| 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 | 13.1 |
| 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 subjects who achieve SVR24 for each HCV genotype, defined as undetectable HCV RNA at follow-up Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess safety, as measured by the frequency of SAEs and discontinuations due to AEs;
• To assess the proportion of subjects with RVR for each HCV genotype, ie, undetectable HCV RNA at Week 4;
• To assess the proportion of subjects with SVR12 for each HCV genotype ie, undetectable HCV RNA at follow-up Week 12;
• To describe resistant variants associated with virologic failure for each HCV genotype.
+ Exploratory Objectives:
• To explore the relationship between endpoints of safety and/or antiviral activity and exposure to BMS-790052 when co-administered with pegIFNα-2a/RBV;
• To explore the relationship between antiviral activity endpoints and single nucleotide polymorphisms (SNPs) in genes encoding proteins of the IFNλ family (IL28A, IL28B, IL29). |
|
| 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 either HCV genotype 2 or 3 (each HCV genotype will be capped at approximately 50% of the randomized study population), as documented by positive HCV RNA and anti-HCV antibody at screening and either:
i) positive anti-HCV antibody, HCV RNA, or a positive HCV genotype test at least 6 months prior to screening; or
ii) liver biopsy consistent with chronic HCV infection (evidence of fibrosis and/or inflammation);
b) No previous exposure to an interferon formulation (ie IFNα, pegIFNα) or RBV;
c) HCV RNA viral load of ≥ 100,000 IU/mL at screening;
d) Results of liver biopsy obtained ≤ 24 months prior to randomization demonstrating the presence or absence of cirrhosis; for compensated cirrhotics, results of liver biopsy documenting cirrhosis can be from any time period prior to randomization (compensated cirrhotics are capped at approximately 10% of randomized population);
e) Body Mass Index (BMI) of 18 to 35 kg/m², inclusive. BMI = weight (kg)/[height (m)]² at screening.
3) Age and Reproductive Status
Males and female, 18 - 70 years of age;
a) Contraception requirements for women who are WOCBP (see Section 3.3.3) and men who are sexually active with WOCBP:
i) Two (2) separate forms of contraception are required from time of screening, throughout the duration of the on-treatment study period, and for at least 24 weeks after the last dose of RBV (or the duration specified by the country-specific RBV label, whichever is longer) in such a manner that pregnancy is minimized. One (1) form of contraception must be an effective barrier method (eg, condom, diaphragm, cervical cap). Oral contraceptive pills (OCPs) may be used in this study as 1 of the 2 effective forms of contraception based on results of a drug interaction study with BMS-790052 and Ortho Tri-Cyclen. Following co-administration of 60 mg BMS-790052 and Ortho Tri-Cyclen for 10 days, no pharmacokinetic interaction was observed; therefore, co-administration of BMS-790052 and an OCP should not alter the efficacy of the OCP.
ii) Exceptions include:
(1) WOCBP who are not heterosexually active or who have male partners who have been vasectomized for a minimum of 6 months;
(2) Sexually active men who are vasectomized for a minimum of 6 months.
b) Female Subjects: Requirements for pregnancy testing:
iii) WOCBP who do not meet the exceptions listed above must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/mL or equivalent units of HCG) within 24 hours prior to the start of investigational product.
(1) Female subjects must not be breastfeeding;
(2) Female subjects must agree to the pregnancy testing requirement in this protocol.
c) Male Subjects: Requirements (based on RBV label):
iv) Male subjects (unless vasectomized) with female partners who are WOCBP must agree to inform their female partners of, and agree to adhere to, the protocol-specified contraception requirements and pregnancy testing recommendations during treatment and post-treatment (2 forms of contraception and monthly pregnancy testing while the subject is on study treatment and for 6 months after the last dose of RBV [or for the post-treatment duration specified in the country-specific RBV label]).
v) 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 other than genotype 2 or 3;
2)Medical History & Concurrent Diseases
a)Liver transplant recipients;
b)Documented or suspected HCC as evidence by imaging or liver biopsy;
c)Evidence of decompensated cirrhosis based on radiologic criteria or biopsy results and clinical criteria;
d)Evidence of medical condition associated with chronic liver disease other than HCV;
e)History of chronic HBV as documented by HBV serologies. Patients with resolved HBV infection may participate;
f)Current or known history of cancer within 5 years prior to enrollment;
g)Any gastrointestinal disease or surgical procedure that may impact study drug absorption;
h)Any other medical, psychiatric and/or social reason including active substance abuse as defined by DSM-IV (Appendix 1), which in the opinion of the investigator, would make the candidate inappropriate for participation;
i)Inability to tolerate oral medication;
j)Poor venous access;
+ exclusion criteria for the use of pegIFNα-2a and/or RBV, based on their respective labels:
k)Severe psychiatric disease, especially untreated or unstable depression, that would prohibit use of pegIFNα-2a, as judged by the investigator;
l)History of hemoglobinopathies, diagnoses associated with an increased baseline risk for anemia, hemolytic anemia, or diseases in which anemia would be medically problematic;
m)Thyroid-stimulating hormone (TSH) < 0.8 x LLN or > 1.2 x ULN of the lab reference range, unless
i)The subject is clinically euthyroid as determined by the investigator, AND
ii)free T4 is ≥ 0.8 x LLN and ≤ 1.2 x ULN
n)History of chronic pulmonary disease associated with functional limitation;
o)History of cardiomyopathy, coronary artery disease, interventive procedure for coronary artery disease, ventricular arrhythmia, or other clinically significant cardiac disease;
p)Historical or current ECG findings indicative of cardiovascular instability;
q)Pre-existing ophthalmologic disorders considered clinically significant on eye;
r)History of uncontrolled diabetes mellitus;
s)Any known contraindication to pegIFNα-2a or RBV, not otherwise specified.
3)Physical & Lab Test Findings
a)Confirmed ALT ≥5 x ULN;
b)Confirmed Total Bilirubin ≥34 μmol/L (≥2 mg/dL);
c)Confirmed INR ≥1.7;
d)Confirmed Albumin ≤3.5 g/dL (35g/L);
e)Confirmed Platelets ≤90×10 billion cells/L;
f)Confirmed ANC ≤1.5×10 billion cells/L (Confirmed ANC ≤1.2×10 billion cells/L for blacks);
g)Confirmed Hemoglobin ≤12g/dL (120 g/L) for women and ≤13g/dL (130 g/L) for men;
h)Confirmed Creatinine Clearance (CrCl) ≤50 mL/min (as estimated by Cockcroft and Gault);
i)Alpha fetoprotein (AFP);
i)AFP >100 ng/mL OR
ii)AFP ≥50 and ≤100 ng/mL requires a liver ultrasound and subjects with findings suspicious for HCC are excluded.
j)QTcF > 450 mSec (males) or > 470 mSec (females);
k)Positive HBsAg, HIV-1 or HIV-2 Ab.
4)Allergies and Adverse Drug Reaction
a)History of hypersensitivity to drugs with a similar biochemical structure to BMS-790052, pegIFNα-2a, or RBV.
5)Sex and Reproductive Status
a)Males and females who do not or cannot meet Inclusion Criterion 3;
b)Sexually active fertile men whose partners are pregnant at screening.
6)Prohibited Treatments and/or Therapies
a)Prior exposure to any HCV direct antiviral agent;
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 associated with a high risk for nephrotoxicity or hepatotoxicity;
d)Strong or moderate inhibitors of CYP3A4 (refer to Section 3.4.1);
e)Inducers of CYP3A4 (refer to Section 3.4.1);
f)P-gp substrates with a narrow therapeutic index are prohibited and other P gp substrates should be used with caution (refer to Section 3.4.1);
g)Strong P-gp inhibitors;
h)Use of proton pump inhibitors (refer to Section 3.4.1 for details).
i)Medications with known or potential anti-HCV activity other than the assigned study treatment;
j) Any prescription or herbal product which is not prescribed by the investigator or licensed physician for treatment of a specific clinical condition.
7)Other
a)Prisoners or subjects who are involuntarily incarcerated;
b)Subjects who are compulsorily detained for treatment of a psychiatric or physical illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects for each HCV genotype with SVR24, defined as undetectable HCV RNA at follow-up Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• To assess safety, as measured by the frequency of SAEs and discontinuations due to AEs;
• To assess the proportion of subjects with RVR for each HCV genotype, ie, undetectable HCV RNA at Week 4;
• To assess the proportion of subjects with SVR12 for each HCV genotype ie, undetectable HCV RNA at follow-up Week 12;
• To describe resistant variants associated with virologic failure for each HCV genotype.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The first three endpoints above after all subjects completed
• Week 16
• Follow-up Week 12
• Follow-up Week 24 or 36
The last bullet above after all subjects completed Follow-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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| France |
| Italy |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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