| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Virus Infection (Genotypes 1 and 4) in Treatment-Naive Subjects |
|
| 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 | 14.1 |
| 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 |
| Both Stage 1 and Stage 2 primary objectives will be based on their respective Week 12 analysis of safety and antiviral activity data. In addition, a co-primary objective of Stage 2 will be based on follow-up anti-viral activity data (SVR). The Week 12 analysis in Stage 1 supports dose selection decisions for Stage 2 while the analyses in Stage 2 will support the overall HCV program (add-on to SOC and combination anti-viral studies) and inform decisions on both dose (Week 12 analysis) and duration (SVR analysis). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the proportion of HCV genotype 1 subjects with rapid virologic response
(RVR), defined as undetectable HCV RNA at Week 4;
• To assess the proportion of HCV genotype 1 subjects with complete early rapid virologic response (cEVR), defined as undetectable HCV RNA at Week 12 (Stage 2 only);
• To assess the proportion of HCV genotype 1 subjects with early virologic response
(EVR), defined as ≥ 2 log10 decrease in HCV RNA from baseline or HCV RNA <
LOQ at Week 12 (Stage 1 only);
• To assess the proportion of HCV genotype 1 subjects with 12-week sustained
virologic response (SVR12), defined as undetectable HCV RNA at follow-up Week
12;
• To assess the proportion of HCV genotype 1 subjects with 24-week sustained
virologic response (SVR24), defined as undetectable HCV RNA at follow-up Week
24 (Stage 1 only);
• 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
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 as documented by: positive for anti-HCV antibody, HCV RNA, or a positive HCV genotype test at least 6 months prior to screening, and positive for HCV RNA and anti-HCV anti-body at the time of screening (Stages 1 and 2);
b) Subjects chronically infected with HCV genotype 4 as documented by: positive for anti-HCV antibody, HCV RNA, or a positive HCV genotype test at least 6 months prior to screening, and positive for HCV RNA and anti-HCV anti-body at the time of screening (Stage 2 only);
c) HCV RNA viral load of ≥ 100,000 IU/mL at screening;
d) Results of a biopsy obtained ≤ 24 months prior to randomization showing no evidence of cirrhosis for subjects that do not have a diagnosis of cirrhosis (Stages 1 and 2); (Note: Genotype 1 subjects with compensated cirrhosis, regardless of time since biopsy, may be included in Stage 2);
e) Body Mass Index (BMI) of 18 to 35 kg/m², inclusive. BMI = weight (kg)/[height (m)]² at screening
3) Age and Sex
a) Men and women, ages 18 to 70;
b) Women of childbearing potential (WOCBP), unless non-heterosexual active or who have vasectomized male partners, and sexually active men (unless vasectomized) with female partners who are WOCBP must use two separate forms of contraception, one of which must be an effective barrier method (eg, condom with spermicide), from screening throughout the duration of the study and for 24 weeks after the last dose of ribavirin. In addition, WOCBP must agree to the pregnancy testing schedule specified in this protocol. Oral contraceptive
pills (OCPs) may be used in this study, but cannot be considered one of the two effective forms of contraception required because drug interaction studies verifying the effectiveness of OCPs when used with BMS-650032 have not been completed. Men (unless vasectomized) with female partners who are WOCBP must agree to inform their female partners of the protocol-specified contraception requirements and pregnancy testing recommendations during treatment and post-treatment (monthly pregnancy testing on-treatment and following
discontinuation of RBV for 6 months post-treatment or the duration specified in the label used for RBV in that country), and agree to adhere to these recommendations for both the on-treatment and post-treatment follow-up period.
WOCBP are defined as a non-menopausal female or a female with menopause ≤ 2 years and who has not had a hysterectomy, bilateral tubal ligation, bilateral oophorectomy or medically documented ovarian failure. Female subjects who are postmenopausal for less than two years are required to have FSH > 40 mIU/mL. If the FSH is ≤ 40 mIU/mL, the subject must agree to use two forms of contraception to participate in the study.
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 > 40 mIU/mL.
Non-menopausal women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence should be considered to be of childbearing potential.
WOCBP must have a negative serum β-HCG at screening and a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product. |
|
| E.4 | Principal exclusion criteria |
1)Sex & Reproductive Status
a)WOCBP unwilling or unable to use an acceptable method to avoid
pregnancy (2 effective forms of contraception) for entire study period (on treatment) & for up to 24 weeks after last dose of investigational product or for duration specified in the label use for RBV in that country, whichever is longer
b)pregnant of breastfeeding Women
c)Women with + pregnancy test on enrollment or prior to IMP administration
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
(contraindicated with RBV use)
2)Medical History & Concurrent Diseases
a)Evidence of medical condition associated with chronic liver disease other than HCV
b)Evidence of decompensated cirrhosis based on radiologic criteria or biopsy results
and clinical criteria (in Stage 2)
c)Evidence of HCC documented by ultrasound (U/S), CT scan, or MRI within 12 months of randomization
d)Evidence of co-infection with HBV, HIV-1 or HIV-2 at screening
e)History of variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis
f)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
g)Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug;
h)Any other medical, psychiatric &/or social reason including active substance or alcohol abuse, as defined by DMS IV, Diagnostic Criteria for Drug and Alcohol Abuse (see Protocol Appendix 3), which in opinion of the investigator, would make the candidate inappropriate for participation in this study
i)Inability to tolerate oral medication
j)Poor venous access
k)Liver transplant recipients
3)Physical & Laboratory Test Findings
a)ALT ≥5 x ULN
b)Total bilirubin ≥2 mg/dL (or ≥ 34 μmol/L)
c)INR≥ 1.7
d)Albumin ≤3.5 g/dL (35 g/L)
e)Creatinine clearance as estimated by Cockcroft and Gault ≤50 mL/min
f)Any ECG finding which in opinion of the investigator would make the
candidate inappropriate for participation in this study (corrected QT value > 450 msec, second/third degree AV block, and 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 pegIFNα & RBV package inserts
a)Severe psychiatric disease, especially untreated or unstable depression, that would prohibit use of pegIFNα 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 diseases in which anemia would be medically problematic
c)Stage 1 - History of thyroid dysfunction not adequately controlled or screening thyroid function tests that indicate abnormal thyroid function
Stage 2 - Thyroid-stimulating hormone (TSH) &/or free T4 < 0.8 times
the LLN or more than 1.2 times > ULN
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 x 10exp9 (1000000000) cells/L
h)ANC ≤ 1.5 x 10exp9 (1000000000) cells/L
i)Hemoglobin ≤12g/dL (120g/L) for women & ≤13g/dL (130 g/L) for men
j)Any known contraindications to pegIFNα or RBV, not otherwise specified
5)Allergies & Adverse Drug Reactions
a) History of hypersensitivity to drugs with a similar biochemical structure to BMS-650032, pegIFNα, or RBV
6)Prohibited Treatments &/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 (refer to Protocol Section 5.5.1)
7)Other
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) |
1/Phase 2a and Phase 2b: Safety, as measured by the frequency of SAEs and discontinuations due to AEs
2/Antiviral activity as determined by proportion of HCV genotype 1
subjects with extended rapid virologic response (eRVR), defined as
undetectable HCV RNA
3/Antiviral activity as determined by proportion of HCV genotype 1
subjects with extended rapid virologic response (eRVR), defined as
undetectable HCV RNA
4/Phase 2b only: Antiviral activity, as determined by the proportion of
HCV genotype 1 subjects with 24-week sustained virologic response
(SVR24), defined as undetectable HCV RNA |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1/Time Frame: 12 weeks after first dose
2/Time Frame: Week 4
3/Time Frame: Week 12
4/Time Frame: at follow-up Week 24 |
|
| E.5.2 | Secondary end point(s) |
1/Proportion of HCV genotype 1 subjects with rapid virologic response
(RVR), defined as undetectable HCV RNA at Week 4
2/Proportion of HCV genotype 1 subjects with complete early rapid
virologic response (eEVR), defined as undetectable HCV RNA at Week 12
(Stage 2 only)
3/Proportion of HCV genotype 1 subjects with early virologic response
(EVR) defined as ≥2 log10 decrease in HCV RNA from baseline at Week
12 (Stage 1 only)
4/Proportion of HCV genotype 1 subjects with 12-week sustained
virologic response (SVR12), defined as undetectable HCV RNA at followup Week 12
5/Proportion of HCV genotype 1 subjects with 24-week sustained
virologic response (SVR24) defined as undetectable HCV RNA at followup
Week 24 (Stage 1 only)
6/Resistant variants associated with virologic failure |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/Time Frame: Week 4
2/Time Frame: at Week 12 (Stage 2 only)
3/Time Frame: Week 12 (Stage 1 only)
4/Time Frame: follow-up Week 12
5/Time Frame: follow-up Week 24 (Stage 1 only)
6/Time Frame: 48 weeks after last dose |
|
| 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 | No |
| 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 | 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 | 2 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Argentina |
| France |
| Germany |
| Ireland |
| Italy |
| Spain |
| United Kingdom |
| 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
|
|
| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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