| 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 | 14.1 |
| 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 |
| The main objective of the trial is to determine if BI207127 + Faldaprevir + Ribavirin for 24 weeks is non-inferior to treatment with telaprevir for 12 weeks + Ribavirin and Pegylated interferon for 24 or 48 weeks. |
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| E.2.2 | Secondary objectives of the trial |
• To descriptively summarise the secondary efficacy endpoints,
• To descriptively present SVR12 rates by important subgroups,
• To descriptively summarise the other safety data.
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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 |
Neurocognitive sub study in selected countries - To compare the effect of treatment with BI207127 + Faldaprevir + Ribavirin to Telaprevir + Ribavirin and Pegylated interferon on the Power of Attention following 12 week of treatment.
Also to assess the change in neurocognitive parameters during treatment and follow up period.
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| E.3 | Principal inclusion criteria |
1. Chronic HCV, diagnosed by HCV RNA ≥ 1,000 IU/mL 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 ALT levels at least 6 months prior to screening.
2. HCV infection of sub-GT1b confirmed by genotypic testing at screening.
3. Treatment naïve defined as:
a. no prior treatment with any interferon, pegylated interferon, and /or ribavirin
and
b. no prior treatment with at least one dose of any other licensed or investigational antiviral agent for acute or chronic hepatitis C infection.
4. Availability of a liver biopsy within three 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. The decision on the inclusion of these patients should be discussed with the CML. Patients with a liver biopsy performed 3 or more years (or fibroscan performed 6 months or more) prior to randomisation, demonstrating cirrhosis do not need to repeat a liver biopsy or fibroscan.
5. Age 18 – 70 years (inclusive).
6. Female patients
a. with documented hysterectomy, or
b. who have had both ovaries removed, or
c. with documented tubal ligation, or
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 on Day 1 (Visit 2), who agree to use two non-hormonal methods of birth control from the date of screening until 7 months after the last dose of ribavirin. They must not breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin.
Accepted methods of contraception for females in this trial are diaphragm with spermicide substances, intrauterine devices, cervical caps 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 consistently and correctly use a condom while their female partners (if of child-bearing potential) 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, and
c. without pregnant female partners. It is in the responsibility of the male patient to ensure that his partner (or partners) is not pregnant prior to enrolment into the study or becomes pregnant during the treatment and follow-up phase. Female partners of childbearing potential must 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).
7. Signed informed consent form prior to trial participation.
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| E.4 | Principal exclusion criteria |
1. HCV infection of mixed genotype (1/2, 1/3, and 1/4), HCV sub-GT1a or GT1 undefined, diagnosed at screening by genotypic testing.
2. 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 disease.
3. HIV infection.
4. Hepatitis B virus (HBV) infection based on presence of Hepatitis B surface antigen.
5. Evidence of decompensated liver disease or history of decompensated liver disease, defined as history of ascites, hepatic encephalopathy, bleeding esophageal varices or any other evidence of previous decompensation and/or any laboratory results (International Normalised Ratio, albumin, bilirubin) indicating a Child-Pugh-Turcotte score > 6 points (i.e. CPT-B or –C) (cf. Appendix 10.2)
6. Confirmed or suspected active malignancy or history of malignancy within the last 5 years (with the exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix).
7. Patients with ongoing or historical photosensitivity or recurrent rash.
8. History of illicit drug use (other than cannabis) or chronic alcohol abuse within 12 months prior to randomization, in the opinion of the Investigator.
9. Body mass index <18 or >35 kg/m2.
10. Usage of any investigational drugs within 28 days prior to randomisation, or the planned usage of an investigational drug during the course of the current study.
11. Known hypersensitivity to any ingredient of the study drugs.
12. 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.
13. Alpha fetoprotein value >100ng/mL at screening; if > 20ng/mL and ≤ 100ng/mL, patients can be included if there is no evidence of liver cancer in an appropriate imaging study within 6 months prior to randomisation.
14. A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease (e.g. congestive heart failure, myocardial infarction, unstable angina and arrhythmic disorders) current or within the previous 12 months before randomisation. Clinically significant Electrocardiogram (ECG) abnormalities. A history of congenital QT prolongation, or a family history of congenital QT prolongation or sudden death.
15. Received silymarin (milk thistle) or glycyrrhizin or Sho-saiko-to (SST) within 28 days prior to randomisation 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.
16. Pre-existing psychiatric conditions that could interfere with the subject’s participation in and completion of the study including but not limited to severe depression or hospitalization for depression, suicidal ideation and attempted suicide, schizophrenia, bipolar illness, severe anxiety or personality disorder, history of craniocerebral trauma or active seizure disorders requiring medication, a period of disability or impairment due to a psychiatric disease current or within the previous 3 years before randomisation.
Note: Patients whose score is 10-14 on the baseline PHQ-9 can be randomized only upon a psychiatrist statement ruling out major depression. Patients with a score of ≥15 must be excluded.
17. Abnormal thyroid function that cannot be controlled effectively by medication.
18. Active autoimmune-mediated disease (e.g., Crohn’s disease, ulcerative colitis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis).
19. Requirement for chronic systemic corticosteroids (inhaled or nasally administered or pulmonary steroids will be allowed).
20. History or other evidence of severe retinopathy or clinically significant ophthalmological disorder due to diabetes mellitus or hypertension (but not limited to these conditions).
21. Hemoglobin <12.0g/ Deciliter (dL) for women and <13.0g/ dL for men.
22. Absolute neutrophil count < 1,500 cells/mm3.
23. Platelet count < 90,000 /mm3.
24. Creatinine clearance ≤50 ml/min.
25. Diabetes mellitus with HbA1c > 8.5%.
26. Clinically evident red blood cell disorders which include but are not limited to thalassemia major, sickle cell anemia or glucose-6-phosphate dehydrogenase deficiency.
27. Evidence of serious or severe bacterial or fungal infection(s), including active tuberculosis.
28. Anticipated need for prohibited medications listed in the ISF throughout the duration of the trial.
29. Active or uncontrolled dermatological condition.
30. Potassium < 3.5 mmol/l.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Sustained Virological Response at Week 12 post-treatment (SVR12): Plasma HCV RNA level <25 IU/mL at 12 weeks after End Of Treatment.
Neurocognitive substudy primary endpoint - change in power of Attention from baseline to week 12. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
This will be 12 weeks after the end of treatment which is Week 36 for treatment group 1 or week 36 or week 60 for patients in treatment group 2.
Neurocognitive timepoint - 12 weeks after start of treatment. |
|
| E.5.2 | Secondary end point(s) |
• SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after End Of Treatment.
• SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after End Of Treatment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SVR4: 4 weeks after end of treatment, which is week 28 for patients in treatment group 1 and week 52 for patients in treatment group 2.
SVR24: 24 weeks after end of treatment, which is week 48 for patients in treatment group 1 and week 72 for patients in treatment group 2. |
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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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Telaprevir and Ribavirin and Pegylated Interferon |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Australia |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Norway |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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