| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021881 |
| E.1.2 | Term | Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10019805 |
| E.1.2 | Term | Hepatobiliary disorders |
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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 two therapeutic regimens of boceprevir dosed 800 mg three times a day (TID) orally (PO) (hereafter called boceprevir) in combination with PegIntron 1.5 µg/kg weekly (QW) subcutaneously (SC) plus weight-based dosing (WBD) of ribavirin (600 mg/day to 1400 mg/day) PO (hereafter called PEG + RBV [WBD]) to therapy with PEG + RBV [WBD] alone in previously untreated adult subjects with chronic hepatitis C (CHC) genotype 1. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of both parts of this study are:
• To evaluate the safety of boceprevir when used in combination with PEG + RBV (WBD).
• To define predictors of sustained virologic response (SVR) such as epidemiologic factors, disease characteristics and on-treatment response.
• To develop the relationship between steady state pharmacokinetic parameters, obtained from population based pharmacokinetic model and responses in a subset of subjects.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis and Criteria for Inclusion: Adult subjects with CHC HCV genotype 1 and with no previous treatment for CHC will be selected for the study.
The subject must meet ALL criteria listed below for entry:
Inclusion Criteria for CHC:
1. Subject must have documented CHC genotype 1 infection. The HCV-RNA result obtained from the central laboratory at the screening visit must confirm genotype 1 infection and be ≥10,000 IU/mL.
2. Subject must have a liver biopsy with histology consistent with CHC and no other etiology. Copies of the pathology report and histology slides are required for the subject to be included in the study. The slides and the pathology report must be available at the study site prior to subject randomization. Two unstained slides are preferred; however, one slide stained with hematoxylin plus eosin (H & E) plus one slide stained with Masson’s trichrome will be accepted (slides should be reviewed by the investigator to confirm adequacy).
a. No cirrhosis: Biopsy must be within 3 years of the Screening visit. For biopsies performed more than 18 months prior to the Screening visit, fibrosis marker testing will be performed to assess level of fibrosis
b. Cirrhosis: Any historic liver biopsy demonstrating cirrhosis will be sufficient regardless of length of time since biopsy.
c. Subjects whose timing of liver biopsy does not meet the criteria for subject eligibility may have a liver biopsy performed between Screening visit and Day 1 after the Screening evaluation confirms that the subject meets the study inclusion criteria
3. Subjects with bridging fibrosis or cirrhosis must have an ultrasound within 6 months of the Screening visit (or between Screening and Day 1) with no findings suspicious for hepatocellular carcinoma (HCC).
General Inclusion Criteria:
4. Subject must be 18 years old or older.
5. Subject must weigh between 40 kg and 125 kg.
6. 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 drug, or longer if dictated by local regulations.
7. Subjects must be willing to give written informed consent.
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| E.4 | Principal exclusion criteria |
Study Part Specific Exclusion Criteria:
A. Black/African American subjects are excluded from Part I of this study.
B. Non-black/African American subjects are excluded from Part II of this study.
-Subjects known to be co-infected with HIV or hepatitis B virus (HBsAg positive), or infected with hepatitis HCV genotypes other than genotype 1 (including mixed genotypes)
-Subjects who received prior treatment for hepatitis C; other than herbal remedies, except those with known hepatotoxicity (which are exclusionary). All herbal remedies used for hepatitis C treatment must be discontinued before Day 1. Only silymarin (milk thistle) is allowed during the study
-Treatment with any investigational drug within 30 days of the randomization visit in this study
-Participation in any other clinical trial within 30 days of randomization or intention to participate in another clinical trial during participation in this study
-Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy
-Diabetic and hypertensive subjects with clinically significant ocular examination findings as defined in the protocol
-Pre-existing psychiatric condition(s), as defined in protocol
-Clinical diagnosis of substance abuse as defined in the protocol by drug type and timeframe
-As further defined in the protocol, any known pre-existing medical condition that could interfere with the subject’s participation in and completion of the study including but not limited to:
a. Central nervous system (CNS) trauma
b. Current or history of seizure disorder
c. History of stroke or transient ischemic attack
d. Immunologically-mediated disease
e. Chronic pulmonary disease
f. Current or history of any clinically significant cardiac abnormalities/dysfunction
g. Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the study
h. Active clinical gout within the last year
i. Hemoglobinopathy
j. Myelodysplastic syndromes
k. Coagulopathy
l. Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair
m. Poor venous access that precludes routine peripheral blood sampling required for this study
n. Subjects with indwelling venous catheters
o. Subjects with a history of gastric surgery (eg, stapling, bypass) or subjects with a history of malabsorption disorders (eg, celiac sprue disease)
-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
-Subjects who are pregnant or nursing. Subjects who intend to become pregnant during the study period. Male subjects with partners who are, or intend to become, pregnant during the study period
-Any other condition which, in the opinion of a physician, would make the subject unsuitable for enrollment or could interfere with the subject participating in and completing the study
-Subjects who are part of the site personnel directly involved with this study
-Subjects who are family members of the investigational study staff
-Subjects who had life-threatening serious adverse event (SAE) during screening period
Laboratory Exclusion Criteria
Note: If any of the laboratory exclusion criteria are met, then the site may have the subject retested for eligibility as described in the protocol
-Hematological, biochemical, and serologic criteria (growth factors may not be used to achieve study entry requirements):
a. Hemoglobin <12 g/dL for females and <13 g/dL for males
b.Neutrophils <1500/mm3 (blacks: <1200/mm3)
c. Platelets <100,000/mm3
d. Direct bilirubin >1.5 x upper limit of normal (ULN) of the laboratory reference range.
Total bilirubin >1.6 mg/dL unless patient has history of Gilbert's disease. If Gilbert’s disease is the proposed etiology, this must be documented in the subject’s chart.
-Serum albumin <LLN (lower limit of normal) of laboratory reference range;
-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 T4/T3 testing
-Serum creatinine >ULN of the laboratory reference
-Serum glucose
a. For subjects not previously diagnosed with diabetes mellitus
1). ≥140 mg/dL (non-fasting) unless HbA1c ≤7% OR
2). ≥100 mg/dL (fasting) unless HbA1c ≤7%
b. For subjects previously diagnosed with diabetes mellitus, HbA1c >8.5%
-PT/PTT values >10% above laboratory reference range
-Anti-nuclear antibodies (ANA) >1:320
-Alpha fetoprotein (AFP)
a. AFP >100 ng/mL OR
b. AFP 50 to 100 ng/mL requires a liver ultrasound and subjects with findings suspicious for hepatocellular carcinoma are excluded
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the achievement of sustained virologic response (SVR) defined as undetectable plasma HCV-RNA at FW 24. Subjects will be declared treatment failures in one of the following ways:
• Subjects in any treatment arm who have detectable HCV-RNA at FW 24.
• Subjects in any treatment arm who have detectable HCV-RNA at TW 24.
• Subjects in any treatment arm who are missing their HCV-RNA at FW 24 with detectable HCV-RNA at FW 12.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| interferon responses (RNA) |
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| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 14 |
| 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 |
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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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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