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    Clinical Trial Results:
    A Single-dose, Open-label, Randomized, Crossover Pivotal Bioequivalence Study in Healthy Participants to Assess the Bioequivalence of Darunavir 675 mg in the Presence of 150 mg Cobicistat When Administered as a Fixed Dose Combination (Darunavir/Cobicistat) Compared to the Co-administration of the Separate Agents (Darunavir and Cobicistat) Under Fed Conditions

    Summary
    EudraCT number
    		 2020-003397-43
    Trial protocol
    		 BE  
    Global end of trial date
    01 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2022
    First version publication date
    12 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC114IFD1004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04718805
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium,
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, 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
    01 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the single-dose pharmacokinetics (PK) and bioequivalence of darunavir (DRV) 675 milligrams (mg) in the presence of cobicistat (COBI) 150 mg when administered as a scored fixed dose combination (FDC) tablet (DRV/COBI) compared to the co-administration as the separate available tablet formulations (DRV 1*600 mg and 1*75 mg tablet and COBI 1*150 mg tablet), under fed conditions in healthy 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 (GCP) and applicable regulatory requirements. Safety assessments included adverse events, deaths, clinical laboratory tests, vital signs, and physical examination results.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 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
    Belgium: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    22
    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 22 subjects were enrolled in the study (in 2 treatment sequences: 11 subjects in each treatment sequence). All 22 enrolled 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
    		 Sequence 1: A-B
    Arm description
    		 Subjects received Treatment A (a single oral dose of Darunavir [DRV] 675 milligrams [mg] and Cobicistat [COBI] 150 mg as a scored fixed dose combination [FDC] tablet [DRV/COBI] under fed conditions) (test) on Day 1 of Treatment Period 1, followed by Treatment B (a single oral dose of DRV 675 mg tablet administered as 1*600 mg plus 1*75 mg and; COBI 1*150 mg tablet under fed conditions) (reference) on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DRV 675 mg/COBI 150 mg (DRV/COBI) FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral tablet of DRV/COBI 675/150 mg FDC on Day 1.

    Investigational medicinal product name
    DRV 675 mg and COBI 150 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single oral tablets of DRV 600 mg, DRV 75 mg, and COBI 150 mg on Day 1.

    Arm title
    		 Sequence 2: B-A
    Arm description
    		 Subjects received Treatment B on Day 1 of Treatment Period 1, followed by Treatment A on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DRV 675 mg/COBI 150 mg (DRV/COBI) FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral tablet of DRV/COBI 675/150 mg FDC on Day 1.

    Investigational medicinal product name
    DRV 675 mg and COBI 150 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single oral tablets of DRV 600 mg, DRV 75 mg, and COBI 150 mg on Day 1.

    Number of subjects in period 1
    		Sequence 1: A-B Sequence 2: B-A
    Started
    11
    11
    Completed
    11
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence 1: A-B
    Reporting group description
    		 Subjects received Treatment A (a single oral dose of Darunavir [DRV] 675 milligrams [mg] and Cobicistat [COBI] 150 mg as a scored fixed dose combination [FDC] tablet [DRV/COBI] under fed conditions) (test) on Day 1 of Treatment Period 1, followed by Treatment B (a single oral dose of DRV 675 mg tablet administered as 1*600 mg plus 1*75 mg and; COBI 1*150 mg tablet under fed conditions) (reference) on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.

    Reporting group title
    Sequence 2: B-A
    Reporting group description
    		 Subjects received Treatment B on Day 1 of Treatment Period 1, followed by Treatment A on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.

    Reporting group values
    		 Sequence 1: A-B Sequence 2: B-A Total
    Number of subjects
    		 11 11 22
    Title for AgeCategorical
    Units: subjects
        Newborns (0-1 years)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 11 22
        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))
    		 43 (20 to 51) 30 (18 to 45) -
    Title for Gender
    Units: subjects
        Female
    		 8 7 15
        Male
    		 3 4 7

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1: A-B
    Reporting group description
    		 Subjects received Treatment A (a single oral dose of Darunavir [DRV] 675 milligrams [mg] and Cobicistat [COBI] 150 mg as a scored fixed dose combination [FDC] tablet [DRV/COBI] under fed conditions) (test) on Day 1 of Treatment Period 1, followed by Treatment B (a single oral dose of DRV 675 mg tablet administered as 1*600 mg plus 1*75 mg and; COBI 1*150 mg tablet under fed conditions) (reference) on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.

    Reporting group title
    Sequence 2: B-A
    Reporting group description
    		 Subjects received Treatment B on Day 1 of Treatment Period 1, followed by Treatment A on Day 1 of Treatment Period 2. For each individual subject, there was a washout period of at least 7 days between doses. Day 1 of a treatment period (day of study drug intake) was the first day of the washout period.

    Subject analysis set title
    Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received a single oral dose of DRV/COBI 675/150 mg as a scored FDC on Day 1 under fed condition.

    Subject analysis set title
    Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received a single oral dose of DRV 675 mg as DRV 600 mg plus DRV 75 mg and COBI 150 mg on Day 1 under fed condition.

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

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    End point title
    		 Maximum Observed Plasma Analyte Concentration (Cmax) of Darunavir (DRV) ‌
    End point description
    Cmax is the maximum observed plasma analyte concentration of DRV. Pharmacokinetics (PK) data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: nanograms per millilitre (ng/mL)
        arithmetic mean (standard deviation)
    7157 ± 1772
    7561 ± 1566
    Statistical analysis title
    		 Treatment A versus Treatment B
    Statistical analysis description
    Subjects analysed for both the treatments as per assigned treatment sequence in respective periods were 22.
    Comparison groups
    Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC v Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    94.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.29
         upper limit
    		 100.22

    Primary: Area Under the Analyte Concentration-Time Curve from Time 0 to Last Quantifiable Time (AUC [0-last]) of DRV

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    End point title
    		 Area Under the Analyte Concentration-Time Curve from Time 0 to Last Quantifiable Time (AUC [0-last]) of DRV
    End point description
    AUC (0-last) is defined as area under the analyte concentration-time curve from time 0 to time of the last quantifiable concentration. AUC (0-last) was calculated by linear-linear trapezoidal summation of DRV. PK data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: nanograms*hour per millilitre (ng*h/mL)
        arithmetic mean (standard deviation)
    82049 ± 24678
    84952 ± 26230
    Statistical analysis title
    		 Treatment A versus Treatment B
    Statistical analysis description
    Subjects analysed for both the treatments as per assigned treatment sequence in respective periods were 22.
    Comparison groups
    Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC v Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Geometric Mean ratio
    Point estimate
    96.24
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.46
         upper limit
    		 102.39

    Primary: Area Under the Analyte Concentration-Time Curve from Time 0 to Infinite Time (AUC [0-Infinity]) of DRV

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    End point title
    		 Area Under the Analyte Concentration-Time Curve from Time 0 to Infinite Time (AUC [0-Infinity]) of DRV
    End point description
    AUC (0-infinity) is defined as area under the analyte concentration-time curve from time 0 to infinite time. PK data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    82254 ± 24705
    85161 ± 26232
    Statistical analysis title
    		 Treatment A versus Treatment B
    Statistical analysis description
    Subjects analysed for both the treatments as per assigned treatment sequence in respective periods were 22.
    Comparison groups
    Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC v Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    96.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.47
         upper limit
    		 102.36

    Secondary: Maximum Observed Plasma Analyte Concentration (Cmax) of Cobicistat (COBI)

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    End point title
    		 Maximum Observed Plasma Analyte Concentration (Cmax) of Cobicistat (COBI)
    End point description
    Cmax is the maximum observed plasma analyte concentration of COBI. Pharmacokinetics (PK) data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: ng/mL
        arithmetic mean (standard deviation)
    807 ± 236
    861 ± 199
    No statistical analyses for this end point

    Secondary: Area Under the Analyte Concentration-Time Curve from Time 0 to Last Quantifiable Time (AUC [0-last]) of COBI

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    End point title
    		 Area Under the Analyte Concentration-Time Curve from Time 0 to Last Quantifiable Time (AUC [0-last]) of COBI
    End point description
    AUC (0-last) is defined as area under the analyte concentration-time curve from time 0 to time of the last quantifiable concentration. AUC (0-last) was calculated by linear-linear trapezoidal summation of COBI. PK data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    6499 ± 2475
    6931 ± 2520
    No statistical analyses for this end point

    Secondary: Area Under the Analyte Concentration-Time Curve from Time 0 to Infinite Time (AUC [0-Infinity]) of COBI

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    End point title
    		 Area Under the Analyte Concentration-Time Curve from Time 0 to Infinite Time (AUC [0-Infinity]) of COBI
    End point description
    AUC (0-infinity) is defined as area under the analyte concentration-time curve from time 0 to infinite time. PK data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose, up to 72 hours postdose (Up to Day 4)
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    6613 ± 2525
    7027 ± 2539
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events (AEs) as a Measure of Safety and Tolerability

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    End point title
    		 Number of Subjects with Adverse Events (AEs) as a Measure of Safety and Tolerability
    End point description
    An AE 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. Safety data analysis set included all subjects who had received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks
    End point values
    		 Treatment A (test): DRV/COBI 675/150 milligrams (mg) FDC Treatment B (reference): DRV/COBI 675/150 milligrams (mg)
    Number of subjects analysed
    22
    22
    Units: subjects
    4
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 6 weeks
    Adverse event reporting additional description
    All subjects who were randomly assigned to treatment and received at least 1 dose of the study drug were included in the safety analysis.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Treatment A (test)
    Reporting group description
    		 Subjects received a single oral dose of DRV/COBI 675/150 milligrams (mg) as a scored FDC on Day 1 under fed condition.

    Reporting group title
    Treatment B (reference)
    Reporting group description
    		 Subjects received a single oral dose of DRV 675 mg as DRV 600 mg plus DRV 75 mg and COBI 150 mg on Day 1 under fed condition.

    Serious adverse events
    		 Treatment A (test) Treatment B (reference)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment A (test) Treatment B (reference)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
    6 / 22 (27.27%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    5
    2
    Muscle Contractions Involuntary
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Catheter Site Oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Neck Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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