| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chronic hepatitis C infection of genotype 1 |
|
| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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 |
Part 1: Safety, antiviral effect and evaluation of any pharmacokinetic (PK) interactions of BI 207127 in combination with BI 201335 and ribavirin for 4 weeks in treatment-naïve patients with chronic HCV genotype 1 infection.
Part 2: Safety and antiviral effect of BI 207127 in combination with BI 201335, with or without ribavirin for 16, 28 or 40 weeks in patients with chronic HCV genotype 1 infection.
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|
| E.2.2 | Secondary objectives of the trial |
|
| 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 immunological substudy is part of the trial protocol. This substudy is intended to investigate innate and adaptive immune responses in HCV-infected patients during suppression of virus replication without PegIFN-mediated immune modulation. The results will improve the understanding of the pathways involved in HCV persistence and thus may contribute to development of new HCV treatments. |
|
| E.3 | Principal inclusion criteria |
1)Chronic hepatitis C infection, diagnosed by positive HCV serology test (HCV Ab positive) or detectable HCV RNA at least 6 months prior to screening, or by a liver biopsy typical of chronic hepatitis C in combination with positive HCV serology
2)HCV infection of genotype 1 (1a or 1b) confirmed by genotypic testing at screening. Note: if central lab is unable to differentiate the subtype, a recent subtyping from local lab within 6 months prior to screening will be accepted for stratification.
3)Treatment naive, defined as no prior treatment with any interferon, pegylated interferon, and /or ribavirin and no prior treatment with at least one dose of any direct antiviral agent for acute or chronic hepatitis C infection
4)Plasma HCV RNA ≥ 100,000 IU/mL at screening
5)Liver biopsy within two years or fibroscan within six months prior to screening. Note: In Part 1, cirrhosis has to be excluded, whereas in Part 2, patients with Child-Pugh A cirrhosis are eligible.
6)Age 18 – 75 years
7)Female patients who are infertile or who are of childbearing potential with a negative pregnancy test and agreeing to abstain from intercourse or to use one accepted method of birth control in addition to the use of a condom, OR
Male patients who are sterile, or who agree to abstain from intercourse or who use a condom while their female partners use one medically accepted method of birth control
8)Signed informed consent form prior to trial participation
|
|
| E.4 | Principal exclusion criteria |
1) Hepatitis C infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening
2) Evidence of liver disease due to causes other than chronic HCV infection
3) Positive ELISA for HIV-1 or HIV-2
4) Hepatitis B virus (HBV) infection based on presence of HBs-Ag
5) Decompensated liver disease, or history of decompensated liver disease
6) Active or suspected 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 alcohol or drug abuse (except cannabis) within the past 12 months
9) Body mass index <18 or > 35 kg/m2
10) Usage of any investigational drugs within 30 days prior to randomisation, or 5 half-lives, whichever is longer; 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 defined as one which in the opinion of the investigator may either interfere with the patient’s capability for participation in the trial or may influence the results of the trial or the patient’s ability to participate in the trial.
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) Total bilirubin > 1.5 x ULN with ratio of direct/indirect > 1
15) AST or ALT > 5 x ULN
16) Prothrombin time INR (International Normalised Ratio) prolonged to >1.5 x ULN
17) Requirement for chronic systemic corticosteroids (nasal or pulmonary steroids will be allowed)
18) Received concomitant systemic antiviral, hematopoietic growth factor, or
immunomodulatory treatment with 30 days prior to randomisation or 5 half-lives,
whichever is longer; patients being treated with oral antivirals such as acyclovir,
famcyclovir, valcyclovir for mild, localised recurrent herpes simplex infection, or
with oseltamivir and zanamivir for Influenza A may be enrolled.
19) Received silymarin (milk thistle) or glycyrrhizin or Sho-saiko-to (SST) within 30 days prior to randomisation
20) Use of any of the medications listed in Appendix 10.2 within 30 days prior to randomisation
21) Hemoglobin <12.0g/dL for women and <13.0g/dL for men
22) White blood cell count <2,000 cells/mm3
23) Absolute neutrophil count < 1,500 cells/mm3
24) Platelet count < 100,000 /mm3
25) Creatinine > 1xULN or creatinine clearance ≤50 ml/min
26) HbA1c > 7.5%
27) TSH and T4 outside normal limits (accepted if thyroid function adequately
controlled)
28) Chronic obstructive pulmonary disease
29) Screening ECG with any abnormalities suggestive of prior or active
cardiovascular disease
30) Chronic cardiac disease (e.g., coronary artery disease, congestive heart failure,
uncontrolled hypertension, significant arrhythmia)
31) Autoimmune disease, including autoimmune hepatitis
32) Hemoglobinopathy (e.g., thalassemia major or sickle cell anemia)
33) Glucose-6-phosphate dehydrogenase deficiency
34) History of moderate, severe or uncontrolled psychiatric disease, especially
depression, including a history of hospitalization or prior suicidal attempt
35) Abnormal findings in fundoscopy precluding IFN treatment within 6 months prior to randomisation
36) Organ transplant history, other than cornea or hair
37) Active seizure disorder within the past 2 years; patients may be enrolled if on stable medication and seizures have not been experienced for more than 2 years before randomisation
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Plasma HCV RNA level <25 IU/mL (detectable or undetectable)* at Week 4
Part 2: Sustained Virological Response (SVR): Plasma HCV RNA not detectable* at 24 weeks after completion of all therapy
*Plasma HCV RNA level will be measured using the quantitative Roche COBAS® Taqman HCV/HPS assay. HCV RNA levels <25 IU/mL will be analysed and reported as being undetectable or detectable. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Week 4
Part 2: Week 40, 52, or 64 (depending on treatment group assignment) |
|
| E.5.2 | Secondary end point(s) |
•Time to virological response: Timepoint of the first measurement of undetectable plasma HCV RNA level
•Plasma HCV RNA level not detectable at Week 4
•Sustained Virological Response at 12 Weeks after completion of all therapy (SVR-12): Plasma HCV RNA level not detectable at 12 weeks after completion of all therapy
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-For time to virological response: any timepoint
-Plasma HCV RNA level not detectable at Week 4: Week 4
-SVR-12: Week 28, 40, 52 (depending on treatment group assignment) |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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) | 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| consists of two subsequent parts: part 1 and part 2 |
|
| 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 | No |
| 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 | 40 |
| 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 | Information not present in EudraCT |
| 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 |
| Austria |
| France |
| Germany |
| New Zealand |
| Portugal |
| Romania |
| Spain |
| Switzerland |
|
| 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 visit 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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