| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus Type-1 (HIV-1) infection |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 100000004862 |
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| 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 |
| Primary Objective is to assess the antiviral activity in HIV-1 infected subjects following administration of BMS-955176 for 10 days. |
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| E.2.2 | Secondary objectives of the trial |
To assess:
-safety and tolerability of BMS-955176 (BMS95) following monotherapy and combination therapy of BMS95 with ATV +/-RTV in HIV-1 infected subjects
-addition of ATV or ATV+RTV, respectively, to the effect of BMS95 on change from baseline in plasma log10 HIV-1 RNA levels in HIV-1 infected subjects
-effect of BMS95 on CD4+ and CD8+ lymphocyte counts and percents following monotherapy and combination therapy of BMS95 with ATV +/-RTV in HIV-1 infected subjects
-effect of RTV on the combined effect of BMS95 and ATV on change from baseline in plasma log10 HIV-1 RNA levels in HIV-1 infected subjects
-to compare the antiviral activities between 10 days and 14 days when 40 mg BMS95 are administered, if applicable
-relationships between change from baseline in log10 HIV-1 RNA and PK exposures for BMS95 following monotherapy and following combination therapy of BMS95 with ATV+/-RTV
-PK of BMS95 following monotherapy and following combination therapy of BMS-955176 with ATV+/-RTV |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent: The signed informed consent form.
2) Target Population
a) HIV-1 infected (clades B or C) subjects meeting the following criteria at the screening visit (within 30 days of enrollment):
i) Plasma HIV-1 RNA ≥ 5,000 copies/mL (may be repeated for confirmation)
ii) Antiretroviral treatment naive (defined as <1 week of ARV treatment) or ART-experienced (protease inhibitor and/or maturation inhibitor naive)
iii) Subjects are not eligible for HIV-1 treatment based on the United States Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents or have declined initiation of cART
iv) CD4+ lymphocyte measurement ≥ 200 cells/μL (may be repeated for confirmation)
v) In Parts A and B, all subjects are infected with clade B HIV-1 virus
vi) In Part C, all subjects are infected with clade C HIV-1 virus
b) Body Mass Index (BMI) of 18.0 to 35.0 kg/m2, inclusive. BMI = weight (kg)/m2
c) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be reconsented and re-numbered.
3) Age and Reproductive Status
a) Men and women, ages 18-55 years, inclusive for Parts A and C
b) Men, ages 18-55 years, inclusive for Part B
c) In Parts A and C, women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 1. Because BMS-955176 may be a selective developmental toxicant and a potential teratogen, subjects must agree to the use of two methods of contraception, one method being highly effective and the other method being highly effective or less effective as defined in Appendix 1. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives (a total of 38 days post the last dose). In addition, WOCBP must follow the methods of contraception at least 4 weeks prior to the first dose and during the treatment.
d) In Parts A and 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.
e) In Parts A and C, women must not be breastfeeding
f) Men who are sexually active with WOCBP must use two methods of contraception, one method being highly effective and the other method being highly effective or less effective (listed in Appendix 1). The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives (for a total of 98 days post the last dose).
g) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile; see Section 3.3.3 for the definition of WOCBP) and azoospermic men do not require contraception. |
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| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
a) History of genotypic and/or phenotypic drug resistance testing showing resistance to protease inhibitors
i) Screening HIV-1 genotypic drug resistance testing at baseline showing primary protease inhibitor resistance mutations as defined by the presence of any of the following: D30N, M46I/L, I47V/A, G48V, I50L, I54M/L, Q58E, T74P, L76V, V82A/F/L/T/S, N83D, I84V, N88S, L90M
2) Medical History and Concurrent Diseases
a) Any significant acute or chronic medical illness which is not stable or is not controlled with medication or not consistent with HIV-1 infection.
b) Current or recent (within 3 months of study drug administration) gastrointestinal disease that, in the opinion of the Investigator or Medical Monitor, may impact on drug absorption.
c) Any major surgery within 4 weeks of study drug administration.
d) Acute diarrhea lasting ≥ 1 day, within 3 weeks prior to randomization. Diarrhea will be defined as the passage of liquid feces and/or a stool frequency greater than three times per day.
e) Subjects with history of Gilbert’s syndrome.
f) Subjects with antiretroviral treatment within 12 weeks prior to screening
g) Subjects currently co-infected with hepatitis C or hepatitis B
h) Subjects previously received an HIV maturation inhibitor or HIV protease inhibitor
i) A personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes. A personal or family history of long QT syndrome.
j) Subjects who are unwilling to practice adequate infection protection during and after study participation to minimize potential for spread of HIV infection, including HIV which may have developed resistance to HIV maturation inhibitor and/or ATV. Such protections could include, but are not limited to behaviors to minimize potential for exposure to the subjects’ bodily fluids or initiation of cART therapy if indicated and recommended by a physician.
k) Any gastrointestinal surgery that could impact upon the absorption of study drug.
l) Donation of blood to a blood bank or in a clinical study (except a screening visit) within 4 weeks of study drug administration (within 2 weeks for plasma only).
m) Blood transfusion within 4 weeks of study drug administration.
n) Inability to tolerate oral medication.
o) Inability to be venipunctured and/or tolerate venous access.
p) Smoking more than 10 cigarettes per day.
q) Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 2).
r) Any other sound medical, psychiatric and/or social reason as determined by the investigator.
3) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations or not consistent with the subject’s degree of HIV infection.
b) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug administration, confirmed by repeat.
i) PR ≥ 210 msec
ii) QRS ≥ 120 msec
iii) QT ≥ 500 msec
iv) QTcF ≥ 470 msec for women and ≥ 450 msec for men
c) Evidence of second or third degree heart block prior to study drug, confirmed by repeat ECG.
d) Positive urine screen for drugs of abuse at either Screening or Day -1 without a valid prescription (subjects positive for cannabinoids and/or amphetamines will be included, unless excluded by exclusion criteria 2n in Section 3.3.2).
e) Positive blood screen for HCV RNA, hepatitis B surface antigen (consistent with active or chronic hepatitis B), or HIV-2 antibody;
f) Any of the following laboratory results outside of the ranges specified below prior to study drug administration, confirmed by repeat analysis.
i) Absolute Neutrophil Count (ANC) < 0.7 x lower limit of normal (LLN)
ii) Hemoglobin < 0.8 x LLN
iii) ALT > 1.25 x upper limit of normal (ULN)
iv) AST > 1.25 x ULN
v) Total Bilirubin > 1.25 x ULN
vi) Creatinine clearance (as estimated by method of Cockcroft and Gault 13) less than 60 mL/min
4) Allergies and Adverse Drug Reaction
a) History of allergy to maturation inhibitor or related compounds.
b) History of allergy to ATV, RTV or related compounds
c) History of allergy to tenofovir, emtricitabine, lamivudine or related compounds (For Part B only)
d) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
5) 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
c) Inability to comply with restrictions and prohibited activities/treatments as listed in Section 3.4
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change in plasma log10 HIV-1 RNA levels from baseline on Day 11. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1) Frequency of AEs, SAEs, discontinuations due to AEs, frequencies of marked abnormalities in vital signs, clinical laboratory tests, ECG readings and physical examinations from Day 1 until Day 24 (Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28 (optional Treatment Group 11), or from Day 1 to Day 42 (Part B).
2) Time course of the change from baseline in plasma log10 HIV-1 RNA levels and the time of maximum decrease during the 10-day monotherapy and combination therapy of BMS-955176 with ATV +/-RTV from Day 1 until Day 24 (optional Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28
(Treatment Group 11), or from Day 1 to Day 42 (Part B).
3) Change from baseline in CD4+ and CD8+ lymphocyte counts and percentages following monotherapy and combination therapy of BMS-955176 with ATV +/-RTV in HIV-1 infected subjects from Day 1 until Day 24 (Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28 (optional Treatment Group 11), or from Day 1 to Day 42 (Part B).
4) Pharmacokinetic parameters on Days 1 and 10 (Treatment Groups 1-4, and 8-10; and 13), Days 1 and 14 (optional Treatment Group 11), and from Days 1 to 28 (Part B) (Cmax, Cmin, Tmax, Ctrough, AUC(TAU), AI, CL/F and T-HALF). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) from Day 1 until Day 24 (Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28 (optional Treatment Group 11), or from Day 1 to Day 42 (Part B).
2) from Day 1 until Day 24 (optional Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28 (Treatment Group 11), or from Day 1 to Day 42 (Part B).
3) from Day 1 until Day 24 (Treatment Groups 1-4, and 8-10; and 13), from Day 1 until Day 28 (optional Treatment Group 11), or from Day 1 to Day 42 (Part B).
4) on Days 1 and 10 (Treatment Groups 1-4, and 8-10; and 13), Days 1 and 14 (optional Treatment Group 11), and from Days 1 to 28 (Part B). |
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| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Parts A and C are double-blinded, Part B is open-labeled. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Parts A and C are placebo-controlled, Part B is SOC-controlled |
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| E.8.2.4 | Number of treatment arms in the trial | 13 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
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| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
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