| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Virus Genotype 1 Infection in Treatment Naïve Subjects |
|
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To describe:
• Safety, as measured by the frequency of SAEs, discontinuations due to AEs, and Grade 3 - 4 laboratory abnormalities and,
• Antiviral activity as determined by the proportion of subjects with extended rapid virologic response (eRVR) defined as HCV RNA < 10 IU/mL at both Weeks 4 and 12. |
|
| E.2.2 | Secondary objectives of the trial |
To describe:
• Proportion of subjects with rapid virologic response (RVR), defined as HCV RNA < 10 IU/mL at Week 4;
• Proportion of subjects with early virologic response (EVR), defined as ≥ 2 log(10) decrease in HCV RNA from baseline at Week 12 (or HCV RNA < 10 IU/mL for subjects with baseline HCV RNA < 1000 IU/mL);
• Proportion of subjects with a sustained virologic response (SVR), defined as HCV RNA < 10 IU/mL at follow-up Week 12 (SVR12) and Week 24 (SVR24), respectively.
Additional exploratory objectives:
• Identification and quantitation of resistant variants associated with clinical failure;
• Relationship between measures of safety or antiviral activity and exposure to BMS-790052 when co-administered with pegIFNα/RBV;
• To describe the pharmacokinetics of BMS-790052, RBV, and PegIFNα;
• To explore the effect of BMS-790052 on expression of IFN stimulated genes (ISGs) when co-administered with PegIFNα and RBV. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Subjects chronically infected with HCV genotype 1;
b) HCV RNA viral load of ≥ 10(5) IU/mL (100,000 IU/mL) at screening;
c) Less than 4 weeks of total therapy with either IFN, pegIFNα, or RBV at any time and with no exposure to IFN, pegIFNα or RBV in the 24 weeks prior to randomization;
d) Results of a biopsy obtained ≤ 24 months prior to randomization;
e) No evidence of cirrhosis based on liver biopsy or clinical criteria;
f) No evidence of HCC documented by ultrasound (U/S), computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 12 months of randomization;
g) Absence of co-infection with hepatitis B virus (HBV), HIV-1 or HIV-2 at screening;
h) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI = weight (kg)/ [height (m)]2 at screening.
3) Age and Sex
a) Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile) and men, ages 18 to 70;
Women are considered surgically sterile only if they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy.
Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) Women of Childbearing Potential (WOCBP)
b) Women who are pregnant or breastfeeding;
c) Women with a positive pregnancy test on enrollment or prior to administration of investigational product;
d) Sexually active fertile men not using effective birth control if their partners are WOCBP;
e) Sexually active fertile men whose partners are pregnant at screening are excluded from this study (a contraindication for RBV use).
2) Medical History and Concurrent Diseases
a) Evidence of a medical condition associated with chronic liver disease other than HCV (such as but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures);
b) History of variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis;
c) Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment;
d) Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug;
e) Any other medical, psychiatric and/or social reason which, in the opinion of the investigator, would make the candidate inappropriate for participation in this study;
f) Inability to tolerate oral medication;
g) Poor venous access.
3) Physical and Laboratory Test Findings at Screening
a) ALT ≥ 5 × ULN;
b) Total bilirubin ≥ 34 μmol/L (or ≥ 2 mg/dL);
c) INR ≥ 1.7;
d) Albumin ≤ 3.5 g/dL (35 g/L);
e) Any ECG finding which in the opinion of the investigator, would make the candidate inappropriate for participation in this study (ie corrected QT value > 450 msec, second/third degree bundle branch block).
4) Medical History or Laboratory Findings that Exclude Subject from pegIFNα or RBV Therapy:
The following exclusion criteria are based on guidelines or recommendations from the pegIFNα22 and RBV23 package inserts.
a) Severe psychiatric disease, especially untreated or unstable depression, that would prohibit use of pegIFNα as judged by investigator;
b) History of hemoglobinopathies (ie, thalassemia major or sickle cell anemia), diagnoses associated with an increased baseline risk for anemia (eg, spherocytosis), hemolytic anemia, or diseases in which anemia would be medically problematic;
c) History of thyroid dysfunction not adequately controlled or screening thyroid function tests that indicate abnormal thyroid function;
d) History of chronic pulmonary disease associated with functional limitation;
e) History of cardiomyopathy, coronary artery disease (including angina), interventive procedure for coronary artery disease (including angioplasty, stent procedure, or cardiac bypass surgery), ventricular arrhythmia, or other clinically significant cardiac disease;
f) Pre-existing ophthalmologic disorders considered clinically significant on eye or retinal exam (all subjects with history of diabetes or hypertension must have a documented eye exam within 12 months prior to randomization);
g) Platelets ≤ 90 × 109 cells/L;
h) ANC ≤ 1.5 × 109 cells/L;
i) Hemoglobin ≤ 12 g/dL (120 g/L) for women and ≤ 13 g/dL (130 g/L) for men;
j) Creatinine clearance (CrCl) as (as estimated by Cockcroft and Gault) ≤ 50 mL/min;
k) Any known contraindication to pegIFNα or RBV, not otherwise specified.
5) Allergies and Adverse Drug Reactions
a) History of hypersensitivity to drugs with a similar biochemical structure to BMS-790052, pegIFNα, or RBV.
6) Prohibited Treatments and/or Therapies
a) Prior exposure to any investigational agent or drug with potential anti-HCV activity (however, less than 4 weeks of total therapy with either IFN, pegIFNα, or RBV at any time that has not occurred in the 24 weeks prior to randomization is allowed);
b) Exposure to any investigational drug or placebo within 4 weeks of study drug administration;
c) Long-term treatment with immunosuppressive agents or with drugs that are associated with a high risk for nephrotoxicity or hepatotoxicity;
d) Strong or moderate inhibitors of CYP3A4 including, but not limited to: grapefruit or grapefruit-containing products, Seville oranges, fluconazole, diltiazem, verapamil, itraconazole, voriconazole, ciprofloxacin, telithromycin, erythromycin, and cimetidine (additional drugs are listed in Section 5.5.1);
e) Inducers of CYP3A4 inducers including, but not limited to: rifampin, rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, phenobarbital, and St John's wort;
f) Use of proton pump inhibitors. Restricted use of H2 receptor antagonists or other acid modifying agents such as antacids are allowed (see Section 5.5.1).
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated;
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety, as measured by the frequency of SAEs, discontinuations due to AEs, and Grade 3 - 4 laboratory abnormalities and,
• Antiviral activity as determined by the proportion of subjects with eRVR |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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