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    Clinical Trial Results:
    A Single-Dose, Open-Label, Randomized, Replicate Crossover Pivotal Bioequivalence Study in Healthy Adult Participants to Assess the Bioequivalence of Darunavir 675 mg, Emtricitabine 200 mg, and Tenofovir Alafenamide 10 mg in the Presence of Cobicistat 150 mg when Administered as a Fixed Dose Combination (Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) Compared to the Co-administration of the Separate Agents (Darunavir, Cobicistat, and Emtricitabine/Tenofovir Alafenamide), Under Fed Conditions

    Summary
    EudraCT number
    		 2020-003396-18
    Trial protocol
    		 NL  
    Global end of trial date
    23 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2022
    First version publication date
    03 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC114FD2HTX1007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04661397
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001280-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the single-dose pharmacokinetic (PK) and pivotal bioequivalence of 3 compounds (darunavir [DRV/D] 675 milligrams (mg), emtricitabine [FTC/F] 200 mg, and tenofovir alafenamide [TAF] 10 mg) in the presence of cobicistat (COBI/C) 150 mg when administered together as a fixed dose combination (FDC) tablet (D/C/F/TAF) compared to the co-administration as the separate commercial formulations (DRV 1*600 mg and 1*75 mg tablet and F/TAF 1*200 mg/10 mg tablet, and COBI 1*150 mg tablet), under fed conditions, in healthy adult subjects.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon the incidence of adverse events reported throughout the study, and on clinical laboratory tests, electrocardiogram (ECG), vital signs, and physical examination.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    37
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 37 healthy subjects were randomized and treated (19 subjects in treatment sequence ABBA and 18 subjects in treatment sequence BAAB). Of these, 32 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Sequence ABBA
    Arm description
    		 Subjects received a single oral dose of Darunavir (675 milligrams [mg])/Cobicistat (150 mg)/Emtricitabine (200 mg)/Tenofovir Alafenamide (10 mg) as one fixed dose combination (FDC) tablet (D/C/F/TAF) under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of Darunavir (DRV) 600 mg and 75 mg tablet, Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF) and Cobicistat (COBI) 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2 followed by Treatment B again on Day 1 of Period 3 and, then Treatment A on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Darunavir 675 mg/Cobicistat 150 mg/Emtricitabine 200 mg/Tenofovir Alafenamide (10 mg) (D/C/F/TAF) FDC
    Investigational medicinal product code
    Other name
    TMC114/JNJ-48763364/JNJ-35807551/JNJ-63625328
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of D/C/F/TAF 675/150/200/10 mg FDC tablet orally as Treatment A on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF)
    Investigational medicinal product code
    Other name
    JNJ-35807551/JNJ-63625328
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of E/TAF 200/10mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Cobicistat (COBI) 150 mg
    Investigational medicinal product code
    Other name
    JNJ-48763364
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of COBI 150 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Darunavir (DRV) 600 mg and 75 mg
    Investigational medicinal product code
    Other name
    TMC114
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of DRV 600 mg and 75 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Arm title
    		 Treatment Sequence BAAB
    Arm description
    		 Subjects received a single oral dose of DRV 600 mg and 75 mg tablet, F/TAF 200/10 mg and COBI 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose D/C/F/TAF 675/150/200/10 mg as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 2 followed by Treatment A on Day 1 of Period 3 and, then Treatment B on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Darunavir (DRV) 600 mg and 75 mg
    Investigational medicinal product code
    Other name
    TMC114
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of DRV 600 mg and 75 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF)
    Investigational medicinal product code
    Other name
    JNJ-35807551/JNJ-63625328
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of E/TAF 200/10mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Cobicistat (COBI) 150 mg
    Investigational medicinal product code
    Other name
    JNJ-48763364
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of COBI 150 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.

    Investigational medicinal product name
    Darunavir 675 mg/Cobicistat 150 mg/Emtricitabine 200 mg/Tenofovir Alafenamide (10 mg) (D/C/F/TAF) FDC
    Investigational medicinal product code
    Other name
    TMC114/JNJ-48763364/JNJ-35807551/JNJ-63625328
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of D/C/F/TAF 675/150/200/10 mg FDC tablet orally as Treatment A on Day 1 as per assigned treatment sequences.

    Number of subjects in period 1
    		Treatment Sequence ABBA Treatment Sequence BAAB
    Started
    19
    18
    Completed
    16
    16
    Not completed
    3
    2
         Adverse event
    1
    -
         Unspecified
    1
    1
         Withdrawal by subject
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Sequence ABBA
    Reporting group description
    		 Subjects received a single oral dose of Darunavir (675 milligrams [mg])/Cobicistat (150 mg)/Emtricitabine (200 mg)/Tenofovir Alafenamide (10 mg) as one fixed dose combination (FDC) tablet (D/C/F/TAF) under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of Darunavir (DRV) 600 mg and 75 mg tablet, Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF) and Cobicistat (COBI) 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2 followed by Treatment B again on Day 1 of Period 3 and, then Treatment A on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Reporting group title
    Treatment Sequence BAAB
    Reporting group description
    		 Subjects received a single oral dose of DRV 600 mg and 75 mg tablet, F/TAF 200/10 mg and COBI 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose D/C/F/TAF 675/150/200/10 mg as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 2 followed by Treatment A on Day 1 of Period 3 and, then Treatment B on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Reporting group values
    		 Treatment Sequence ABBA Treatment Sequence BAAB Total
    Number of subjects
    		 19 18 37
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 18 37
        From 65 to 84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    		 26 (18 to 54) 27.5 (19 to 55) -
    Title for Gender
    Units: subjects
        Female
    		 8 5 13
        Male
    		 11 13 24

    End points

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    End points reporting groups
    Reporting group title
    Treatment Sequence ABBA
    Reporting group description
    		 Subjects received a single oral dose of Darunavir (675 milligrams [mg])/Cobicistat (150 mg)/Emtricitabine (200 mg)/Tenofovir Alafenamide (10 mg) as one fixed dose combination (FDC) tablet (D/C/F/TAF) under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of Darunavir (DRV) 600 mg and 75 mg tablet, Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF) and Cobicistat (COBI) 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2 followed by Treatment B again on Day 1 of Period 3 and, then Treatment A on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Reporting group title
    Treatment Sequence BAAB
    Reporting group description
    		 Subjects received a single oral dose of DRV 600 mg and 75 mg tablet, F/TAF 200/10 mg and COBI 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose D/C/F/TAF 675/150/200/10 mg as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 2 followed by Treatment A on Day 1 of Period 3 and, then Treatment B on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Subject analysis set title
    Treatment A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received a single oral dose of Darunavir (675 milligrams [mg])/Cobicistat (150 mg)/Emtricitabine (200 mg)/Tenofovir Alafenamide (10 mg) as one fixed dose combination (FDC) tablet (D/C/F/TAF) under fed conditions (Treatment A, test) on Day 1 of Period 1.

    Subject analysis set title
    Treatment B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received a single oral dose of DRV 600 mg and 75 mg tablet, F/TAF 200/10 mg and COBI 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1.

    Primary: Maximum Observed Plasma Concentration (Cmax) of Darunavir (DRV)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Darunavir (DRV)
    End point description
    Cmax was defined as the maximum observed plasma concentration of Darunavir. Pharmacokinetic (PK) data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: nanograms per millilitre (ng/mL)
        arithmetic mean (standard deviation)
    6363 ( 1449 )
    6426 ( 1277 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed pharmacokinetic (PK) parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    98.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 94.1
         upper limit
    		 102.18
    Notes
    [1] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125 percent (%).

    Primary: Maximum Observed Plasma Concentration (Cmax) of Emtricitabine (FTC)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Emtricitabine (FTC)
    End point description
    Cmax was the maximum observed plasma concentration of FTC. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: ng/mL
        arithmetic mean (standard deviation)
    1806 ( 385 )
    1835 ( 366 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    98.64
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.66
         upper limit
    		 103.89
    Notes
    [2] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Primary: Maximum Observed Plasma Concentration (Cmax) of Tenofovir Alafenamide (TAF)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Tenofovir Alafenamide (TAF)
    End point description
    Cmax was the maximum observed plasma concentration of TAF. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: ng/mL
        arithmetic mean (standard deviation)
    144 ( 86.8 )
    134 ( 78.8 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    105.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.86
         upper limit
    		 121.87
    Notes
    [3] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (Non-below Quantification Limit [non-BQL]) Concentration (AUC[0-last]) of Darunavir (DRV)

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (Non-below Quantification Limit [non-BQL]) Concentration (AUC[0-last]) of Darunavir (DRV)
    End point description
    AUC(0-last) was area under the plasma concentration-time curve from time zero to the time of the last measurable (non-BQL) concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: hour*nanogram per millilitre (h*ng/mL)
        arithmetic mean (standard deviation)
    74698 ( 23915 )
    72380 ( 22435 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    102.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.11
         upper limit
    		 107.6
    Notes
    [4] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Emtricitabine (FTC)

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Emtricitabine (FTC)
    End point description
    AUC(0-last) was area under the plasma concentration-time curve from time zero to the time of the last measurable non-BQL concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    9967 ( 1854 )
    9995 ( 1802 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    100.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.83
         upper limit
    		 102.4
    Notes
    [5] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Tenofovir Alafenamide (TAF)

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Tenofovir Alafenamide (TAF)
    End point description
    AUC(0-last) was area under the plasma concentration-time curve from time zero to the time of the last measurable non-BQL concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Primary
    End point timeframe
    Pre dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    124 ( 36.7 )
    113 ( 44.1 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    113.41
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 106.82
         upper limit
    		 120.41
    Notes
    [6] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Area Under the Plasma was Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Darunavir

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    End point title
    		 Area Under the Plasma was Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Darunavir
    End point description
    The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Secondary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    74891 ( 23974 )
    72564 ( 22502 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    102.73
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.1
         upper limit
    		 107.58
    Notes
    [7] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Cobicistat

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Cobicistat
    End point description
    The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Secondary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    6276 ( 2169 )
    6476 ( 2190 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    97.68
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.44
         upper limit
    		 102.1
    Notes
    [8] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Emtricitabine (FTC)

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Emtricitabine (FTC)
    End point description
    The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to plasma time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods. Here, N (Number of Subjects Analysed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    30
    28
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    10174 ( 1900 )
    10199 ( 1791 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    101.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 99.31
         upper limit
    		 103.24
    Notes
    [9] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 25. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Tenofovir Alafenamide (TAF)

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Tenofovir Alafenamide (TAF)
    End point description
    The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods. Here, N (Number of Subjects Analysed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    25
    25
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    127 ( 38.4 )
    116 ( 43.8 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    115.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 107.31
         upper limit
    		 123.25
    Notes
    [10] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 19. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Cobicistat

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Cobicistat
    End point description
    Cmax was the maximum observed plasma concentration of Cobicistat. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Secondary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: ng/mL
        arithmetic mean (standard deviation)
    842 ( 206 )
    898 ( 202 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    93.67
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 89.63
         upper limit
    		 97.9
    Notes
    [11] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Cobicistat

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable (non-BQL) Concentration (AUC[0-last]) of Cobicistat
    End point description
    AUC(0-last) was area under the plasma concentration-time curve from time 0 to the time of the last measurable non-BQL concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who completed all treatment periods and for which an evaluable PK parameter could be obtained in all treatment periods.
    End point type
    Secondary
    End point timeframe
    Pre dose and 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72 hours post dose
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    33
    32
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    6160 ( 2116 )
    6366 ( 2113 )
    Statistical analysis title
    		 Treatment B Versus Treatment A
    Statistical analysis description
    Log transformed PK parameters were analyzed by mixed model analysis of variance with period, treatment, treatment sequence as fixed effects, and subject within-sequence as a random effect and the results were back-transformed using anti-logarithm.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    97.45
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.18
         upper limit
    		 101.91
    Notes
    [12] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 32. Pre-defined bioequivalence limits were 80 to 125%.

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment. Safety analysis set included all subjects who received at least one dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to 5 weeks
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    36
    36
    Units: Subjects
    20
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of the Informed consent form (ICF) till the last study-related activity (up to 9 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Treatment B
    Reporting group description
    		 Subjects received a single oral dose of DRV 600 mg and 75 mg tablet, F/TAF 200/10 mg and COBI 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose D/C/F/TAF 675/150/200/10 mg as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 2 followed by Treatment A on Day 1 of Period 3 and, then Treatment B on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Reporting group title
    Treatment A
    Reporting group description
    		 Subjects received a single oral dose of Darunavir (675 milligrams [mg])/Cobicistat (150 mg)/Emtricitabine (200 mg)/Tenofovir Alafenamide (10 mg) as one fixed dose combination (FDC) tablet (D/C/F/TAF) under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of Darunavir (DRV) 600 mg and 75 mg tablet, Emtricitabine 200 mg/Tenofovir Alafenamide 10 mg (F/TAF) and Cobicistat (COBI) 150 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2 followed by Treatment B again on Day 1 of Period 3 and, then Treatment A on Day 1 of Period 4. Each period was separated by a washout period of at least 7 days.

    Serious adverse events
    		 Treatment B Treatment A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment B Treatment A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 36 (58.33%)
    20 / 36 (55.56%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    5 / 36 (13.89%)
    6 / 36 (16.67%)
         occurrences all number
    6
    9
    General disorders and administration site conditions
    Catheter Site Bruise
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    3
    Fatigue
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 36 (11.11%)
         occurrences all number
    4
    4
    Catheter Site Related Reaction
         subjects affected / exposed
    7 / 36 (19.44%)
    6 / 36 (16.67%)
         occurrences all number
    9
    7
    Vessel Puncture Site Reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Abdominal Discomfort
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         occurrences all number
    2
    4
    Diarrhoea
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    13 / 36 (36.11%)
    8 / 36 (22.22%)
         occurrences all number
    19
    11
    Vomiting
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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