L (<1.2 billion cells/L for Black/African-Americans);
• Platelets < 90 billion cells/L;
• Hemoglobin < 12 g/dL for females or < 13 g/dL for males;
• ALT≥ 5 x ULN
• In subjects without cirrhosis, total bilirubin ≥ 34 μmol/L (or ≥ 2 mg/dL) unless subject has a documented history of Gilbert’s disease;
• In subjects with cirrhosis, total bilirubin ≥ 26 μmol/L (or ≥ 1.5 mg/dL);
• INR≥ 1.7
• QTcF or QTcB > 500 mSec
• CrCl≤ 50 mL/min
• AFP > 100 ng/mL OR
• AFP ≥ 50 ng/mL and ≤ 100 ng/mL requires a liver ultrasound (HCC are excluded)
• Albumin < 3.5 g/dL (35 g/L) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Antiviral activity, as determined by the proportion of subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for each cohort defined by the previous response status (Naive, Null), HCV genotype, initial treatment regimen and treatment duration.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• On-treatment safety, as measured by the frequency of SAEs and discontinuations due to AEs from start (Day 1) to end of treatment (up to 24 weeks) plus 7 days.
• Proportion of subjects with SVR12 (HCV RNA < LOQ at post-treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene for each treatment arm.
• Proportion of subjects with HCV RNA < LOQ at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms;
• Proportion of subjects with HCV RNA undetectable at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 12 and post-treatment Week 24 for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• from start (Day 1) to end of treatment (up to 24 weeks) plus 7 days.
• post treatment week 12
• at each of the following time points:
Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms;
• at each of the following time
points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 12 and post-treatment Week 24 for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms.
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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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker; Resistance testing |
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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) | 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 | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
DCV/TMC435 combination with or without RBV |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 17 |
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 | No |
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 |
Argentina |
Chile |
France |
Germany |
Hungary |
Russian Federation |
Spain |
United States |
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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
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The last visit is defined as the date of the last post-treatment follow-up visit. The end of the study is defined as the last subject’s last visit date or when the last data point required for statistical analysis is received from the last subject, whichever is later. |
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 2 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 2 |