| 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 |
| Hepatitis C Infektion vom Genotyp 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047457 |
| E.1.2 | Term | Viral 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 |
To investigate antiviral effect, safety and pharmacokinetics of treatment with 120mg or 240mg once daily BI 201335 NA as soft gelatin capsules in HCV genotype 1 infected treatment-naive patients for 24 weeks in combination with pegylated interferon-alfa 2a and ribavirin (PegIFN/RBV), with or without a 3-day (72+/-12) hour lead-in with PegIFN/RBV.
was amended to:
To investigate antiviral effect, safety and pharmacokinetics of treatment with 120mg or 240mg once daily BI 201335 NA as soft gelatin capsules in HCV genotype 1 infected treatment-naïve patients and of treatment with 240mg once daily or 240mg twice daily BI 201335 NA as soft gelatin capsules in HCV genotype 1 infected treatment-experienced patients for 24 weeks in combination with 24 or 48 weeks of pegylated interferon-α 2a and ribavirin (PegIFN/RBV) with or without a 3-day (72 +/- 12-hour) lead-in with PegIFN/RBV. |
|
| E.2.2 | Secondary objectives of the trial |
Investigation of drug-drug interactions between BI 201335 NA and RBV and PegIFN.
Exploration of early expression and genotype of interferon signalling genes and interferon stimulated genes. |
|
| 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 |
| An optional pharmacokinetic substudy includes intensive PK blood collection at Week 10. A second optional substudy investigates early expression and genotype of interferon signalling genes and interferon stimulated genes on Days 1, 4 and 8 of treatment. |
|
| E.3 | Principal inclusion criteria |
1)Chronic hepatitis C infection, diagnosed by seropositivity for anti-HCV antibodies or detectable HCV RNA at least 6 months prior to screening, or diagnosis confirmed by histology if less than 6 months prior to screening.
2)HCV infection of genotype 1(1a, 1b or mixed 1a/1b) diagnosed by genotypic testing or screening
3. For treatment-naïve patients (treatment arms 1 to 4):
Therapy-naïve to interferon (including any experimental or investigational interferon products as monotherapy or in combination with any other agents), pegylated interferon, or ribavirin for acute or chronic hepatitis C infection
For treatment-experienced patients (treatment arms 5 to 7):
Confirmed virological failure during or after combination treatment with an approved dose of alfa-2a or alfa-2b peginterferon combined with ribavirin; such patients must have received at least 12 weeks of therapy with a 90 day washout period prior to screening and must have documentation of medical history prior to enrolment in 1220.5.
Confirmed virologic failure in this protocol is defined as (a) Null Responder: <1 log10 maximum reduction in HCV RNA any time during treatment (b) Partial Responder: maximal reduction in HCV RNA (at any time point) > 1 log10 but never achieved HCV RNA below level of detection (with any assay with a detection limit of ≤ 50iU/mL).
4)HCV viral load>=100.000 IU/mL at screening
5) Liver biopsy within 24 months prior to study enrolment that provides histological evidence of any degree of chronic necroinflammatory activity or the presence of fibrosis, but no evidence of cirrhosis (Ishak grade 1-4 or Metavir Grade 1-3)
6)Normal finding on fundoscopy within 6 months prior to Day 1
6) Age 18 to 65
7) 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) childbearing potential with a negative serum pregnancy test at screening and on Day 1 (Visit 2) that either agree to abstain from intercourse, or agree to use one of the appropriate medically accepted methods of birth control (see below) from the date of screening until 6 months after the last dose of ribavirin in addition to the consistent and correct use of a condom, and that are not breast-feeding or nursing or plan to nurse at any time from the date of screening until 6 months after the last dose of ribavirin.
Note : Pregnancy tests must be performed every 4 weeks after screening until 6 months after the last dose of ribavirin for females of childbearing potential. Note: Medically accepted methods of contraception for females in this trial are ethinyl estradiol containing contraceptives, diaphragm with spermicide substance, and cervical cap.
8)Male patients (a) who are documented to be sterile, or (b) who agree to abstain from intercourse from the date of screening until 6 months after the last dose of ribavirin, or (c) who consistently and correctly use a condom while their female partners (if applicable) agree to use one of the appropriate medically accepted methods of birth control (see below) from the date of screening until 6 months after the last dose of ribavirin, and (d) 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 entry into the study or becomes pregnant during the treatment and follow-up phase. Female partners of childbearing potential must agree to perform a monthly pregnancy test from the date of screening until 6 months after the last dose of ribavirin
9) Signed informed consent from prior to trial participation.
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|
| E.4 | Principal exclusion criteria |
1) Hepatitis C infection of mixed genotype diagnosed by genotypic testing at screening
2) Patients who have been previously treated with at least one dose of any protease inhibitor for acute or chronic hepatitis C infection
3) Evidence of liver disease due to causes other than chronic HCV infection
4) Positive ELISA for HIV-1 or HIV-2
5) Hepatitis B virus (HBV) infection based on presence of HBs-Ag
6) Decompensated liver disease, or history of decompensated liver disease, as evidenced by ascites, portal hypertension, jaundice or hepatic encephalopathy, coagulopathy, varices, history of variceal bleeding, or any other clincial evidence of decompensation
7) 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)
8) History of alcohol or drug abuse within the past 12 months. Patients with documented drug and alcohol addiction free history of at least 12 months who are, in the opinion of the investigator, unlikely to relapse, may be enrolled in the study.
Note: Patients with a positive drug screen other than cannabis at time of screening will be excluded from the trial.
9) Usage of any investigational drugs within 30 days prior to enrolment, or 5 half-lives, whichever is longer; or the planned usage of an investigational drug during the course of the current study
10) Known hypersensitivity to any ingredient of the study drug
11) A condition that is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study
12) 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 two congruent imaging studies (e.g., ultrasound, CT scan, MRI) within 6 months of Day 1
13) Total bilirubin >1.5xULN with ratio of direct/indirect > 1. (Patients with Gilbert's polymorphism are not excluded.)
14) ALT or AST levels >5xULN
15) INR prolonged to >1.5xULN
16) Hemoglobin<12g/dL for women and <13g/dL for men
17) White blood cell count <2000cells/mm3
18) Absolute neutrophil count <1500cells/mm3
19) Platelet count<100.000cells/mm3
20) TSH and T4 outside normal limits and not adequately controlled thyroid function; patients with TSH below the lower limit of normal my be enrolled if free T4 is normal and there is no clinical evidence of hyperthyroidism or hypothyroidism
21) Poorly controlled diabetes mellitus as evidenced by HbA1c>7.5%
22) Patients who are at risk for bleeding (NSAIDs therapy, anticoagulant therapy, vitamin K deficiency, known coagulopathy, hemophilia)
23) Hemoglobinopathy (e.g. thalassemia major or sickle cell anemia)
24) History of moderate, severe or uncontrolled psychiatric disease, especially depression.
25) Clinical evidence of chronic cardiac disease
26) Clinically significant abnormalities on screening ECG
27) Clinical evidence of chronic pulmonary disease (e.g., chronic obstructive pulmonary disease) associated with functional impairment
28) Active autoimmune disease, including autoimmune hepatitis
29) Evidence of acute or chronic renal disease
30) Organ transplant history, other than cornea or hair
31) 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.
32) Requirement for chronic systemic corticosteroids (nasal or pulmonary steroids will be allowed)
33) Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to enrolment or 5 half-lives, whichever is longer; patients being treated with oral antivirals such as acyclovir, famiclovir, or valacyclovir for mild, localised recurrent herpes simplec infection may be enrolled
34) Received silymarin (milk thistle) or glycyrrhizin or Sho-saiko-to (SST) within 30 days prior to enrolment
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two co-primary efficacy endpoints in this trial:
1) End of Treatment Response of BI 201335 NA or placebo plus 4 weeks (ETR-1335/pcb + 4 wks), defined as plasma HCV RNA level below the lower limit of detection (<10IU/mL in the quantitative Roche COBAS Taqman HCV/HPS assay) at Week 28.
2) Sustained Virological Response (SVR), which is 24 weeks after completion of all therapy: Plasma HCV RNA level below the lower limit of detection, which will be at Week 48 or 72.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) End of Treatment
2) 24 weeks after End of Treatment |
|
| E.5.2 | Secondary end point(s) |
| other virologic response criteria and pharmacokinetics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| throughout the whole study |
|
| 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) | 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 | 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Romania |
| Spain |
| 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
|
| LPO: end of observation visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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