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Bioequivalence Study of Individual Atazanavir and Cobicistat Compared With Atazanavir in Fixed-dose Combination With Cobicistat (Atazanavir)

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ClinicalTrials.gov Identifier: NCT01837719
Recruitment Status : Completed
First Posted : April 23, 2013
Results First Posted : August 29, 2014
Last Update Posted : August 29, 2014
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Human Immunodeficiency Virus Type 1 (HIV-1)
Interventions Drug: Atazanavir
Drug: Cobicistat
Drug: Atazanavir/Cobicistat FDC
Enrollment 64
Recruitment Details  
Pre-assignment Details A total of 149 patients were enrolled and 64 randomized to 1 of 8 treatment sequences (ABCDE, ABDCE, BACDE, BADCE, ABCD, ABDC, BACD, or BADC), with a 7-day washout period between treatments. Approximately 32 were to be discharged after Period 4, based on treatment sequence. Those remaining were to continue to and be discharged at end of Period 5.
Arm/Group Title All Participants Who Received Treatment
Hide Arm/Group Description All participants who received atazanavir with cobicistat in 1 of 8 treatment sequences (ABCDE, ABDCE, BACDE, BADCE, ABCD, ABDC, BACD, or BADC). Treatment A: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat, 150 mg as tablet, following a light meal on Day 1 or 8. Treatment B: Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8. Treatment C: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day15 or 22. Treatment D: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22. Treatment E: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29.
Period Title: Period 1: Days 1-7 (Treatment A or B)
Started 64 [1]
Completed 64
Not Completed 0
[1]
Received treatment
Period Title: Period 2: Days 8-14 (Treatment B or A)
Started 64
Completed 63
Not Completed 1
Reason Not Completed
Withdrawal by Subject             1
Period Title: Period 3: Days 15-21 (Treatment C or D)
Started 63
Completed 63
Not Completed 0
Period Title: Period 4: Days 22-28 (Treatment D or C)
Started 63
Completed 63 [1]
Not Completed 0
[1]
Number finishing period; 32 patients were discharged following Period 4, as per protocol
Period Title: Period 5: Days 29-31 (Treatment E)
Started 31 [1]
Completed 30
Not Completed 1
Reason Not Completed
Poor compliance/noncompliance             1
[1]
Reflects the 31 patients remaining after 32 were discharged at the end of Period 4, as per protocol
Arm/Group Title All Participants Who Received Treatment
Hide Arm/Group Description All participants who received atazanavir with cobicistat in 1 of 8 treatment sequences (ABCDE, ABDCE, BACDE, BADCE, ABCD, ABDC, BACD, or BADC). Treatment A: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8. Treatment B: Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8. Treatment C: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22. Treatment D: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day15 or 29. Treatment E: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29.
Overall Number of Baseline Participants 64
Hide Baseline Analysis Population Description
All participants who received at least 1 dose of study drug
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 64 participants
32.5  (7.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants
Female
24
  37.5%
Male
40
  62.5%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 64 participants
White 29
Black 33
Asian 2
Body mass index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 64 participants
26.5  (2.9)
1.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Atazanavir
Hide Description Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
3832
(39%)
4104
(32%)
2585
(45%)
2941
(44%)
2545
(43%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir Cmax, with treatment, period, and sequence as fixed effects, and participant (sequence) as a random effect.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was concluded if the 90% CI for the ratios of geometric means of the test formulation (fixed-dose combination [FDC] tablet of 300/150 mg atazanavir/cobicistat) to the reference formulation (300-mg atazanavir capsule coadministered with 150-mg cobicistat) were contained within 0.80 to 1.25 for atazanavir Cmax, area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC[0-T]) and AUC from time 0 to infinity. (AUC[0-T])
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.073
Confidence Interval (2-Sided) 90%
1.012 to 1.137
Estimation Comments Geometric mean ratio is calculated as Treatment B/Treatment A
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.423
Confidence Interval (2-Sided) 90%
1.273 to 1.590
Estimation Comments Geometric mean ratio was calculated as Treatment B/Treatment D
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir Cmax with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.137
Confidence Interval (2-Sided) 90%
1.000 to 1.292
Estimation Comments Geometric mean ratio is calculated as Treatment D/Treatment C
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.862
Confidence Interval (2-Sided) 90%
0.701 to 1.059
Estimation Comments Geometric mean ratio is calculated as Treatment E/Treatment D
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.643
Confidence Interval (2-Sided) 90%
0.545 to 0.759
Estimation Comments Geometric mean ratio is calculated as Treatment E/Treatment B
2.Primary Outcome
Title Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir
Hide Description Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC(0-T)
32775
(38%)
34905
(32%)
25017
(46%)
27875
(41%)
25873
(40%)
AUC(0-INF)
33523
(39%)
35673
(32%)
25547
(47%)
28378
(42%)
26510
(40%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments Bioequivalence was concluded if the 90% confidence intervals for the ratios of geometric means of the test formulation (FDC tablet of 300/150 mg atazanavir/cobicistat) to the reference formulation (300-mg atazanavir capsule coadministered with 150-mg cobicistat) were contained within 0.80 to 1.25 for atazanavir Cmax, AUC(0-T) and AUC(INF).
Type of Statistical Test Non-Inferiority or Equivalence
Comments To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-T), with treatment, period, and sequence as fixed effects, and participant (sequence) as a random effect.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.065
Confidence Interval (2-Sided) 90%
1.012 to 1.120
Estimation Comments Geometric mean ratio for AUC(0-T) is calculated as Treatment B/Treatment A
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as a random effect was used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.275
Confidence Interval (2-Sided) 90%
1.166 to 1.393
Estimation Comments Geometric mean ratio for AUC(0-T) was calculated as Treatment B/Treatment D
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.113
Confidence Interval (2-Sided) 90%
0.993 to 1.248
Estimation Comments Geometric mean ratio for AUC(0-T) is calculated as Treatment D/Treatment C
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.950
Confidence Interval (2-Sided) 90%
0.804 to 1.122
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated as Treatment E/Treatment D
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and participant as a random effect will be used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.746
Confidence Interval (2-Sided) 90%
0.655 to 0.849
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated as Treatment E/Treatment B
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF), with treatment period and sequence as fixed effects, and patient (sequence) as a random effect.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was concluded if the 90% confidence intervals for the ratios of geometric means of the test formulation (FDC tablet of 300/150 mg atazanavir/cobicistat) to the reference formulation (300-mg atazanavir capsule coadministered with 150-mg cobicistat) were contained within 0.80 to 1.25 for atazanavir Cmax, AUC(0-T) and AUC(INF).
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.064
Confidence Interval 90%
1.011 to 1.120
Estimation Comments Geometric mean ration for AUC(INF) is calculated as Treatment B/Treatment A
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and participant as a random effect was used to estimate the effect of a light meal and fthe fasted state on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.280
Confidence Interval (2-Sided) 90%
1.171 to 1.398
Estimation Comments Geometric mean ratio for AUC(INF) was calculated as Treatment B/Treatment D
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.110
Confidence Interval (2-Sided) 90%
0.991 to 1.244
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment D/Treatment C
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.956
Confidence Interval (2-Sided) 90%
0.810 to 1.128
Estimation Comments Geometric mean of AUC(INF) was calculated as Treatment E/Treatment D
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and participant as a random effect was used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when administered as an FDC.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.749
Confidence Interval (2-Sided) 90%
0.658 to 0.852
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment E/Treatment B
3.Secondary Outcome
Title Number of Participants Who Died and With Serious Adverse Events (SAEs)
Hide Description An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant who receives an investigational product and that does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is any untoward medical occurrence that at any dose results in death; is life-threatening; or requires or prolongs inpatient hospitalization.
Time Frame On Day 24 or 31
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of any study drug.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 64 64 64 63 30
Measure Type: Number
Unit of Measure: Participants
Deaths 0 0 0 0 0
SAEs 0 0 0 0 0
4.Secondary Outcome
Title Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests
Hide Description LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment; h=high; hpf=high power field. Abnormal criteria: Leukocytes, low (*10^3 c/uL): <0.85*preRx if preRx<LLN; <0.9*LLN if LLN≤preRx≤ULN;< 0.9*LLN if preRx=missing;<LLN if preRX>ULN. Neutrophils, low (*10^3 c/uL): <0.85*preRx if preRx<1.5; <1.5 if preRx=missing; <1.5 if preRx ≥1.5. Bilirubin, h (mg/dL): >1.1* ULN if preRx≤ULN; >1.1*ULN if preRx=missing; >1.25*preRx if preRx>ULN. Bilirubin, h (mg/dL): >1.1* ULN if preRx≤ULN; >1.1*ULN if preRx=missing; >1.25*preRx if preRx>ULN. Blood, urine, h: ≥2*preRx if preRx≥1; ≥2 if preRx <1; ≥2 if preRx=missing. RBCs/WBCs, h (hpf): ≥2 if preRx=missing ≥2 if preRx<2 ≥4 if preRx ≥2. Creatine kinase, h (U/L): >1.5*preRx if preRx>ULN; >1.5*ULN if preRx≤ULN; >1.5*ULN if preRx=missing; AST, h (U/L): >1.25* preRx if preRx>ULN; >1.25*ULN if preRx≤ULN; >1.25*ULN if preRx=missing. Lactate dehydrogenase, h (U/L): >1.25*ULN if preRx≤ULN; >1.25*ULN if preRx=missing; >1.5*preRx if preRx>ULN.
Time Frame At Screening and on Days -1,4, 11, 18, and 31 (study discharge)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of study drug and had laboratory test results available.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 63 63 63 30
Measure Type: Number
Unit of Measure: Participants
Leukocytes (low) 3 2 3 1 1
Neutrophils, absolute (low) 2 4 3 2 1
Bilirubin, total (high) 1 0 0 3 4
Bilirubin, direct 0 0 0 1 1
Blood, urine (high) 1 0 0 1 1
Red blood cells (RBC), urine (high) 1 0 0 0 1
White blood cells (WBC), urine (high) 2 0 0 3 2
Creatine kinase (high) 0 1 1 0 0
Aspartate aminotransferase (AST) (high) 0 0 1 0 0
Lactate dehydrogenase (high) 0 0 1 0 0
5.Secondary Outcome
Title Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings
Hide Description A 12-lead ECG was recorded at predose and 4 hours post dose at screening, Days -1, 1, 8 15, 22, 29 and study discharge. ECGs were recorded after the patient had been supine for at least 5 minutes. All ECG readings post dosing (including unscheduled) were included.
Time Frame At screening; on Day -1; predose and 4 hours postdose on Days 1, 18, 15, 22, and 29; and at study discharge (Day 31)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of study medication and were evaluable.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 63 63 63 30
Measure Type: Number
Unit of Measure: Participants
PR interval >210 msec 0 0 0 1 0
QRS interval >120 msec 1 1 0 0 0
QT interval >500 msec 0 0 0 0 0
QTcF>450 msec 1 0 0 0 0
6.Secondary Outcome
Title Time of Maximum Observed Concentration (Tmax) of Atazanavir
Hide Description Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Median (Full Range)
Unit of Measure: Hours
3.00
(2.0 to 5.5)
2.50
(2.0 to 4.05)
2.00
(1.00 to 8.00)
2.00
(1.00 to 6.00)
3.54
(2.00 to 8.02)
7.Secondary Outcome
Title Observed Concentration at 24 Hours (C24) of Atazanavir
Hide Description Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. C24 was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
416
(58%)
449
(52%)
295
(63%)
337
(56%)
398
(45%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.084
Confidence Interval (2-Sided) 90%
1.014 to 1.158
Estimation Comments Geometric mean ratio was calculated as Treatment B/Treatment A
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.349
Confidence Interval (2-Sided) 90%
1.215 to 1.498
Estimation Comments Geometric mean ratio of C24 was calculated as Treatment B/Treatment D
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.144
Confidence Interval 90%
1.006 to 1.300
Estimation Comments Geometric mean ratio was calculated as Treatment D/Treatment C
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.231
Confidence Interval (2-Sided) 90%
1.023 to 1.483
Estimation Comments Geometric mean ratio was calculated as Treatment E/Treatment D
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.912
Confidence Interval 90%
0.789 to 1.054
Estimation Comments Geometric mean ratio was calculated as Treatment E/Treatment B
8.Secondary Outcome
Title Apparent Terminal Half-life (T-HALF) of Atazanavir
Hide Description Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Mean (Standard Deviation)
Unit of Measure: Hours
7.54  (2.91) 7.50  (2.60) 7.25  (2.49) 7.21  (2.28) 7.14  (2.99)
9.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Cobicistat
Hide Description Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day15 or22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1321
(32%)
1348
(29%)
952
(39%)
1033
(38%)
1060
(32%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.023
Confidence Interval (2-Sided) 90%
0.991 to 1.057
Estimation Comments Geometric mean ratio was calculated as Treatment B/Treatment A
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.305
Confidence Interval (2-Sided) 90%
1.215 to 1.402
Estimation Comments Geometric mean ratio was calculated as Treatment B/Treatment D
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir cobicistat
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.085
Confidence Interval (2-Sided) 90%
0.925 to 1.273
Estimation Comments Geometric mean ratio was calculated as Treatment D/Treatment C
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.040
Confidence Interval (2-Sided) 90%
0.937 to 1.154
Estimation Comments Geometric mean ratio was calculated asTreatment E/Treatment D
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.784
Confidence Interval (2-Sided) 90%
0.717 to 0.858
Estimation Comments Geometric mean ratio was calculated as Treatment E/Treatment B
10.Secondary Outcome
Title Time of Maximum Observed Concentration (Tmax) of Cobicistat
Hide Description Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Median (Full Range)
Unit of Measure: Hours
2.52
(1.00 to 5.00)
2.52
(1.00 to 5.00)
2.00
(1.00 to 5.00)
2.00
(1.00 to 5.00)
4.00
(1.00 to 12.00)
11.Secondary Outcome
Title Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat
Hide Description Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis. n=evaluable participants
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description:
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high fat meal on Day 29
Overall Number of Participants Analyzed 63 62 63 63 30
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC(0-T)
8738
(42%)
8866
(38%)
6541
(47%)
7204
(44%)
7916
(39%)
AUC(INF) (n=63, 62, 63, 63, 28)
9045
(45%)
9178
(41%)
7884
(45%)
7408
(46%)
8298
(39%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.019
Confidence Interval (2-Sided) 90%
0.983 to 1.057
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated as Treatment B/Treatment A
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.232
Confidence Interval 90%
1.141 to 1.331
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated as Treatment B/Treatment D
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.102
Confidence Interval (2-Sided) 90%
0.929 to 1.307
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated as Treatment D/Treatment C
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.127
Confidence Interval 90%
1.017 to 1.248
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated asTreatment E/Treatment D
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and a light meal on the natural logarithms of exposure of cobicistat when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.890
Confidence Interval (2-Sided) 90%
0.825 to 0.960
Estimation Comments Geometric mean ratio of AUC(0-T) was calculated asTreatment E/Treatment B
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Treatment A: Atazanavir + Cobicistat Coadministered, Treatment B: Atazanavir/Cobicistat FDC
Comments To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF), with treatment, period, and sequence as fixed effects, and participant (sequence) as a random effect.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioequivalence was concluded if the 90% CI for the ratios of geometric means of the test formulation (FDC tablet of 300/150 mg atazanavir/cobicistat) to the reference formulation (300-mg atazanavir capsule coadministered with 150-mg cobicistat) were contained within 0.80 to 1.25 for atazanavir Cmax, AUC(0-T), and AUC(INF).
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.019
Confidence Interval (2-Sided) 90%
0.982 to 1.058
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment B/Treatment A
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.240
Confidence Interval (2-Sided) 90%
1.148 to 1.340
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment B/Treatment D
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Treatment C: Atazanavir + Cobicistat Coadministered, Treatment D: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(INF) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.976
Confidence Interval (2-Sided) 90%
0.886 to 1.075
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment D/Treatment C
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Treatment D: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and fasted on the natural logarithms of exposure of cobicistat when given as an FDC.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.116
Confidence Interval (2-Sided) 90%
1.012 to 1.231
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment E/Treatment D
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Treatment B: Atazanavir/Cobicistat FDC, Treatment E: Atazanavir/Cobicistat FDC
Comments A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and light meal on the natural logarithms of exposure of atazanavir when given as an FDC
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.904
Confidence Interval (2-Sided) 90%
0.836 to 0.978
Estimation Comments Geometric mean ratio of AUC(INF) was calculated as Treatment E/Treatment B
12.Secondary Outcome
Title T-HALF of Cobicistat
Hide Description Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.
Time Frame Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
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Hide Analysis Population Description
All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
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Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29
Overall Number of Participants Analyzed 63 62 61 63 28
Mean (Standard Deviation)
Unit of Measure: Hours
4.34  (1.45) 4.33  (1.42) 4.23  (1.32) 4.09  (1.20) 4.27  (1.39)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Hide Arm/Group Description Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat, 150 mg as tablet, following a light meal on Day 1 or 8. Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8. Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22. Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22. Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29.
All-Cause Mortality
Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/64 (0.00%)   0/64 (0.00%)   0/63 (0.00%)   0/63 (0.00%)   0/31 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Treatment A: Atazanavir + Cobicistat Coadministered Treatment B: Atazanavir/Cobicistat FDC Treatment C: Atazanavir + Cobicistat Coadministered Treatment D: Atazanavir/Cobicistat FDC Treatment E: Atazanavir/Cobicistat FDC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/64 (1.56%)   3/64 (4.69%)   0/63 (0.00%)   0/63 (0.00%)   0/31 (0.00%) 
Nervous system disorders           
Dizziness  1  1/63 (1.59%)  3/63 (4.76%)  0/63 (0.00%)  0/63 (0.00%)  0/30 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01837719     History of Changes
Other Study ID Numbers: AI424-511
First Submitted: April 18, 2013
First Posted: April 23, 2013
Results First Submitted: June 9, 2014
Results First Posted: August 29, 2014
Last Update Posted: August 29, 2014