| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic infection with HCV - genotype 1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic infection with Hepatitis C virus |
|
| 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 | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
Aim of the trial is to confirm efficacy and safety of treatment with 600 mg of BID BI 207127 in combination with 120 mg QD Faldaprevir (previously called BI 201335) and RBV for 16 and 24 weeks in target chronically infected HCV GT1 treatment naïve patients, including patients with compensated cirrhosis. This “target” population excludes GT1a infected patients with the host IL28B rs12979860 CT or TT (non-CC) genotypes.
Primary objective of the trial is to determine if there is a clinically meaningful difference between 16- and 24-week treatment durations. |
|
| E.2.2 | Secondary objectives of the trial |
| To determine if a minimum historical target SVR12 rate of 71% can be achieved by the combination treatments of BI 207127, Faldaprevir and RBV, including patients with compensated cirrhosis. |
|
| 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 |
| pharmacokinetic (PK) substudy, 45 patients, 3 PK days with 5 blood draws per days |
|
| E.3 | Principal inclusion criteria |
1. Chronic hepatitis C infection diagnosed by 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 sub-GT1b confirmed by genotypic testing at screening, or HCV
infection of sub-GT1a, GT1 with undefined subtype or 1a/1b subtype confirmed by
genotypic testing at screening in patients with IL-28b CC genotype.
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 of for acute or chronic hepatitis C infection
4. Plasma HCV RNA ≥ 1,000 IU/mL at screening
5. Liver biopsy within three years or fibroscan within 6 months prior to randomisation.
Note: 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. Patients with a liver biopsy performed 3 or more years (or
fibroscan performed 6 months or more) prior to randomisation, negative for the presence
of cirrhosis need to repeat the liver biopsy or fibroscan, with the result available before
randomisation visit.
6. Age 18 – 75 years (inclusive)
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. of childbearing potential with a negative pregnancy test at screening and on Day 1
(Visit 2), that 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).
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. HCV subtype 1a, GT1 undefined or 1a/1b in patients with IL28b non-CC
polymorphism
3. Evidence of liver disease mainly due to causes other than chronic HCV infection
such as autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis or
Wilson’s disease.
Note: patients with steatosis as part of the histologic findings on liver biopsy are not
excluded.
4. HIV-1 or HIV-2 infection
5. Hepatitis B virus (HBV) infection based on presence of HBs-Ag
6. 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
7. International Normalized Ratio (INR) of ≥1.7
8. Serum albumin ≤3.5 g/dL
9. Serum total bilirubin >2.0 times the upper limit of normal (ULN), unless history of
Gilbert’s disease
10. 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)
11. Patients with ongoing or historical photosensitivity or recurrent rash
12. Alcohol or drug abuse (except cannabis) within the past 12 months
13. Body mass index <18 or > 35 kg/m2
14. 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
15. Known hypersensitivity to any ingredient of the study drugs
16. 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
17. 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
18. 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
19. Received concomitant hematopoietic growth factor, or immunomodulatory treatment
within 28 days prior to randomisation
20. 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.
The following exclusion criteria are potential contraindications for the use of PegIFN
+/- RBV (for rationale please cf. Section 3.2)
21. Pre-existing psychiatric conditions including but not limited to severe depression or
hospitalization for depression, suicidal ideation and attempted suicide, schizophrenia,
bipolar illness, severe anxiety or personality disorder, a period of disability or
impairment due to a psychiatric disease current or within the previous 3 years before
randomisation
22. Abnormal thyroid function that cannot be controlled effectively by medication
23. Active autoimmune-mediated disease known to be exacerbated by peginterferon
therapy (e.g., Crohn’s disease, ulcerative colitis, idiopathic thrombocytopenic
purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma,
severe psoriasis)
24. Requirement for chronic systemic corticosteroids (nasal or pulmonary steroids will
be allowed)
25. History or other evidence of severe retinopathy or clinically significant
ophthalmological disorder due to diabetes mellitus or hypertension (but not limited to
these conditions). For subjects with a history of hypertension or diabetes, written
clearance from an ophthalmologist has to be obtained before the start of treatment
26. Hemoglobin <11.0g/dL for women and <12.0g/dL for men
27. Absolute neutrophil count < 1,500 cells/mm3
28. Platelet count < 90,000 /mm3
29. Creatinine clearance ≤50 ml/min
30. Diabetes mellitus with HbA1c > 8.5%
31. Clinically evident red blood cell disorders which include but are not limited to
thalassemia major, sickle cell anemia or glucose-6-phosphate dehydrogenase
deficiency or glucose-6-phosphate dehydrogenase deficiency |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Sustained Virologic Response at Week 12 after end of active* treatment (SVR12): Plasma HCV RNA level <25 IU/mL at 12 weeks after end of active* treatment.
*As patients included in Group 1 and respectively Groups 2 and 3 have different durations of
active treatment, SVR 4, 12 and 24 will be assessed at different timepoints, taken into
consideration the time after end of active treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after end of active treatment, meaning Week 28 for Group 1 (16 weeks of active therapy), and Week 36 for Groups 2 and 3 (24 weeks of active therapy), respectively |
|
| E.5.2 | Secondary end point(s) |
- SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after end of active* treatment.
- SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after end of active*
treatment.
*As patients included in Group 1 and respectively Groups 2 and 3 have different durations of
active treatment, SVR 4, 12 and 24 will be assessed at different timepoints, taken into
consideration the time after end of active treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SVR 4: 4 weeks after end of active treatment, meaning Week 20 for Group 1 (16 weeks of active therapy), and Week 28 for Groups 2 and 3 (24 weeks of active therapy),respectively.
SVR 24: 24 weeks after end of active treatment, meaning Week 40 for Group 1 (16 weeks of active therapy), and Week 48 for Groups 2 and 3 (24 weeks of active therapy), respectively |
|
| 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 | 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 |
| groups 1 and 2: double blind, placebo-controlled, group 3: 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 | 12 |
| 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 |
| Argentina |
| Austria |
| Brazil |
| Canada |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Switzerland |
| 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
|
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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