BMS AI452032: Phase 3 open label study evaluating the efficacy and safety of pegylated interferon lambda-1a, in combination with ribavirin and daclatasvir for treatment of chronic HCV infection with treatment naive genotypes 1, 2, 3 or 4 in subjects co-infected with HIV
This study is a phase 3 open label study in approximately 300 subjects with HiV-1 infection who have chronic HCV infection with genotype 1, 2, 3 or 4. Participants will be enrolled in 2 groups and treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for another 12 or 36 weeks
Participants with genotype 2 or 3 will be treated for 12 weeks with Lambda/RBV/DCV followed by an additional 12 weeks of Lambda/RBV. The total duration of treatment will be 24 weeks.
The duration of treatment for participants with genotype 1 or 4 will be depend on early viral response as defined below:
- Participants who have a HCV Rna target not detected at Weeks 4 and 12 will be treated for 12 weeks with Lambda/RBV/DCV followed by an additional 12 weeks with Lambda/RBV for a total of 24 weeks.
- Participants who have a HCV Rna that is detected at Week 4 or 12 will be treated for 12 weeks with Lambda/RBV/DCV followed by an additional 36 weeks with Lambda/RBV for a total of 48 weeks
Proportion of subjects with SVR12 defined as HCV Rna [Less Than] LLoQ (25 iu/mL; target detected or not detected) at 12 weeks post treatment.
1) Proportion of subjects with RVR and eRVR, where RVR is defined as [Less Than] LLoQ target not detected at Week 4 and eRVR defined as [Less Than] LLoQ target not detected at Weeks 4 and 12.
2) Proportion of subjects in each group/duration who achieve HCV Rna [Less Than] LLoQ target detected or not detected, at end of therapy (SVR24).
3) Proportion of subjects with treatment emergent cytopenic abnormalities (anemia as defined by Hb [Less Than] 10 g/dL, and/or neutropenia as defined by anC [Less Than] 750 mm3 and/or thrombocytopenia as defined by platelets [Less Than] 50,000 mm3) during the treatment period
4) Proportion of subjects with the following on-treatment iFn-associated symptoms:
- Flu-like symptoms (as defined by pyrexia or chills or pain)
- Musculoskeletal symptoms (as defined by arthralgia or myalgia or back pain)
5) Frequency of deaths, serious adverse events (Saes), discontinuations due to aes, dose reductions, and severity Grade 3/4 laboratory abnormalities.
6) absolute and percent change from baseline in the CD4 cell count, lymphocyte cell count, and platelet count
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 GT-1, -2, -3 or -4 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) GT-1, -2, -3 or -4 infection and treatment naive with no prior treatment of HCV infection with peg interferon or DAAs;
c) HCV RNA viral load of > or = than 10,000 IU/mL at screening;
d) HIV-1 infection (approximately 200 subjects receiving HAART, up to approximately 100 subjects not receiving HAART);
e) For subjects receiving HAART, HIV RNA must be < 40 copies/mL at screening and must be < 200 copies/mL for at least 8 weeks prior to screening;
f) CD4 cell count at screening must be > or = 100 cells/uL if receiving HAART or > or = 350 cells/uL if not receiving HAART
g) Seronegative for HBsAg;
h) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI = weight (kg)/[height (m)]2 at screening;
i) Subjects with mild or moderate hemophilia are permitted. Mild and moderate hemophilia are defined as:
i) Mild: factor level activity of 6-40% or
ii) Moderate: factor level activity of 1-5%
j) Subjects with compensated cirrhosis are permitted. If cirrhosis is present, any prior liver biopsy is sufficient. Subjects must have one of the following assessments to evaluate for cirrhosis based on local country/institution requirements:
i. Liver biopsy:
For eligible non-cirrhotic subjects, liver biopsy results consistent with chronic HCV (evidence of fibrosis and/or inflammation) must be obtained within 3 years prior to enrollment. For eligible compensated cirrhotic subjects, biopsy documenting cirrhosis can be from any time period prior to enrollment. Non cirrhotic subjects must have a documented liver biopsy with an Ishak score < or = 4 or Metavir fibrosis score < or = 3. Compensated cirrhotic subjects must have a documented liver biopsy with an Ishak fibrosis score of > or = 5 or a Metavir fibrosis score of 4.
For countries where liver biopsy is not required prior to treatment and where noninvasive imaging tests (Fibroscan ultrasound) are standard of care for staging of liver disease, a Fibroscan done prior to screening is acceptable if it was performed within one year of screening (> or = 14.6 kPa should be considered consistent with cirrhosis). If the prior Fibroscan was not performed within one year of screening, a new Fibroscan is required before study drug dosing. If a subject has both liver biopsy and Fibroscan, the results of the liver biopsy take precedence over those of the Fibroscan.
FibroTest results may be used as an alternative: For countries where liver biopsy is not required prior to treatment and where non-invasive imaging tests are standard of care for staging of liver disease.
FibroTest result < or = .74 will be considered equivalent to a METAVIR Score of F0-F3, and FibroTest results > or = .75 will be considered equivalent to a METAVIR score of F4. If the prior FibroTest was not performed within one year of screening, a new FibroTest is required before study drug dosing.
3. Age and Reproductive Status
a) Men and women, ages 18 years of age and above
b) Women of childbearing potential (WOCBP) must use method(s) of contraception based on the table in Appendix 4 of the protocol. Where appropriate, consultation with a contraceptive health expert should be sought.
i) Hormonal contraceptives may be used in this study but cannot be considered one of the two forms of effective birth control required because a drug interaction study verifying the effectiveness of hormone based contraceptives has not been conducted with Lambda. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug.
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) Men who are partners of WOCBP must use method(s) of contraception based on the table in Appendix 4. Where appropriate, consultation with a contraceptive health expert should be sought.
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, two forms of contraception and monthly pregnancy testing while the subject is enrolled in the study and 6 months following discontinuation of study drugs or of RBV [or for the post treatment duration specified in the country-specific RBV label]), and agree to adhere
to these recommendations both on treatment and during the post treatment follow-up period
ii) Male subjects must confirm that their female sexual partners are not pregnant at the time of screening.
f) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) and azoospermic men do not require contraception.