Study to Evaluate a HIV Drug for the Treatment of HIV Infection

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01803074
• Other study ID #: 206739
• Secondary ID: 2012-004124-38AI
• Status: Completed
• Phase: Phase 2
• Start date: April 4, 2013
• Est. completion date: November 29, 2014

Study information

• Verified date: November 2019
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: November 29, 2014
• Est. primary completion date: November 29, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Communicable Diseases
• HIV Infections
• Infection
• Infection, Human Immunodeficiency Virus

Intervention

Drug:
• BMS-955176
BMS-955176
• Placebo matching with BMS-955176
Placebo matching with BMS-955176
• Atazanavir
Atazanavir
• Ritonavir
Ritonavir
• Tenofovir
Tenofovir
• Emtricitabine
Emtricitabine

Locations

Country	Name	City	State
Germany	GSK Investigational Site	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Plasma Log10 HIV-1 Ribonucleic Acid (RNA) Levels From Baseline to Day 11	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.	Baseline (Day 1) and Day 11 after the final dose with BMS-955176
Secondary	Time to Reach Maximum Plasma Concentration (Tmax) - Part A and C	Time to reach the maximum plasma concentration was directly determined from concentration time data.	Pre-dose Day 1 and Day 10
Secondary	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	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug.	Day 1 to end of the study (Day 42)
Secondary	Maximum Decline From Baseline in Log10 HIV-1 RNA - Part A and C	Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Maximum decline from Baseline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 24
Secondary	Maximum Decline From Baseline in Log10 HIV-1 RNA - Part B	Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Maximum decline from Baseline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 42
Secondary	Time to Maximum Decline in Log 10 HIV-1 RNA - Part A and C	Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Time to maximum decline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 24
Secondary	Time to Maximum Decline in Log 10 HIV-1 RNA - Part B	Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Time to maximum decline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 42
Secondary	Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part A and C	Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 24
Secondary	Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part B	Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 42
Secondary	Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part A and C	Percent Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 24
Secondary	Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part B	Percent Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values.	Baseline (Day 1) up to Day 42
Secondary	Time to Reach Maximum Plasma Concentration (Tmax) - Part B	Tmax was directly determined from concentration time data.	Pre-dose Day 1 and Day 28
Secondary	Maximum Observed Plasma Concentrations (Cmax) - Part A and C	Cmax was defined as the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.	Pre-dose Day 1 and Day 10
Secondary	Plasma Concentration 24 Hours Post-Dose (C24) - Part A and C	C24 was defined as the plasma concentration of BMS-955176 at 24 hours post-dose.	24 hours post-dose
Secondary	Maximum Observed Plasma Concentrations (Cmax) - Part B	Cmax was defined as the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.	Pre-dose Day 1 and Day 28
Secondary	Plasma Concentration 24 Hours Post-Dose (C24) - Part B	C24 was defined as the plasma concentration of BMS-955176 at 24 hours post-dose.	24 hours post-dose
Secondary	Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC([Tau]) - Part A and C	AUC(tau) was defined as the area under the plasma concentration - time curve over the dosing interval.	Pre-dose Day 1 and Day 10
Secondary	Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC[Tau]) - Part B	AUC(tau) was defined as the area under the plasma concentration - time curve over the dosing interval.	Pre-dose Day 1 and Day 28
Secondary	Accumulation Index (AI): Part A and C	Accumulation index was calculated by dividing the AUC(tau) or Cmax or C24 of BMS-955176 on Day 10 by the AUC(TAU) or Cmax or C24, respectively, of BMS-955176 on Day 1.	Baseline and Day 10
Secondary	Apparent Total Body Clearance: Part A and C	Apparent total body clearance was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7).	Baseline (Day 1) to Day 10
Secondary	Degree of Fluctuation (DF): Part A and C	DF was calculated as the difference between Cmax and Cmin divided by Css-avg. DF was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7).	Baseline (Day 1) to Day 10
Secondary	Average Observed Plasma Concentration at Steady State (Css-avg): Part A and C	Css-avg was calculated by the quotient of AUC(TAU) and the dosing interval (24 h). Css-avg was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7).	Baseline (Day 1) to Day 10
Secondary	Plasma Half-life: Part A and C	Half-life of the terminal log-linear phase, (T-half), was calculated as natural logarithm of 2 (ln2)/?, where ? is the absolute value of the slope of the terminal log-linear phase. T-half was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7).	Baseline (Day 1) to Day 10
Secondary	Number of Participants With Clinically Significant Grade 3/4 Laboratory Abnormalities From Baseline	Laboratory abnormalities were determined and graded using the Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 1.0, December 2004.	Day 1 to up to end of the study (Day 42)
Secondary	Number of Participants With Clinically Significant Changes in Heart Rate	Heart rate was measured after the participants had been seated quietly for at least 5 minutes. Criteria used to determine heart rate that are outside of a pre-specified range, where changes from Baseline are based on matched postural positions and are calculated as parameter value - Baseline parameter value: Value >100 and change from Baseline > 30, or Value < 55 and change from Baseline < -15.	Day 1 to end of the study (Day 42)
Secondary	Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)	Participants with out of range ECG intervals were summarized. Criteria used to determine ECG results that are outside of a pre-specified range: PR (milliseconds [msec]): Value >200; QRS (msec): Value >120; QT (msec): Value >500 or change from Baseline >30; corrected QT interval Fridericia's formula (QTcF) (msec): Value >450 or change from Baseline >30.	Day 1 to end of the study (Day 42)
Secondary	Number of Participants With Abnormal Changes in Physical Examination	Participants with abnormal changes in physical examination is presented.	Day 1 to end of the study (Day 42)
Secondary	Number of Participants With Clinically Significant Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Systolic BP (millimeter of mercury [mmHg]): value >140 and change from Baseline >20, or value <90 and change from Baseline <-20; Diastolic BP (mmHg): value >90 and change from Baseline >10, or value <55 and change from Baseline <-10.	Day 1 to end of the study (Day 42)

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