Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and BMS-955176 With Atazanavir +/- Ritonavir (Open-Labeled) in HIV-1 Infected Subjects
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 试验地点
- 1
- 主要终点
- Change in Plasma Log10 HIV-1 Ribonucleic Acid (RNA) Levels From Baseline to Day 11
研究概览
简要总结
The primary purpose of this study is to study the safety and tolerability of a HIV drug and to evaluate a decrease of HIV-1 virus level in blood after treatments in HIV-1 infected patients
详细描述
Masking: Open-Part B. Double Blind-Parts A and C
Gender: Both female and male participants for Parts A and C. Male participants for Part B.
HIV = Human Immunodeficiency Virus RNA = Ribonucleic acid
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-55 years inclusive
- •Men and women: (Parts A and C); men only (Part B)
- •Women of childbearing potential (WOCBP) must not be pregnant and nursing
- •BMI: 18.0-35.0 kg/m2
- •Subjects are infected with HIV-1 (clades B or C) and meet following criteria at the screening:
- •i) Plasma HIV-1 RNA ≥5,000 copies/mL; 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; v) In Parts A and B, all subjects are infected with HIV-1 clade B vi) In Part C, all subjects are infected with HIV-1 clade C
排除标准
- •History of genotypic and/or phenotypic drug resistance testing showing resistance to protease inhibitors
- •Any significant acute or chronic medical illness which is not stable or is not controlled with medication or not consistent with HIV-1 infection
- •Receive antiretroviral treatment within 12 weeks prior to screening
- •Currently co-infected with hepatitis C or hepatitis B
- •Previously received an HIV maturation inhibitor or HIV protease inhibitor
- •Current or recent (within 3 months of study drug administration) gastrointestinal disease
- •Any major surgery within 4 weeks of study drug administration
- •Acute diarrhea lasting ≥1 day, within 3 weeks prior to randomization
- •Subjects with history of Gilbert's syndrome
- •Subjects previously received an HIV maturation inhibitor or HIV protease inhibitor
- •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
- •Patients 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
- •Any gastrointestinal surgery that could impact upon the absorption of study drug
- •Smoking >10 cigarettes per day
- •PR ≥210 msec; QRS ≥120 msec; QT ≥500 msec; and QTcF ≥470 msec for women and ≥450 msec for men
- •Evidence of second or third degree heart block prior to study drug
- •Absolute Neutrophil Count <(ANC) 0.7 x lower limit of normal (LLN)
- •Hemoglobin <0.8 x LLN
- •Alanine aminotransferase (ALT) >1.25 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) >1.25 x ULN
- •Total Bilirubin >1.25 x ULN
- •Creatinine clearance <60 mL/mim
- •Positive urine screen for drugs of abuse without a valid prescription (subjects positive for cannabinoids and/or amphetamines will be included)
- •Positive blood screen for hepatitis C virus (HCV) RNA, hepatitis B surface antigen (consistent with active or chronic hepatitis B), or HIV-2 antibody
- •History of any significant drug allergy
研究组 & 干预措施
Part A-Group 1: BMS-955176 (5 mg) or Placebo
BMS-955176 5 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part A-Group 1: BMS-955176 (5 mg) or Placebo
BMS-955176 5 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 2: BMS-955176 (10 mg) or Placebo
BMS-955176 10 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part B-Group 6: BMS-955176 + Atazanavir + Ritonavir
BMS-955176 40 mg solution by mouth once daily for 28 days
Atazanavir 1 x 300 mg capsules by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
干预措施: Atazanavir (Drug)
Part A-Group 2: BMS-955176 (10 mg) or Placebo
BMS-955176 10 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 3: BMS-955176 (20 mg) or Placebo
BMS-955176 20 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part A-Group 3: BMS-955176 (20 mg) or Placebo
BMS-955176 20 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 4: BMS-955176 (40 mg) or Placebo
BMS-955176 40 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part A-Group 4: BMS-955176 (40 mg) or Placebo
BMS-955176 40 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part B-Group 5: BMS-955176 + Atazanavir
BMS-955176 40 mg solution by mouth once daily for 28 days
Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days
干预措施: BMS-955176 (Drug)
Part B-Group 5: BMS-955176 + Atazanavir
BMS-955176 40 mg solution by mouth once daily for 28 days
Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days
干预措施: Atazanavir (Drug)
Part B-Group 6: BMS-955176 + Atazanavir + Ritonavir
BMS-955176 40 mg solution by mouth once daily for 28 days
Atazanavir 1 x 300 mg capsules by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
干预措施: BMS-955176 (Drug)
Part B-Group 6: BMS-955176 + Atazanavir + Ritonavir
BMS-955176 40 mg solution by mouth once daily for 28 days
Atazanavir 1 x 300 mg capsules by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
干预措施: Ritonavir (Drug)
Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine
Atazanavir 1 x 300 mg capsule by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
Tenofovir 1 x 300 mg tablet by mouth once daily for 28 days
Emtricitabine 1 x 200 mg capsule once daily for 28 days
干预措施: Atazanavir (Drug)
Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine
Atazanavir 1 x 300 mg capsule by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
Tenofovir 1 x 300 mg tablet by mouth once daily for 28 days
Emtricitabine 1 x 200 mg capsule once daily for 28 days
干预措施: Ritonavir (Drug)
Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine
Atazanavir 1 x 300 mg capsule by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
Tenofovir 1 x 300 mg tablet by mouth once daily for 28 days
Emtricitabine 1 x 200 mg capsule once daily for 28 days
干预措施: Tenofovir (Drug)
Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine
Atazanavir 1 x 300 mg capsule by mouth once daily for 28 days
Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days
Tenofovir 1 x 300 mg tablet by mouth once daily for 28 days
Emtricitabine 1 x 200 mg capsule once daily for 28 days
干预措施: Emtricitabine (Drug)
Part C-Group 8: BMS-955176 (40 mg) or Placebo
BMS-955176 40 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part C-Group 8: BMS-955176 (40 mg) or Placebo
BMS-955176 40 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 9: BMS-955176 (80 mg) or Placebo
BMS-955176 80 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part A-Group 9: BMS-955176 (80 mg) or Placebo
BMS-955176 80 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 10: BMS-955176 (120 mg) or Placebo
BMS-955176 120 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part A-Group 10: BMS-955176 (120 mg) or Placebo
BMS-955176 120 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part A-Group 11 (Optional): BMS-955176 (≤120 mg) or Placebo
BMS-955176 ≤120 mg solution by mouth once daily for 14 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 14 days
干预措施: BMS-955176 (Drug)
Part A-Group 11 (Optional): BMS-955176 (≤120 mg) or Placebo
BMS-955176 ≤120 mg solution by mouth once daily for 14 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 14 days
干预措施: Placebo matching with BMS-955176 (Drug)
Part B-Group 12: BMS-955176 (80 mg) + Atazanavir
BMS-955176 80 mg solution by mouth once daily for 28 days
Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days
干预措施: BMS-955176 (Drug)
Part B-Group 12: BMS-955176 (80 mg) + Atazanavir
BMS-955176 80 mg solution by mouth once daily for 28 days
Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days
干预措施: Atazanavir (Drug)
Part C-Group 13: BMS-955176 (120 mg) or Placebo
BMS-955176 120 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: BMS-955176 (Drug)
Part C-Group 13: BMS-955176 (120 mg) or Placebo
BMS-955176 120 mg solution by mouth once daily for 10 days
OR
Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days
干预措施: Placebo matching with BMS-955176 (Drug)
结局指标
主要结局
Change in Plasma Log10 HIV-1 Ribonucleic Acid (RNA) Levels From Baseline to Day 11
时间窗: Baseline (Day 1) and Day 11 after the final dose with BMS-955176
Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Change in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 monotherapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.
次要结局
- Time to Reach Maximum Plasma Concentration (Tmax) - Part A and C(Pre-dose Day 1 and Day 10)
- Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), and Discontinuations Due to AEs During the Study(Day 1 to end of the study (Day 42))
- Maximum Decline From Baseline in Log10 HIV-1 RNA - Part A and C(Baseline (Day 1) up to Day 24)
- Maximum Decline From Baseline in Log10 HIV-1 RNA - Part B(Baseline (Day 1) up to Day 42)
- Time to Maximum Decline in Log 10 HIV-1 RNA - Part A and C(Baseline (Day 1) up to Day 24)
- Time to Maximum Decline in Log 10 HIV-1 RNA - Part B(Baseline (Day 1) up to Day 42)
- Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part A and C(Baseline (Day 1) up to Day 24)
- Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part B(Baseline (Day 1) up to Day 42)
- Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part A and C(Baseline (Day 1) up to Day 24)
- Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part B(Baseline (Day 1) up to Day 42)
- Time to Reach Maximum Plasma Concentration (Tmax) - Part B(Pre-dose Day 1 and Day 28)
- Maximum Observed Plasma Concentrations (Cmax) - Part A and C(Pre-dose Day 1 and Day 10)
- Plasma Concentration 24 Hours Post-Dose (C24) - Part A and C(24 hours post-dose)
- Maximum Observed Plasma Concentrations (Cmax) - Part B(Pre-dose Day 1 and Day 28)
- Plasma Concentration 24 Hours Post-Dose (C24) - Part B(24 hours post-dose)
- Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC([Tau]) - Part A and C(Pre-dose Day 1 and Day 10)
- Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC[Tau]) - Part B(Pre-dose Day 1 and Day 28)
- Accumulation Index (AI): Part A and C(Baseline and Day 10)
- Apparent Total Body Clearance: Part A and C(Baseline (Day 1) to Day 10)
- Degree of Fluctuation (DF): Part A and C(Baseline (Day 1) to Day 10)
- Average Observed Plasma Concentration at Steady State (Css-avg): Part A and C(Baseline (Day 1) to Day 10)
- Plasma Half-life: Part A and C(Baseline (Day 1) to Day 10)
- Number of Participants With Clinically Significant Grade 3/4 Laboratory Abnormalities From Baseline(Day 1 to up to end of the study (Day 42))
- Number of Participants With Clinically Significant Changes in Heart Rate(Day 1 to end of the study (Day 42))
- Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)(Day 1 to end of the study (Day 42))
- Number of Participants With Clinically Significant Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Day 1 to end of the study (Day 42))
- Number of Participants With Abnormal Changes in Physical Examination(Day 1 to end of the study (Day 42))