| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
genotype 1 chronic hepatitis C
infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis C Virus Infection |
|
| 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 |
|
| 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 objective of this trial is to show superior efficacy of treatment with BI 201335 combined with PegIFN/RBV as compared to PegIFN/RBV alone (SOC). |
|
| 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 weeks or BI 201335 120 mg given for 12 or 24 weeks (BI-RGT) both in combination with PegIFN/RBV as compared to standard of care (SOC) with PegIFN/RBV alone
|
|
| 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 |
The optional PK sub-study to evaluate plasma concentrations of BI 201335, pegylated interferon α-2a and ribavirin will be performed at visits 2, 2a, 2b, 4, 6 and at week 24:
A plasma sample will be collected for the analysis of ribavirin concentrations and a serum sample for the analysis of pegylated interferon α-2a concentrations from each patient on Visits 6 and Week 24 visit.
A plasma sample collected after the morning BI 201335 dose will be collected at Visit 2, 2a, 2b, 4 and 6.
|
|
| E.3 | Principal inclusion criteria |
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. Therapy-naïve to interferon, pegylated interferon, ribavirin or any antiviral / immunomodulatory drug for acute or chronic HCV infection.
4. HCV RNA ≥ 1,000 IU/mL at screening
5. Documentation of a liver biopsy within 3 years or fibroscan within 6 months prior to the screening visit.
Note: If cirrhosis has been previously demonstrated on a biopsy, then biopsies obtained more than 3 years before randomization need not be repeated. Biopsies may be waived for patients who would be placed at risk from the procedure. Inability to do a liver biopsy should not exclude patients from a trial.
6. Age 18 to 70 years
7. Female patients:
a. with documented hysterectomy,
b. who have had both ovaries removed,
c. with documented tubal ligation,
d. who are post-menopausal with last menstrual period at least 12 months prior to screening, or
e. of childbearing potential with a negative serum pregnancy test at screening and Day 1, that, if sexually active, agree to use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin in addition to the consistent and correct use of a condom. Patients must agree not to breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin.
Medically accepted methods of contraception for females in this trial are ethinyl estradiol containing contraceptives, diaphragm with spermicide substance and intra-uterine device.
Male patients:
a. who are documented to be sterile, or
b. who are without pregnant female partner(s) and consistently and correctly use a condom while their female partner(s) (if of child-bearing potential) use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin. It is in the responsibility of the male patient to ensure that his partner(s) is not pregnant prior to screening into the study or becomes pregnant during the treatment and the observation phase.
Female partners of childbearing potential should perform monthly pregnancy tests from the date of screening until 7 months after the last dose of ribavirin (tests will be provided by the sponsor).
8. Signed informed consent form prior to trial participation
|
|
| E.4 | Principal exclusion criteria |
1. HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening
2. Evidence of acute or chronic liver disease due to causes other than chronic HCV infection. Incidental steatosis diagnosed by biopsy is not an exclusion criterion
3. HIV co-infection
4. Hepatitis B virus (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 (SST) within 28 days prior to randomization and throughout the treatment phase of this trial.
11. Known hypersensitivity to any ingredient of the study drugs.
12. 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 (Visit 2).
13. 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 up to ≥ 7 points according to the Child-Turcotte-Pugh (CTP) classification (Appendix 10.6)
14. 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, homicidal ideation, bipolar disorders, mania, a period of disability or impairment due to a psychiatric disease within the past 5 years.
15. 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.
16. Clinical evidence of chronic pulmonary disease (e.g. chronic obstructive pulmonary disease) associated with functional impairment.
17. Active autoimmune disease, including autoimmune hepatitis.
18. 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 (Visit 2) is required.
19. Organ transplant history other than cornea or hair.
20. Require chronic systemic corticosteroids (nasal or pulmonary steroids will be allowed).
21. 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.)
22. 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 (e.g. sickle cell trait or thalassemia minor) may be enrolled if the disease did not result in anemia, according to the investigator’s clinical judgment.
23. Body weight < 40 or > 125 kg
24. 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
25. Hemoglobin < 12 g/dL for women and < 13 g/dL for men.
26. White blood cell count < 2,000 cells/mm3.
27. Absolute neutrophil count < 1,500 cells/mm3.
28. Platelet count < 90,000 cells/mm3.
29. Poorly controlled diabetes mellitus, defined as HbA1c ≥ 8.5%
30. Serum creatinine > 1.5xULN or creatinine clearance ≤ 50 ml/min
31. Antinuclear antibody (ANA) titer ≥ 1:640
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Sustained Virological Response (SVR12): Plasma HCV RNA <25 IU/mL and undetected at 12 weeks after the originally planned treatment duration. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Virological response after 12 weeks of treatment discontinuation (SVR12):
Plasma HCV RNA level < 25 IU/mL, undetected; 12 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 and AST normalisation. ALT and AST normal at end of treatment and post-treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 8 weeks / 24 weeks / 60 weeks |
|
| 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 | 3 |
| 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 | 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 |
| European Union |
| Austria |
| Belgium |
| France |
| Germany |
| Japan |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
| The last patient last visit (Extended Follow-up Visit) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
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