| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
| chronic hepatitis C virus (HCV) infection of genotype 1 |
|
| 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 | 17.0 |
| 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 |
|
| 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 aim of the study is to confirm efficacy and safety of treatment with 600 mg of BID BI 207127 in combination with 120 mg QD Faldaprevir (FDV) and ribavirin (RBV) for 16 or 24 weeks in “target” chronically infected HCV genotype 1b (GT1b) treatment naïve patients, including patients with compensated cirrhosis.
The primary objective is to determine if a minimum historical target Sustained Virologic Response (SVR) rate at 12 weeks of 71% for peginterferon (PegIFN) eligible patients and 50% for PegIFN-ineligible patients can be achieved by the combination treatments of BI 207127, FDV and RBV in GT1b patients, including patients with compensated cirrhosis.
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to determine if there is a clinically meaningful difference between 16- and 24-week treatment durations. |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 at least one of the following:
a. positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening, or
b. liver biopsy indicating chronic HCV infection, or
c. history of elevated alanine aminotransferase (ALT) levels at least 6 months prior to screening.
2. HCV infection of GT1b confirmed by genotypic testing at screening
3. HCV viral load ≥ 1,000 IU/mL at screening.
4. Patients who have never been previously treated with interferon alone, interferon+RBV, PegIFN+RBV or PegIFN+RBV+an investigational/approved DAA or any other HCV treatment regimen.
5. Availability of a liver biopsy within 3 years or fibroscan within 6 months prior to randomisation. Note: patients who do not have a liver biopsy (nor fibroscan) due to contraindication of the procedure should not be excluded for this reason and will be assigned to 24-week therapy. The decision on the inclusion of these patients should be discussed with the CML. Patients with a liver biopsy performed 3 or more years prior to screening demonstrating cirrhosis do not need to repeat a liver biopsy or fibroscan.
6. Age 18 to 75 years (inclusive).
7. Female patients with a negative urine pregnancy test (dipstick) at Visit 2 prior to randomization:
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, who, if sexually active, agree to use two non-hormonal methods of birth control from the date of screening until 7 months after the last dose of RBV. Patients must agree not to breast-feed at any time from the date of screening until 7 months after the last dose of RBV. Accepted methods of contraception in the study include diaphragm with spermicidal substance, cervical caps, intrauterine devices and condoms. Note: Systemic hormonal contraceptives may not be as effective in women taking BI 207127/FDV combination therapy and are not accepted methods of contraception in the study.
OR
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 RBV. 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 RBV (tests will be provided by the sponsor).
8. Signed informed consent form prior to trial participation
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| E.4 | Principal exclusion criteria |
1. HCV infection of mixed GT (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening.
2. HCV infection of sub-GT1a, mixed GT1a/1b, or undefined GT1.
3. Liver disease due to causes other than chronic HCV infection which may include but is not limited to hemochromatosis, Wilson's disease, or autoimmune liver diseases. Note: patients with steatosis as part of the histological findings of the liver biopsy are not excluded.
4. HIV infection.
5. Hepatitis B virus (HBV) infection based on presence of HBs-Ag.
6. Confirmed or suspected 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).
7. History of illicit drug abuse other than cannabis or chronic alcohol abuse within 12 months prior to randomisation.
8. Subject is not willing to comply with the precautionary measures to prevent photosensitivity (avoid excessive sun exposure and use sun block on a daily basis).
9. A condition that is insufficiently diagnosed, treated or clinically unstable which in the opinion of investigator may put the patient at risk because of participation in this study, influence the results of this study, or limit the patient’s ability to participate in this study, including but not limited to severe chronic obstructive pulmonary disease, uncontrolled psychiatric disease.
10. Decompensated liver disease, or history of decompensated liver disease, as evidenced by ascites, hepatic encephalopathy, history of esophageal variceal bleeding, or any other evidence of previous decompensation.
11. Total bilirubin >2 mg/dL with ratio of direct/indirect >1.
12. Serum albumin ≤3.3 g/dL.
13. Prothrombin time Institutional Normalised Ratio (INR) ≥1.7.
14. Clinical evidence of unstable cardiovascular disease which may further decompensate due to anemia, including unstable angina, recent myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension or significant arrhythmia.
15. Red blood cell (RBC) 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 at screening, according to the investigator’s clinical judgment.
16. Body weight <40 kg or >125 kg.
17. Usage of any investigational drugs within 28 days prior to randomisation, or planned usage of an investigational drug during the course of this study.
18. Received concomitant hematopoietic growth factor within 28 days prior to randomisation.
19. Received silymarin (milk thistle), glycyrrhizin, Sho-saiko-to (SST) or any medication listed in a restricted medication list provided in ISF within 28 days prior to randomisation, with the exception of parenteral analgesics used during liver biopsy procedure.
20. Known hypersensitivity to any ingredient of the study drugs.
21. 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, computer tomography (CT) scan, or Medical Resonance Imaging (MRI)) within last 6 months prior to randomization.
22. Haemoglobin <11 g/dL for women and <12 g/dL for men.
23. Absolute neutrophil count <1,000 cells/mm3.
24. Platelet count <70,000 cells/mm3.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Sustained Virologic Response at Week 12 post-treatment (SVR12): Plasma HCV RNA level <25 IU/mL at 12 weeks after EOT
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after end of treatment |
|
| E.5.2 | Secondary end point(s) |
1. SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after EOT
2. SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after EOT
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 4 weeks after end of treatment
2. 24 weeks after end of treatment |
|
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Arms 1 and 2: randomised, double-blind, placebo-controlled, Arm 3 (for cirrhotic patients): open |
|
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 111 |
| 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 |
| Belgium |
| Canada |
| France |
| Greece |
| Italy |
| New Zealand |
| Portugal |
| Australia |
| Germany |
| Korea, Republic of |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| Last follow up Visit (EOO - End of Observation, at 96 weeks after End of Treatment) of the last patient undergoing the trial |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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