| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 boceprevir 800 mg three times a day (TID) orally (PO) in combination with peginterferon alfa-2a (PEG2a) 180 mcg weekly (QW) subcutaneously (SC) plus ribavirin (1000 mg/day to 1200 mg/day) PO to the same PEG2a/ribavirin regimen without boceprevir for 48 weeks in adult subjects with chronic hepatitis C (CHC) genotype 1 with demonstrated interferon responsiveness who failed prior treatment with peginterferon/ribavirin. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of boceprevir when used in combination with PEG2a/Ribavirin
• To define predictors of sustained virologic response (SVR), such as epidemiologic factors, disease characteristics, and on-treatment response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For inclusion in the study, subjects must have a qualifying regimen defined as PEG2a/ribavirin or peginterferon alfa-2b (PEG2b)/ribavirin for a minimum of 12 weeks. If a subject has received more than one such regimen, the most recent regimen is considered the qualifying regimen
Note: Maintenance therapy, following failure of qualifying therapy, with any interferon alfa is acceptable; however, the subject must have discontinued the maintenance therapy at least 1 month prior to the Screening Visit
2. During the qualifying regimen, subjects must have either:
a. A documented undetectable HCV-RNA within 30 days of EOT and a subsequent detectable HCV-RNA during follow-up OR
b. A documented decline in HCV-RNA by >/= 2 log10 by TW 12.
Note: For subjects who did not participate in Schering-Plough Research Institute (SPRI) protocols, qualifying virology reports and documentation of qualifying previous treatment regimen must be completely de-identified and faxed to the sponsor's project physician for confirmation that the subject qualifies for this study
3. Subject must have previously documented CHC genotype 1 infection. Subjects with other or mixed genotypes are not eligible. The HCV-RNA result obtained from the central laboratory at the Screening Visit must confirm genotype 1 infection and be equal or greater than 10,000 IU/mL
4. Subject must have a liver biopsy with histology consistent with CHC and no other etiology. Copies of the pathology report and slides are required for the subject to be included in the study. The study site must be able to access the pathology report and histology slides 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). The central pathologist’s reading will be used for analysis purposes
a. No cirrhosis: Biopsy must be within 3 years of the Screening Visit
b. Cirrhosis: Any historic liver biopsy demonstrating cirrhosis will be accepted regardless of length of time since biopsy
c. Subjects whose timing of liver biopsy does not meet this criterion for subject eligibility may have a liver biopsy performed between Screening and Day 1, if their Screening Visit confirms that the subject meets the other study inclusion criteria
5. 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)
6. Subjects participating in SPRI maintenance protocols P02570 or P02569 must have completed the study (ie, finished last contact) to be eligible for this protocol
7. Subject must be 18 years of age
8. Subject must weigh between 40 kg and 125 kg
9. Subject and subject’s partner(s) must each agree to use acceptable methods of contraception 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
10. Subjects must be willing to give written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Subjects known to be coinfected w/HIV or HBV
2. Subjects requiring discontinuation of previous interferon or ribavirin regimen for an AE considered to be possibly/probably related to ribavirin &/or interferon
3. Treatment w/ribavirin w/in 90 days & any interferon alfa w/in 1 month of Screening
4. Treatment for hepatitis C w/any investigational drug. Prior treatment with herbal remedies w/known hepatotoxicity
5. Treatment w/any investigational drug w/in 30 days of the randomization
6. Participation in any other clinical trial w/in 30 days of randomization
7. Evidence of decompensated liver disease including history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy
8. Diabetic &/or hypertensive subjects w/clinically significant ocular findings
9. Pre-existing psychiatric condition(s), including but not limited to:
a. Current moderate or severe depression (mild depression may be enrolled)
b. History of depression associated with: Hospitalization; Electroconvulsive therapy; prolonged absence from work &/or significant disruption of daily functions
c. Suicidal or homicidal ideation &/or attempt
d. History of severe psychiatric disorders
e. Past/current use of lithium
f. Past/current use of antipsychotic drugs
10. Clinical diagnosis of substance abuse of the following drugs w/in the following timeframes:
a. Alcohol, intravenous drugs, inhalational (not including marijuana), psychotropics, narcotics, cocain, prescription or over-the-counter drugs: w/in 1 year of the Screening Visit, OR
b. Multi-drug abuse w/in 3 years of Screening Visit OR
c. Subjects receiving opiate agonist substitution therapy w/in 1 year of Screening (except for subjects monitored in an opioid substitution maintenance program) OR
d. Historic marijuana use is deemed excessive by a physician, or is interfering with the subject's life
11. Any known pre-existing medical condition that could interfere w/the participation in & completion of study, including but not limited to:
a. Central nervous system trauma
b. Current or history of seizure disorder unless >10 years ago, a single isolated event, no anti-seizure medications prescribed, & a normal neurological examination documented in study files w/in 6 months of Day 1
c. History of stroke/transient ischemic attack
d. Immunologically mediated disease
e. Chronic pulmonary disease
f. Current or history of any clinically significant cardiac abnormalities/dysfunction including current uncontrolled hypertension or history of antianginal agents for cardiac conditions
g. Any medical condition requiring chronic systemic administration of corticosteroids during study
h. Active clinical gout w/in 1 year
i. Hemoglobinopathy
j. Myelodysplastic syndromes
k. Coagulopathy
l. Organ transplants other than corneal & hair
m. Poor venous access precluding routine peripheral blood sampling
n. Subjects w/indwelling venous catheters
o. Subjects w/a history of gastric surgery or malabsorption disorders
12. Evidence of active or suspected malignancy or a history of malignancy w/in the last 5 years. Subjects under evaluation for malignancy are not eligible
13. Subjects who are pregnant, nursing or intend to become pregnant during study. Male subjects w/partners who are or intend to become pregnant during study
14. Other conditions making the subject unsuitable for enrollment or could interfere w/the subject participating in & completing study
15. Subjects who are part of the site personnel directly involved with study, family members of study staff, or had a life-threatening SAE during the screening period
18. Any history of pancreatitis
Laboratory Exclusion Criteria
If a single value is within 10% of the exclusion criterion value & the value is considered not clinically significant by the investigator, the subject may be considered for enrollment
1. Hematologic, biochemical & serologic criteria (growth factors may not be used to achieve entry requirements):
a. Hemoglobin Females:<12 g/dL Males:<13 g/dL
b. Neutrophils <1500/mm3 (blacks: <1200/mm3)
c. Platelets <100,000/mm3
d. Direct bilirubin >1.5xULN. Total bilirubin >1.6 mg/dL unless a history of Gilbert's disease
2. Serum albumin < lower limit of normal (LLN)
3. Thyroid-stimulating hormone (TSH)>1.2xULN or <0.8xLLN w/the following exception:
a. The subject may be enrolled if clinically euthyroid, AND
b. The euthyroid function is confirmed by T4/T3 testing
4. Serum creatinine >ULN
5. Serum glucose:
a. Subjects not previously diagnosed with diabetes mellitus:
1) >/=140 mg/dL (nonfasting) unless hemoglobin, A1c subtype (HbA1c)</=7% OR
2). >/=100 mg/dL (fasting) unless HbA1c </=7%
b.For subjects previously diagnosed w/diabetes mellitus: HbA1c>8.5%
6. PT/PTT >10% above lab reference range
7. Anti-nuclear antibodies (ANA)>1:320
8. Alpha fetoprotein (AFP)
a. AFP >100 ng/mL OR
b. AFP 50-100 ng/mL requires a liver ultrasound & subjects w/findings suspicious for HCC are excluded |
|
| 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 FW 24. Subjects will be declared treatment failures in one of the following ways:
• Subjects in any treatment arm with detectable HCV-RNA at Follow-up Week (FW) 24
• Subjects in any treatment arm with detectable HCV-RNA at TW 12
•Subjects in any treatment arm who are missing their HCV-RNA at FW 24 with detectable or missing HCV RNA at FW 12
|
|
| 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 | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
|
| 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 | 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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