| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 assess:
• Antiviral activity, as determined by the proportion of HCV genotype 1 subjects with eRVR, defined as undetectable HCV RNA at both Weeks 4 and 12;
• Antiviral activity, as determined by the proportion of HCV genotype 1 subjects with SVR24 , defined as undetectable HCV RNA at follow-up Week 24;
• Safety, as measured by the frequency of SAEs and discontinuations due to AEs. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the proportion of HCV genotype 1 subjects with rapid virologic response (RVR), ie, undetectable HCV RNA at Week 4;
• To assess the proportion of HCV genotype 1 subjects with complete early virologic response (cEVR), ie, undetectable HCV RNA at Week 12;
• To assess the proportion of HCV genotype 1 subjects with 12-week sustained virologic response (SVR12), ie, undetectable HCV RNA at follow-up Week 12;
• To describe resistant variants associated with virologic failure. |
|
| 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 or 4 (genotype 4 will be capped at 10% of the randomized study population), as documented by both positive HCV RNA and anti-HCV antibody at the time of screening, and positive HCV RNA, anti-HCV antibody, or HCV genotype test at least 6 months prior to screening;
b) HCV RNA viral load of ≥ 105 IU/mL (100,000 IU/mL) at screening;
c) No previous exposure to interferon, pegIFNα, or RBV;
d) Results of a liver biopsy demonstrating the presence or absence of cirrhosis.
Compensated cirrhotics (based on clinical criteria) with HCV genotype 1 infection are eligible, but will be capped at 10% of the randomized study population. For eligible compensated cirrhotic subjects, biopsy documenting cirrhosis can be from any time period prior to randomization. For eligible non-cirrhotic subjects, liver biopsy results must be obtained ≤ 24 months prior to randomization;
e) Ultrasound (U/S), computed tomography (CT) scan, or magnetic resonance imaging (MRI) results 12 months prior to randomization that do not demonstrate evidence of HCC;
f) Body Mass Index (BMI) of 18 to 35 kg/m², inclusive. BMI = weight (kg)/[height (m)]² at screening.
3) Age and Reproductive Status
a) Men or women, 18 - 70 years of age
b) Men and women of childbearing potential (WOCBP) must be using 2 separate methods of contraception to avoid pregnancy throughout the study and for up to 24 weeks after the last dose of RBV (or time specified by the country specific RBV label, whichever is longer) in such a manner that the risk of pregnancy is minimized; see Protocol Section 3.3.3 for the definition of WOCBP.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product. Female subjects must agree to the pregnancy testing requirements in this protocol.
d) Women must not be breastfeeding.
e) Requirements for male subjects (based on RBV label):
i) Male subjects (unless vasectomized for at least 6 months) with female partners who are WOCBP must agree to inform their females partners of the protocol-specified contraception requirements and pregnancy testing recommendations during treatment and post-treatment (ie, 2 forms of contraception and monthly pregnancy testing while the subject is enrolled in the study, and 6 months following discontinuation of RBV or the duration specified in the country-specific RBV-label), and agree to adhere to these recommendations both on-treatment and during the post dosing follow-up period.
ii) Male subjects must confirm that their female sexual partners are not pregnant at the time of screening. |
|
| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
a) Infected with HCV genotypes other than 1 or 4;
b) Positive HBsAg, or HIV-1/HIV-2 antibody at screening.
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, and toxin exposure);
b) Evidence of decompensated cirrhosis based on radiologic criteria or biopsy results and clinical criteria;
c) HCV genotype 4 subjects with compensated cirrhosis;
d) Current or known history of cancer within 5 years prior to enrollment (exceptions to this criteria are in situ carcinoma of the cervix or adequately controlled non-melanoma skin cancers);
e) Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug;
f) Any other medical, psychiatric and/or social reason including active substance abuse or alcohol abuse as defined by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 1) which in the opinion of the investigator, would make the candidate inappropriate for participation in this study;
g) Inability to tolerate oral medication;
h) Poor venous access.
3) Physical and Laboratory Test Findings
a) Confirmed ALT ≥ 5 x ULN;
b) Confirmed total bilirubin ≥ 34 μmol/L (or ≥ 2 mg/dL);
c) Confirmed INR ≥ 1.7;
d) Confirmed albumin ≤ 3.5 g/dL (35 g/L);
e) Confirmed platelets ≤ 90 x 10 billion cells/L;
f) Confirmed ANC ≤ 1.5 x 10 billion cells/L;
g) Confirmed hemoglobin ≤ 12 g/dL (120 g/L) for women and ≤ 13 g/dL (130 g/L) for men;
h) Confirmed creatinine clearance (CrCl) (as estimated by Cockcroft and Gault) ≤ 50 mL/min;
i) Patients with a screening QTcF > 450 msec (males) or > 470 msec (females), based on the average of 3 or more ECGs (ECGs obtained 5 minutes apart while subject is resting in a supine position).
4) Medical History or Laboratory Findings that Exclude Subjects from Peg-Interferon Alfa-2a or Ribavirin Therapy
The following exclusion criteria are based on guidelines or recommendations from the pegIFNα-2a and RBV package inserts:
a) Severe psychiatric disease, especially untreated or unstable depression, that would prohibit use of pegIFNα-2a as judged by the 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 disease 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) Unstable or clinically significant cardiovascular disease or hypertension that could be expected to progress, recur or change during study period to such an extent that it could bias the assessment of the clinical status of the patient;
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) History of uncontrolled diabetes mellitus;
h) Any known contraindication to peg-IFNα-2a or ribavirin, not otherwise specified.
5) Allergies and Adverse Drug Reaction
a) History of hypersensitivity to drugs with a similar biochemical structure to BMS-790052, pegIFNα-2a, or RBV.
6) Prohibited Treatments and/or Therapies
a) Prior exposure to any investigational agent or drug with potential anti-HCV activity;
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, fluconazle, diltiazem, verapamil, itraconazole, voriconazole, ciprofloxacin, telithromycin, erythromycin, and cimetidine (additional drugs are listed in Section 3.4.1);
e) Inducers of CYP3A4 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 certain H2 receptor antagonists or other acid modifying agents (not otherwise prohibited) such as antacids are allowed (see Section 3.4.1).
7) Sex and Reproductive Status
a) Sexually active fertile men not using effective birth control if their partners are WOCBP.
8) 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) |
To measure:
• Antiviral activity, as determined by the proportion of HCV genotype 1
subjects with eRVR;
• Antiviral activity, as determined by the proportion of HCV genotype 1
subjects with SVR24;
• Safety, as measured by the frequency of SAEs and discontinuations
due to AEs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Week 4 and 12
• Follow-Up Week 24
• Week 12, Week 24, and follow-up Week 12 |
|
| E.5.2 | Secondary end point(s) |
• To assess the proportion of HCV genotype 1 subjects with rapid
virologic response, ie, undetectable HCV RNA
• To assess the proportion of HCV genotype 1 subjects with complete
early virologic response, ie, undetectable HCV RNA
• To assess the proportion of HCV genotype 1 subjects with 12-week
sustained virologic response, ie, undetectable HCV RNA
• To describe resistant variants associated with virologic failure |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Week 4
• Week 12
• Follow-up Week 12
• Ffollow-up Week 48 |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | 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 | Yes |
| 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 |
| Site/subject-blinded until Week 24 analysis; Sponsor-blinded until Week 12 primary analysis. |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Australia |
| Canada |
| Denmark |
| Egypt |
| France |
| Germany |
| Italy |
| Mexico |
| Puerto Rico |
| Sweden |
| United States |
|
| 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
|
| The end of the study is defined as the date of the last visit for the last subject to complete the study. The last visit is defined as the last post-treatment follow-up subject visit. |
|
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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