E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic hepatitis C infection genotype 1 |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019744 |
E.1.2 | Term | 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 |
The objectives of this trial are:
1. Evaluate the efficacy and the safety of BI 201335, 240 mg given for 12 or 24 weeks in combination with PegIFN/RBV given for 24 to 48 weeks as compared to PegIFN/RBV alone in chronic GT-1 hepatitis C virus infected patients who failed (previous partial responders or relapsers) a prior PegIFN/RBV treatment.
2. Evaluate the efficacy and the safety of BI 201335, 240 mg given for 12 or 24 weeks in combination with PegIFN/RBV given for 48 weeks as compared to historical PegIFN/RBV in chronic genotype 1 hepatitis C virus infected patients who failed (previous null-responders) a prior PegIFN/RBV treatment. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and efficacy of two different treatment regimens with BI 201335 (240 mg given for 12 or 24 weeks) in combination with PegIFN/RBV (24 or 48 weeks).
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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 |
Trough for PegIFN and RBV. A plasma sample will be collected for the analysis of RBV concentrations and a serum sample for the analysis of PegIFN α-2a concentrations at Week 0 (Day2, Visit 2a), Week 1 (visit 2b), Week 12 (Visit 6) and Week 24 (Visit 8),
A plasma sample collected after the morning BI 201335 dose will be collected at 2 h at Week 0 (Visit 2, Day 1) and at varying time at Week 4 (Visit 4) and Week 12 (Visit 6). In addition, a trough plasma sample for BI 201335 will be collected at Week 0 (Day 2, Visit 2a) and Week 1 (Visit 2b).
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E.3 | Principal inclusion criteria |
1. 1. Chronic hepatitis C infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening in addition to:
(a) Positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening; or,
(b) Liver biopsy consistent with chronic HCV infection,
2. HCV genotype 1 infection confirmed by genotypic testing at screening,
3. Confirmed prior virological failure (non-response) or (relapse) with an approved dose of PegIFN/RBV defined as following :
• Null response:
Absence of HCV RNA drop by ≥2 log10 from baseline at Week 12,
Lack of Early Virological Response (EVR),
• Partial response: (Partial Responder and Breakthrough)
HCV RNA drop by ≥2 log10 from baseline at Week 12 (EVR) but not achieving HCV RNA undetectable at end of treatment (based on an assay considered sensitive at the time of treatment),
• Prior relapse:
Undetectable HCV RNA (based on an assay considered sensitive at the time of treatment) at the end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment follow up.
4. HCV RNA ≥1,000 IU/mL at screening,
5. Documentation of liver biopsy within 3 years or fibroscan within 6 months prior to randomization visit,
Subject’s documentation of the liver biopsy or fibroscan performed will be requested at the randomization visit,
6. Age 18 to 70 years,
7. Female patients who are infertile or who are of childbearing potential with a negative pregnancy test and agreeing to use one accepted method of birth control in addition to the use of a condom by their male partners. female partners of childbearing potential shouldperform monthhly pregnancy tests from the date of screening until 7 months afer the last dose of RBV.
or
Male patients who are infertile, who are without pregnant female partners or who consistently and correctly use condoms.
8. Signed informed consent form prior to trial participation |
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E.4 | Principal exclusion criteria |
1. HCV infection of mixed genotype diagnosed by genotypic testing at screening,
2- Evidence of acute or chronic liver disease due to causes other than chronic HCV infection, incidental steaotosis disgnosis by biopsy is not an exclusion criteria
3- HIV co-infection,
4- HBV infection based on presence of HBs-Ag,
5- Active malignancy, or history of malignancy within the last 5 years prior to screening (with an exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix),
6- Active or, history of alcohol or illicit drug abuse other than cannabis within the past 12 months,
7- A condition that is defined as one which in the opinion of investigator may put the patient at risk because of participation in this study, may influence the results of this study, or limit the patient’s ability to participate in this study,
8- Usage of any investigational drugs within 30 days prior to screening, or planned usage of an investigational drug during the course of this study,
9- Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to randomization. Patients being treated with oral antivirals such as acyclovir, famiclovir or valacyclovir for recurrent herpes simplex infection; or with oseltamivir or zanamivir for influenza A infection, may be screened,
10- Received silymarin (milk thistle), glycyrrhizin, or Sho-saiko-to within 28 days prior to randomization and throughout the treatment phase of this trial,
11- Patients who have been previously treated with at least one dose of any antiviral or immunomodulatory drug other than interferon alfa or ribavirin for acute or chronic HCV infection including and not restricted to protease or polymerase inhibitors,
12- Known hypersensitivity to any ingredient of the study drugs,
13- Alpha fetoprotein value >100 ng/mL at screening; if >20 ng/mL and ≤100 ng/mL, patients may be included if there is no evidence of liver cancer in an appropriate imaging study (e.g., ultrasound, CT scan, or MRI) within last 6 months prior to randomization,
14- Decompensated liver disease, or history of decompensated liver disease, as defined by the presence of: hepatic encephalopathy, ascites, or esophageal variceal bleeding, and/or laboratory values which add to >= 7 points (CPB) according to the Child-Turcotte-Pugh (CTP) classification,
15. Pre-existing psychiatric condition that could interfere with the subject’s participation in and completion of the study including but not limited to prior suicidal attempt, schizophrenia, major depression syndrome, severe anxiety, severe personality disorder, a period of disability or impairment due to a psychiatric disease within the past 5 years, homicidal ideation, bipolar disorders, mania,
16. Clinical evidence of significant or unstable cardiovascular disease, including angina, myocardial infarction within 6 months, pulmonary hypertension, cardiomyopathy, congestive heart failure, uncontrolled hypertension, significant arrhythmia or clinically significant abnormalities on ECG at screening,
17. Clinical evidence of chronic pulmonary disease associated with functional impairment,
18. Active autoimmune disease, including autoimmune hepatitis,
19. History or evidence of retinopathy or clinically significant ophthalmological disorder including diabetic or hypertensive retinopathy, retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy, or retinal artery/vein obstruction. An eye examination performed within 6 months prior to randomization is required,
20. Organ transplant history other than cornea or hair,
21. Require chronic systemic corticosteroids (nasal or pulmonary steroids will be allowed),
22. Active seizure disorder within the last 2 years (Note: Patients may be enrolled if on stable medication and without seizures for more than 2 years prior to screening.),
23. Red blood cell disorders which include but are not limited to thalassemia major, sickle cell anemia or G6PD deficit. Patients with traits or minor diseases may be enrolled if the disease does not result in anemia, according to the investigator’s clinical judgment,
24. Body weight <40 or >125 kg,
25. TSH and T4 outside normal limits and inadequately controlled thyroid function; patients with abnormal TSH may be enrolled if free T4 is normal and there is no clinical evidence of hyperthyroidism or hypothyroidism,
26. Hemoglobin <12 g/dL for women and <13 g/dL for men,
27. Poorly controlled diabetes mellitus, defined as HbA1c ≥8.5%,
28. White blood cell count <2,000 cells/mm3
29. Absolute neutrophil count <1,500 cells/mm3
30. Platelet count <90,000 cells/mm3
31. Serum creatinine >1.5xULN or creatinine clearance =< 50 mL/min
32. Antinuclear antibody titer ≥1:640 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Sustained Virological Response (SVR): Plasma HCV RNA <25 IU/mL undetected at 12 weeks after the originally planned treatment duration. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after the originally planned treatment duration |
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E.5.2 | Secondary end point(s) |
• Virological response after 24 weeks of treatment discontinuation (SVR24): Plasma HCV RNA level <25 IU/mL, undetected; 24 weeks after the originally planned treatment duration,
• Early Treatment Success (ETS): Plasma HCV RNA level <25 IU/mL (detected or undetected) at Week 4 and HCV RNA <25 IU/mL, undetected at Week 8,
• ALT normalisation. ALT normal 24 weeks after end of the originally planned treatment duration.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•24 weeks of treatment discontinuation
•at Week 4 and week 8,
•24 weeks after end of the originally planned treatment duration.
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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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
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 | 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.8.2.4 | Number of treatment arms in the trial | 7 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 |
Austria |
Belgium |
Canada |
France |
Germany |
Japan |
Portugal |
Romania |
Spain |
Switzerland |
United Kingdom |
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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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 | 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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |