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    Clinical Trial Results:
    A Study to Evaluate the Comparative Bioavailability of the Investigational Oral Pediatric Minitablet Formulation of MK-1439 Compared to the Adult Formulation of MK-1439 in Healthy Adult Subjects

    Summary
    EudraCT number
    		 2016-004728-48
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    27 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2017
    First version publication date
    08 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1439-043
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001676-PIP01-14 EMEA-001695-PIP01-14
    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
    27 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the comparative bioavailability of a single-dose of the investigational oral pediatric mini-tablet formulation of MK-1439 (doravirine), 0.8 mg (100 mg total dose) compared to the adult formulation of doravirine tablets,100 mg in healthy adult males and females under fasted conditions.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2015
    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
    United States: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Healthy, non-tobacco using, adult male and females, 18-55 years of age were enrolled in this trial.

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

    Arms
    Arm title
    		 All Randomized Participants
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adult Doravirine 100 mg x 1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Following an overnight fast of at least 10 hours, a single doravirine adult formulation 100 mg tablet was administered orally.

    Investigational medicinal product name
    Pediatric Doravirine 0.8 mg x 125
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Following an overnight fast of at least 10 hours, 125 doravirine oral pediatric formulation mini-tablets (equivalent to 100 mg) was administered orally.

    Number of subjects in period 1
    		All Randomized Participants
    Started
    24
    Completed
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 24 24
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 24 24
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.6 ± 9.4 -
    Gender Categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    Adult Doravirine 100 mg x 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following an overnight fast of at least 10 hours, a single doravirine adult formulation 100 mg tablet was administered orally.

    Subject analysis set title
    Pediatric Doravirine 0.8 mg x 125
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following an overnight fast of at least 10 hours, 125 doravirine oral pediatric formulation 0.8 mg mini-tablets (equivalent to 100 mg) was administered orally.

    Subject analysis sets values
    		 Adult Doravirine 100 mg x 1 Pediatric Doravirine 0.8 mg x 125
    Number of subjects
    24
    24
    Age Categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    24
    24
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    34.6 ± 9.4
    34.6 ± 9.4
    Gender Categorical
    Units: Subjects
        Female
    7
    7
        Male
    17
    17

    End points

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    End points reporting groups
    Reporting group title
    All Randomized Participants
    Reporting group description
    		 -

    Subject analysis set title
    Adult Doravirine 100 mg x 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following an overnight fast of at least 10 hours, a single doravirine adult formulation 100 mg tablet was administered orally.

    Subject analysis set title
    Pediatric Doravirine 0.8 mg x 125
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following an overnight fast of at least 10 hours, 125 doravirine oral pediatric formulation 0.8 mg mini-tablets (equivalent to 100 mg) was administered orally.

    Primary: Area under the concentration versus time curve from time 0-infinity (AUC0-∞) of doravirine

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    End point title
    		 Area under the concentration versus time curve from time 0-infinity (AUC0-∞) of doravirine
    End point description
    Blood samples were collected at pre-dose and at intervals up to 72 hours after dosing in each period, and the plasma concentrations of doravirine were determined. Values were natural log-transformed before analysis and analyzed with a linear mixed effects model with fixed effects terms for treatment and period. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between different treatment measurements within the same subject. The populations analyzed was all participants as treated during each treatment period.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 24, 48, and 72 hours post-dose
    End point values
    		 Adult Doravirine 100 mg x 1 Pediatric Doravirine 0.8 mg x 125
    Number of subjects analysed
    24
    24
    Units: µM.hr
        geometric mean (confidence interval 95%)
    38.3 (32.3 to 45.3)
    28.1 (23.4 to 33.9)
    Statistical analysis title
    		 Ratio Pediatric/Adult tablet
    Statistical analysis description
    Geometric Mean Ratio (GMR)
    Comparison groups
    Adult Doravirine 100 mg x 1 v Pediatric Doravirine 0.8 mg x 125
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 GMR
    Point estimate
    0.73
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.8
    Notes
    [1] - The number of participants in this analysis was not 48. As this was a crossover study, the 48 observations were from 24 participants.

    Primary: Maximum concentration (Cmax) of doravirine

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    End point title
    		 Maximum concentration (Cmax) of doravirine
    End point description
    Blood samples were collected at pre-dose and at intervals up to 72 hours after dosing in each period, and the plasma concentrations of doravirine were determined. Values were natural log-transformed before analysis and analyzed with a linear mixed effects model with fixed effects terms for treatment and period. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between different treatment measurements within the same subject. The populations analyzed was all participants as treated during each treatment period.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 24, 48, and 72 hours post-dose
    End point values
    		 Adult Doravirine 100 mg x 1 Pediatric Doravirine 0.8 mg x 125
    Number of subjects analysed
    24
    23 [2]
    Units: nM
        geometric mean (confidence interval 95%)
    2170 (1820 to 2580)
    1150 (992 to 1320)
    Notes
    [2] - One participant with a missing concentration value was not included in the analysis
    Statistical analysis title
    		 Ratio Pediatric/Adult tablet
    Statistical analysis description
    GMR
    Comparison groups
    Adult Doravirine 100 mg x 1 v Pediatric Doravirine 0.8 mg x 125
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 GMR
    Point estimate
    0.53
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.59
    Notes
    [3] - The number of participants in this analysis was not 47. As this was a crossover study, the 47 observations were from 24 participants.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment on Day 1 up to Day 4 of each treatment period
    Adverse event reporting additional description
    All participants as treated during each treatment period by the treatment received at the time of the event. As this was a crossover study, and each participant received more than one treatment, participants could be counted more than once.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Doravirine 100 mg x 1
    Reporting group description
    		 Following an overnight fast of at least 10 hours, a single doravirine adult formulation 100 mg tablet was administered orally.

    Reporting group title
    Doravirine 0.8 mg x 125
    Reporting group description
    		 Following an overnight fast of at least 10 hours, 125 doravirine oral pediatric formulation 0.8 mg mini-tablets (equivalent to 100 mg) was administered orally.

    Serious adverse events
    		 Doravirine 100 mg x 1 Doravirine 0.8 mg x 125
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Doravirine 100 mg x 1 Doravirine 0.8 mg x 125
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 24 (16.67%)
    2 / 24 (8.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 May 2015
    Amendment 1: Included description of the size and the number of mini-tablets to be administered with dosing

    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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    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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