AI444-043: A Phase 3, Open Label Study of Safety and Efficacy with BMS-790052 plus Peg-Interferon Alfa 2a and Ribavirin in Previously Untreated HCV Patients Coinfected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV)
This is an open label study. approximately 300 subjects will begin treatment with BMS-790052 plus peg-iFn[RegisteredTM]-2a/RBV for 24 weeks. of these 300 subjects, approximately 250 subjects will be on highly active antiretroviral therapy (HaaRT) and up to 50 subjects will not be on HaaRT. These 300 subjects will be at least 40% each of HCV genotype 1 subtype 1a or 1b.
Study drug will begin on Day 1. Subjects will receive BMS-790052 (60 mg or 30 mg) tablets to be taken once daily by mouth. The total daily dose of BMS-790052 can be 90, 60, or 30 mg and is dependent on whether or not subjects are taking medications for their HiV infection and if they are, it is dependent on the type of stable HiV medications being taken. in addition to BMS- 790052, subjects will receive treatment with peginterferon-alfa-2a and ribavirin.
The dose of peginterferon-alfa-2a will be180 micrograms once a week by injection.
The dose of ribavirin will be either 1000 mg or 1200 mg per day divided into a morning and evening dose each day and taken by mouth. Subjects that weigh less than 165 pounds will start with 1000 mg per day of Ribavirin. Subjects that weigh more than or equal to 165 pounds will start with 1200 mg per day of ribavirin.
Subjects will be evaluated for Virologic Response, defined as HCV Rna [Less Than] LoD at Weeks 4 and 12. This
will be referred to as VR (4 and 12). Treatment will be assigned as follows:
* Subjects who achieve VR (4 and 12) will complete 24 weeks of triple therapy
* Subject not achieving VR (4 and 12) will be required to receive 48 weeks total duration of therapy
(additional 24 weeks of pegiFn[RegisteredTM]-2a/RBV).
The primary efficacy endpoint is the rate of SVR12, defined as HCV Rna [Less Than] LoQ (detectable or undetectable) at post-treatment Week 12. SVR12 will be assessed via HCV viral load analysis of Rna performed at a central laboratory.
The secondary efficacy endpoints will be:
* Proportion of subjects with Genotype 1 infection who achieve HCV Rna [Less Than] LoQ (detectable or undetectable) at weeks: 1, 2, 4, 6, 8, and 12; Weeks 4 and 12; eoT, post-treatment Week 24 (SVR24) post-treatment Week 48 (SVR48) for subjects who achieve VR (4 [and] 12).
* Proportion of subjects with Genotype 1 infection who achieve HCV Rna undetectable at weeks: 1, 2, 4, 6, 8 and 12; Weeks 4 and 12; eoT, post-treatment Week 12; post-treatment Week 24 posttreatment Week 48 (SVR48) for subjects who achieve VR (4 [and] 12).
1) Signed Written Informed Consent
a) Freely given informed consent must be obtained from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study.
2) Target Population
a) Subjects chronically infected with HCV genotype 1 (at least 40% each of subtype 1a or 1b) 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) HCV-Treatment naive;
c) No previous exposure to any interferon formulation (ie, IFN(RegisteredTM), peg-IFN(RegisteredTM)) or RBV;
d) HCV RNA > 10,000 IU/mL at screening;
e) HIV-1 infection (approximately 250 subjects receiving HAART, up to 50 subjects not receiving HAART);
f) For subjects receiving HAART, HIV RNA must be below < 40 copies/mL at screening and must be < 400 copies/ml for at least 6 months prior to screening;
g) CD4 cell count at screening must be >= 100 cells/[MICRO-SYMBOL]L if receiving HAART or >= 350
cells/[MICRO-SYMBOL]L if not receiving HAART)
h) Seronegative for HBsAg;
i) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI = weight (kg)/[height (m)]2 at screening;
j) Subjects with compensated cirrhosis are permitted. If a subject does not have cirrhosis, a liver biopsy within three years prior to enrollment is required to demonstrate the absence of cirrhosis. If cirrhosis is present, any prior liver biopsy is sufficient. For countries where liver biopsy is not required prior to treatment and where non-invasive imaging tests (Fibroscan(RegisteredTM) ultrasound) are approved for staging of liver disease, non-invasive imaging test results may be used to assess
the extent of liver disease. A Fibroscan(RegisteredTM) done prior to screening is acceptable if it was performed within one year of screening (>= 14.6 kPa should be considered consistent with cirrhosis). If the prior Fibroscan(RegisteredTM) was not performed within one year of screening, a new Fibroscan(RegisteredTM)is required before study drug dosing. If a patient has both liver biopsy and Fibroscan(RegisteredTM), the result of the liver biopsy take precedence over those of the Fibroscan
3) Age and Reproductive Status
a) Males and females, 18 to 70 years of age;
b) Contraception Requirements: Men and women of childbearing potential (WOCBP) must be using 2 separate methods of contraception to avoid pregnancy from time of screening, throughout the study and for up to 24 weeks after the last dose of ribavirin (or time specified by the country specific ribavirin label, whichever is longer) in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP. 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. Exceptions include:
i) WOCBP who are not heterosexually active or who have male partners who have been vasectomized for a minimum of 6 months;
ii) Sexually active men who are vasectomized for a minimum of 6 months with a history of confirmed azoospermia.
c) WOCBP 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.
d) Women must not be breastfeeding
e) Requirements for male subjects (based on ribavirin label):
i) Male subjects (unless vasectomized for at least 6 months with a history of confirmed azoospermia) with female partners who are WOCBP must agree to inform their female partners of the protocol-specified contraception requirement 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.