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 |
Chronic Hepatitis C infected patient who is not cirrhotic |
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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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019183 |
E.1.2 | Term | HCV |
E.1.2 | System Organ Class | 100000004848 |
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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 primary objective of this study is to compare the efficacy of the two boceprevir (BOC) containing therapeutic regimens using non-inferiority in treatment naïve subjects with chronic hepatitis C genotype 1 who have the IL28B CC allele. The regimens differ in the treatment for subjects who achieve HCV RNA undetectability at the end of the Peginterferon Alfa-2a /ribavirin (PEG2a/R) 4 week lead-in.
The primary endpoint of this study is sustained virologic response (SVR) defined as undetectable plasma HCV-RNA at Follow-up Week (FW) 24. |
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E.2.2 | Secondary objectives of the trial |
To estimate the difference in the SVR rate in subjects who have undetectable HCV RNA at TW4 (rapid virologic response, RVR) in Arm 2a compared to Arm 1a. These subjects receive 4 weeks of PEG2a/R and then:
1) Arm 1a: an additional 20 weeks of PEG2a/R for a 24 week regimen.
2) Arm 2a: an additional 20 weeks of therapy with BOC plus PEG2a/R for a 24 week regimen.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Each subject must be willing and able to provide written informed consent for the trial.
2. Subjects must be willing to give written informed consent for pharmacogenetic testing, and able to adhere to dose and visit schedules.
3. Each subject must be ≥ 18years of age.
4. Each subject’s weight must be ≥ 40 kg and ≤ 125 kg
5. Subject must have previously documented CHC genotype 1 infection where genotyping is performed as standard of care. If genotyping is not considered standard of care, then determination can be done at screening. Subjects with other or mixed genotypes are not eligible. The HCV-RNA result obtained from the central laboratory at the Screening Visit must confirm HCV genotype 1 infection with HCV RNA ≥10,000 IU/mL.
6. Subjects must have IL28b CC allele gene (with SNP rs12979860)
7. Subject has had a liver biopsy without evidence of cirrhosis and hepatocellular carcinoma. A liver biopsy done prior to screening is acceptable if:
Within 3 years of screening and the result was METAVIR (or equivalent) Stage 0 (F0) to 2 (F2).
Within 1 year of screening and the result was Stage 3 (F3).
If the prior liver biopsy was obtained outside the acceptable windows, a repeat biopsy may be performed, and the results must show no evidence of cirrhosis and hepatocellular carcinoma in order for the subject to be randomized in the study.
For countries where liver biopsy is not performed prior to treatment and where noninvasive tests (for e.g. FibroScan and/or FibroTest) are used for staging of liver disease, these results may be used to assess eligibility. Subjects with a documented FibroScan score of ≤9.5 kPa, or FibroTest score of ≤0.58 are
allowed to be enrolled in the study. These non-invasive tests done prior to screening are acceptable if they were performed within 1 year of screening and meet the indicated cut-offs. If the prior non-invasive tests were not performed within 1 year of screening, results from one of these non-invasive tests is required before study drug dosing. If a subject has both liver biopsy and one of these non-invasive tests, whichever test demonstrates the presence of cirrhosis would be used to determine eligibility. In other words, if the liver biopsy shows cirrhosis, the subject is excluded, regardless of results of the non-invasive assay. If the liver biopsy does not show cirrhosis, but the non-invasive assay does, then the subject is still excluded.
8. Subject has had an ECG within 6 months without clinically significant abnormalities prior to the screening visit (or between the screening visit and Day 1).
9. Subject and subject’s partner(s) must each agree to use acceptable methods of contraception as specified in Section 7.6.1 for at least 2 weeks prior to Day 1
and continue until at least 6 months after last dose of study medication, or longer if dictated by local regulations. Postmenopausal women are not required to use contraception. Postmenopausal is defined as at least 12 consecutive months without a spontaneous menstrual period. Each sexually active male subject with
a female partner(s) of child-bearing potential must also provide written informed consent to provide information regarding any pregnancy.
For the purposes of this protocol, a male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as: one who has undergone a
successful vasectomy. A successful vasectomy is defined as: (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy.
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E.4 | Principal exclusion criteria |
1. Subject is under the age of legal consent, is mentally or legally incapacitated, has significant emotional problems at the time of pre-study screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.
2. Subjects co-infected with the human immunodeficiency virus (HIV) or hepatitis B virus (Hepatitis B surface antigen [HBsAg] or HIV positive).
3. Subjects who were previously treated with an interferon or ribavirin regimen or HCV direct acting anti-viral regimen.
4. Treatment for hepatitis C with any investigational medication. Prior treatments with herbal remedies with known hepatotoxity are exclusionary.
5. Subjects receiving any of the following medication(s) within 2 weeks prior to the Day 1 visit that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations could be associated with serious and/or life- threatening events such as orally administered midazolam, pimozide, amiodarone, flecainide, propafenone, quinidine, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine).
6. Subject has participated, is currently participating, or intent to participate in another clinical trial with an investigational compound within 30 days of the screening visit. Collection of additional blood, urine, or tissue samples or additional data, beyond that specified in this protocol, is prohibited
7. Evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy.
8. Subject has evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.
9. Subject is diabetic and/or hypertensive with clinically significant ocular examination findings within 6 months prior to the screening visit or between the screening visit and Day 1: retinopathy, cotton wool spots, optic nerve disorder, retinal hemorrhage, or any other clinically significant abnormality.
10. Subject has pre-existing psychiatric condition(s)
11. Subject has a clinical diagnosis of substance abuse
12. Subject has any known medical condition that could interfere with the subject’s participation in and completion of the trial
13. Subject has evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible.
14. Female subject is pregnant, lactating, expecting to conceive or donate eggs Male subject is planning to impregnate or provide sperm donation or has a female sexual partner who is pregnant or is of childbearing potential and is unwilling to commit to using two methods of birth control throughout treatment and after the completion of all treatment
15. Subject has any other condition which, in the opinion of the principal investigator or physician, would make the subject unsuitable for enrollment or could interfere with the subject participating in and completing the study or might confound the results of the study.
16. Subject had a life-threatening SAE during the screening period.
17. Subject is a member or a family member of the investigational study staff or sponsor staff directly involved with this study.
18. Subject has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis,
and autoimmune hepatitis.
19. Hemoglobin <12 g/dL for females and <13 g/dL for males;
20. Neutrophils <1500/mm3, or <1,200/mm3 for subjects of African descent
21. Platelets <150,000/mm3;
22. Direct bilirubin >1.5 x upper limit of normal (ULN) of the laboratory reference range. Total bilirubin >1.6 mg/dL unless the subject has a history of Gilbert's disease.
23. Serum albumin below the lower limit of normal (LLN) of laboratory reference range.
24. Thyroid-stimulating hormone (TSH) >1.2 x ULN or <0.8 x LLN of laboratory reference range with the following exceptions:
a) The subject may be enrolled if clinically euthyroid, AND
b) The euthyroid function is confirmed by thyroxine/triiodothyronine (T4/T3) testing
25. Serum creatinine >ULN of the laboratory reference
26. Serum glucose:
a) For subjects not previously diagnosed with diabetes mellitus:
i. ≥140 mg/dL unless hemoglobin, A1c subtype (HbA1c) ≤7%; OR
ii. ≥100 mg/dL (fasting) unless HbA1c ≤7%
b) For subjects previously diagnosed with diabetes mellitus, HbA1c >8.5%
27. Prothrombin time (PT) or INR values >10% above the upper limit of the normal laboratory reference range.
28. Anti-nuclear antibodies (ANA) > 1:320
29. Alpha fetoprotein (AFP): AFP >100 ng/mL
30. A positive pregnancy test
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E.5 End points |
E.5.1 | Primary end point(s) |
The Primary Efficacy Endpoint is the achievement of SVR, defined as undetectable plasma HCV-RNA at Follow-up Week (FW) 24 in all randomized subjects in two boceprevir containing therapeutic regimens Arm 2 compared to Arm 1. If a subject is missing HCV-RNA data at FW 24 window but has data available after FW 24, the data after FW 24 will be used for the SVR evaluation. If a subject is missing data at and after FW 24 window and has undetectable HCV-RNA at FW 12, the subject will be considered a sustained virologic responder.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
HCV-RNA at Follow-up Week (FW) 24 |
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E.5.2 | Secondary end point(s) |
The Key Secondary Efficacy Endpoint is the achievement of SVR defined as undetectable HCV-RNA at FW 24 in randomized subjects who are HCV-RNA undetectable at Treatment Week (TW) 4 (RVR) and are assigned shorter treatment duration PEG2a/R for additional 20 weeks (Arm 1a) or BOC + PEG2a/R 20 weeks (Arm 2a).
Other Secondary Efficacy Endpoints:
• The achievement of SVR12 defined as undetectable HCV-RNA at FW 12 in subjects in Arm 2 compared to Arm 1.
• The achievement of SVR12 defined as undetectable HCV-RNA at FW 12 in subjects who are HCV-RNA undetectable at TW 4, Arm 2a compared to Arm 1a
• The proportion of subjects with undetectable HCV-RNA at TW 4 in each Arm (1, 2)
• The proportion of subjects with an undetectable HCV RNA at TW 8, TW 12 for Arm 1a, and 4 and 8 weeks after the addition of Boceprevir in Arm 2 (2a and 2b) and Arm 1b,
• The SVR rates in subjects with an undetectable HCV RNA at TW 8 or TW 12 for Arm 1a, 2a and 2b, and at TW 10 or TW 14 for Arm 1b.
• The proportion of subjects in each Arm (1 and 2) and subarms (1a, 1b, 2a, 2b) who relapse as defined as having undetectable HCV RNA at the end of therapy with detectable HCV RNA in the follow-up period (post-treatment)
• Change from baseline in the log10 HCV RNA at TW 4, and SVR by log change from baseline at TW 4
• The proportion of subjects with HCV virologic breakthrough
• The proportion of subjects with incomplete virologic response/rebound |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For key secondary end point: HCV-RNA at Follow-up Week (FW) 24
For Other Secondary Efficacy Endpoints: HCV-RNA at TWs 4, 8, 12 for Arms 1a, 2a, and 2b (or TWs 4, 10, 14 for Arm 1b), end of treatment, FWs 12 and 24.
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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 | No |
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 | 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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Boceprevir + Pegasys/ Ribavirin will be compared to only Pegasys/ Ribavirin |
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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 | No |
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 | 82 |
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 |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Czech Republic |
Estonia |
France |
Germany |
Guatemala |
Hong Kong |
Hungary |
India |
Israel |
Korea, Republic of |
Lithuania |
Malaysia |
Mexico |
New Zealand |
Peru |
Philippines |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
Singapore |
Spain |
Sweden |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
Venezuela, Bolivarian Republic of |
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E.8.7 | Trial has a data monitoring committee | No |
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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In the protocol we refer to ET as end of treatment. It could be the patient completed the scheduled visits or discontinue the medication. The end of trial visit will be 24 week follow up visit after the last dose of therapy for all randomized patients. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |