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    Clinical Trial Results:
    A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Doravirine/Islatravir in Pediatric Participants with HIV-1 Infection who are Virologically Suppressed or Treatment-Naïve, are Less Than 18 Years of Age, and Weigh Greater Than or Equal to 35 kg

    Summary
    EudraCT number
    		 2019-003597-10
    Trial protocol
    		 IT   Outside EU/EEA  
    Global end of trial date
    25 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Aug 2023
    First version publication date
    02 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-8591A-028
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04295772
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002707-PIP19-01
    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
    25 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a phase 2, single-group, multi-site, open-label study of a doravirine/islatravir 100 mg/0.75 mg (DOR/ISL, MK-8591A) fixed dose combination (FDC) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric participants who are virologically suppressed (VS) on antiretroviral therapy (ART) for ≥3 months or are treatment-naive (TN). The primary purposes of the study are 1) to examine the steady-state pharmacokinetics (PK) of ISL in plasma; 2) the steady-state PK of ISL-triphosphate (ISL-TP) in peripheral blood mononuclear cells (PBMCs); and 3) to examine the safety and tolerability of DOR/ISL (100 mg/0.75 mg).
    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
    26 Nov 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    40
    EEA total number of subjects
    3
    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)
    3
    Adolescents (12-17 years)
    35
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Pediatric participants who were ≥35 kg body weight and <18 years of age were recruited at 18 study sites located in Italy, Russian Federation, Thailand, South Africa, and the United States. Two VS participants are excluded from results due to a consent issue.

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DOR/ISL: Virologically Suppressed Cohort
    Arm description
    		 VS participants (had taken stable 2- or 3-drug combination ART for ≥3 months) pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DOR/ISL
    Investigational medicinal product code
    MK-8591A
    Other name
    Doravirine/islatravir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.

    Arm title
    		 DOR/ISL: Treatment Naive Cohort
    Arm description
    		 TN participants with HIV-1 infection receive DOR/ISL for 96 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DOR/ISL
    Investigational medicinal product code
    MK-8591A
    Other name
    Doravirine/islatravir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.

    Number of subjects in period 1
    		DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Started
    37
    3
    Completed
    22
    2
    Not completed
    15
    1
         Ongoing for safety monitoring
    14
    1
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Extended Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring
    Arm description
    		 A subset of VS participants who completed the study opted to participate in an extended safety monitoring period.
    Arm type
    		 Safety Monitoring

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 DOR/ISL: Treatment Naive Cohort: Extended Monitoring
    Arm description
    		 A TN participant who completed the study opted to participate in an extended safety monitoring period.
    Arm type
    		 Safety Monitoring

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring DOR/ISL: Treatment Naive Cohort: Extended Monitoring
    Started
    14
    1
    Completed
    14
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A subset of participants who completed the main study opted to participate in an extended monitoring period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DOR/ISL: Virologically Suppressed Cohort
    Reporting group description
    		 VS participants (had taken stable 2- or 3-drug combination ART for ≥3 months) pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.

    Reporting group title
    DOR/ISL: Treatment Naive Cohort
    Reporting group description
    		 TN participants with HIV-1 infection receive DOR/ISL for 96 weeks.

    Reporting group values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort Total
    Number of subjects
    		 37 3 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 3 0 3
        Adolescents (12-17 years)
    		 32 3 35
        Adults (18-64 years)
    		 2 0 2
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.7 ( 2.2 ) 15.7 ( 1.5 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 14 1 15
        Male
    		 23 2 25
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 9 3 12
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 20 0 20
        White
    		 8 0 8
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 35 3 38
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    DOR/ISL: Virologically Suppressed Cohort
    Reporting group description
    		 VS participants (had taken stable 2- or 3-drug combination ART for ≥3 months) pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.

    Reporting group title
    DOR/ISL: Treatment Naive Cohort
    Reporting group description
    		 TN participants with HIV-1 infection receive DOR/ISL for 96 weeks.
    Reporting group title
    DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring
    Reporting group description
    		 A subset of VS participants who completed the study opted to participate in an extended safety monitoring period.

    Reporting group title
    DOR/ISL: Treatment Naive Cohort: Extended Monitoring
    Reporting group description
    		 A TN participant who completed the study opted to participate in an extended safety monitoring period.

    Primary: Maximum plasma concentration (Cmax) of ISL 0.75 mg

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    End point title
    		 Maximum plasma concentration (Cmax) of ISL 0.75 mg [1] [2]
    End point description
    The Cmax of ISL 0.75 mg in plasma was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: µmol/L
        geometric mean (geometric coefficient of variation)
    0.0245 ( 53.4 )
    No statistical analyses for this end point

    Primary: Area under the plasma drug concentration-time curve from 0 to 24 hours post-dose (AUC0-24) of islatravir (ISL) 0.75 mg

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    End point title
    		 Area under the plasma drug concentration-time curve from 0 to 24 hours post-dose (AUC0-24) of islatravir (ISL) 0.75 mg [3] [4]
    End point description
    The AUC0-24 of ISL 0.75 mg in plasma was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: hr*µmol/L
        geometric mean (geometric coefficient of variation)
    0.114 ( 28.6 )
    No statistical analyses for this end point

    Primary: Time to reach maximum plasma concentration (Tmax) of ISL 0.75 mg

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    End point title
    		 Time to reach maximum plasma concentration (Tmax) of ISL 0.75 mg [5] [6]
    End point description
    The Tmax of ISL 0.75 mg in plasma was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: hours
        median (full range (min-max))
    1.00 (0.50 to 4.00)
    No statistical analyses for this end point

    Primary: AUC0-last of ISL-triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMCs)

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    End point title
    		 AUC0-last of ISL-triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMCs) [7] [8]
    End point description
    The AUC0-24 of ISL-TP in PBMCs was determined at steady state. A subset of VS participants was included in the Intensive PBMC PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on intracellular PBMC PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 4 and 24 hours post-dose on Day 28
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    12
    Units: hr*pmol/10^6 cells
        geometric mean (geometric coefficient of variation)
    52.3 ( 74.9 )
    No statistical analyses for this end point

    Primary: Cmax of ISL-TP in PBMCs

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    End point title
    		 Cmax of ISL-TP in PBMCs [9] [10]
    End point description
    The Cmax of ISL-TP in PBMCs was determined at steady state. A subset of VS participants was included in the Intensive PBMC PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on intracellular PBMC PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 4, and 24 hours post-dose on Day 28
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    12
    Units: pmol/10^6 cells
        geometric mean (geometric coefficient of variation)
    2.87 ( 91.6 )
    No statistical analyses for this end point

    Primary: C24 of ISL-TP in PBMCs

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    End point title
    		 C24 of ISL-TP in PBMCs [11] [12]
    End point description
    The C24 of ISL-TP in PBMCs was determined at steady state. A subset of VS participants was included in the Intensive PBMC PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on intracellular PBMC PK parameters.
    End point type
    Primary
    End point timeframe
    24 hours post-dose on Day 28
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    12
    Units: pmol/10^6 cells
        geometric mean (geometric coefficient of variation)
    2.05 ( 71.7 )
    No statistical analyses for this end point

    Primary: Apparent volume of distribution during terminal phase (Vz/F) of ISL 0.75 mg

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    End point title
    		 Apparent volume of distribution during terminal phase (Vz/F) of ISL 0.75 mg [13] [14]
    End point description
    The Vz/F of ISL 0.75 mg was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: Liters
        geometric mean (geometric coefficient of variation)
    536 ( 61.1 )
    No statistical analyses for this end point

    Primary: Apparent total clearance from plasma (CL/F) of ISL 0.75 mg

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    End point title
    		 Apparent total clearance from plasma (CL/F) of ISL 0.75 mg [15] [16]
    End point description
    The CL/F of ISL 0.75 mg from plasma was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    22.5 ( 28.6 )
    No statistical analyses for this end point

    Primary: Apparent plasma terminal half-life (t½) of ISL 0.75 mg

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    End point title
    		 Apparent plasma terminal half-life (t½) of ISL 0.75 mg [17] [18]
    End point description
    The t½ of ISL 0.75 mg in plasma was determined at steady state. A subset of VS participants was included in the Intensive PK Cohort, consisting of participants who complied with the protocol sufficiently to ensure data were likely to exhibit the effects of the study intervention on plasma PK parameters.
    End point type
    Primary
    End point timeframe
    Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    15
    Units: hours
        geometric mean (geometric coefficient of variation)
    16.5 ( 70.0 )
    No statistical analyses for this end point

    Primary: Number of participants experiencing ≥1 adverse event (AE)

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    End point title
    		 Number of participants experiencing ≥1 adverse event (AE) [19]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study intervention are included.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
    21
    2
    No statistical analyses for this end point

    Primary: Number of participants discontinuing from study treatment due to an AE

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    End point title
    		 Number of participants discontinuing from study treatment due to an AE [20]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study intervention are included.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in CD4+ T-cells in TN participants

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    End point title
    		 Change from baseline in CD4+ T-cells in TN participants [21]
    End point description
    CD4+ T-cell counts were measured by a central laboratory. Negative and positive results represent a decrease and increase, respectively, from baseline CD4+ T-cell counts. TN participants who received ≥1 dose of study intervention and had baseline and Week 24 data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    1 [22]
    Units: cells/mm^3
        number (not applicable)
    705.0
    Notes
    [22] - 95% CI were not calculable due to n=1.
    No statistical analyses for this end point

    Secondary: Percentage of virologically suppressed (VS) participants with HIV-1 ribonucleic acid (RNA) ≥50 copies/mL

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    End point title
    		 Percentage of virologically suppressed (VS) participants with HIV-1 ribonucleic acid (RNA) ≥50 copies/mL [23]
    End point description
    The percentage of VS participants with HIV-1 RNA ≥50 copies/mL was determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL. Participants who were VS at baseline (on stable combination antiretroviral therapy [ART] for ≥3 months) and had data available are included.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    34
    Units: percentage of participants
        number (confidence interval 95%)
    2.9 (0.1 to 15.3)
    No statistical analyses for this end point

    Secondary: Percentage of VS participants with HIV-1 RNA <50 copies/mL

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    End point title
    		 Percentage of VS participants with HIV-1 RNA <50 copies/mL [24]
    End point description
    The percentage of VS participants with HIV-1 RNA <50 copies/mL will be determined at the central laboratory with an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. Participants who were VS at baseline (on stable combination ART for ≥3 months) and had data available are included.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    34
    Units: percentage of participants
        number (confidence interval 95%)
    94.1 (80.3 to 99.3)
    No statistical analyses for this end point

    Secondary: Percentage of treatment naive (TN) participants with HIV-1 RNA <50 copies/mL

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    End point title
    		 Percentage of treatment naive (TN) participants with HIV-1 RNA <50 copies/mL [25]
    End point description
    The percentage of TN participants with HIV-1 RNA <50 copies/mL will be determined at the central laboratory with an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. Participants who were TN at baseline and had data available are included.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    1
    Units: percentage of participants
        number (confidence interval 95%)
    100.0 (2.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in cluster of differentiation 4+ (CD4+) T-cells in VS participants

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    End point title
    		 Change from baseline in cluster of differentiation 4+ (CD4+) T-cells in VS participants [26]
    End point description
    CD4+ T-cell counts were measured by a central laboratory. Negative and positive results represent a decrease and increase, respectively, from baseline CD4+ T-cell counts. All VS participants who received ≥1 dose of study intervention and had data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subset of participants is included in the PK assessment.
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort
    Number of subjects analysed
    33
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    -112.1 (-175.8 to -48.4)
    No statistical analyses for this end point

    Secondary: Incidence of viral drug resistance to DOR

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    End point title
    		 Incidence of viral drug resistance to DOR
    End point description
    The number of participants with viral drug resistance to DOR was determined. Participants who received ≥1 dose of study intervention are included.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence of viral drug resistance to ISL

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    End point title
    		 Incidence of viral drug resistance to ISL
    End point description
    The number of participants with viral drug resistance to ISL was determined. Participants who received ≥1 dose of study intervention are included.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Palatability of DOR/ISL tablet

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    End point title
    		 Palatability of DOR/ISL tablet
    End point description
    The palatability of the DOR/ISL tablet (whole or split) was assessed with a modified 5-point facial hedonic scale. Responses ranged from 1 ("very bad") to 5 ("very good"). Data show the number of VS and TN participants responding at each score at the designated time points. All VS and TN participants who received ≥1 dose of study intervention and have data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 4, and Week 24
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
        Very Bad - Day 1
    0
    0
        Very Bad - Week 4
    0
    0
        Very Bad - Week 24
    2
    0
        Bad - Day 1
    0
    0
        Bad - Week 4
    0
    0
        Bad - Week 24
    3
    0
        Neither good or bad - Day 1
    12
    0
        Neither good or bad - Week 4
    11
    0
        Neither good or bad - Week 24
    8
    0
        Good - Day 1
    9
    2
        Good - Week 4
    11
    2
        Good - Week 24
    5
    1
        Very Good - Day 1
    16
    1
        Very Good - Week 4
    15
    1
        Very Good - Week 24
    4
    0
    No statistical analyses for this end point

    Secondary: Acceptability of DOR/ISL tablet

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    End point title
    		 Acceptability of DOR/ISL tablet
    End point description
    The acceptability of the DOR/ISL tablet (whole or split) was assessed. Acceptability was assessed by monitoring for refusing the tablet, throwing up or spitting out the tablet, and gagging on the tablet. Data show the number of VS and TN participants responding at each score at the designated time points. All VS and TN participants who received ≥1 dose of study intervention and have data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 4, and Week 24
    End point values
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort
    Number of subjects analysed
    37
    3
    Units: participants
        Refusing - Day 1
    0
    0
        Refusing - Week 4
    0
    0
        Refusing - Week 24
    0
    0
        Throwing Up/Spitting Out - Day 1
    0
    0
        Throwing Up/Spitting Out - Week 4
    0
    0
        Throwing Up/Spitting Out - Week 24
    0
    0
        Gagging - Day 1
    0
    0
        Gagging - Week 4
    0
    0
        Gagging - Week 24
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored for up to ~15.3 months in the main study, and for an additional 12.5 months for those participating in the Extended Follow-Up period.
    Adverse event reporting additional description
    All-cause mortality is assessed in all randomized participants. Adverse events (AEs) and serious AEs (SAEs) are assessed in all treated participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    DOR/ISL: Virologically Suppressed Cohort
    Reporting group description
    		 VS participants (had taken stable 2- or 3-drug combination ART for ≥3 months) pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.

    Reporting group title
    DOR/ISL: Treatment Naive Cohort: Extended Monitoring
    Reporting group description
    		 A subset of TN participants who completed the study opted to participate in an extended safety monitoring period.

    Reporting group title
    DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring
    Reporting group description
    		 A subset of VS participants who completed the study opted to participate in an extended safety monitoring period.

    Reporting group title
    DOR/ISL: Treatment Naive Cohort
    Reporting group description
    		 TN participants with HIV-1 infection receive DOR/ISL for 96 weeks.

    Serious adverse events
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort: Extended Monitoring DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring DOR/ISL: Treatment Naive Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DOR/ISL: Virologically Suppressed Cohort DOR/ISL: Treatment Naive Cohort: Extended Monitoring DOR/ISL: Virologically Suppressed Cohort: Extended Monitoring DOR/ISL: Treatment Naive Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 37 (35.14%)
    1 / 1 (100.00%)
    12 / 14 (85.71%)
    2 / 3 (66.67%)
    General disorders and administration site conditions
    Vaccination site pain
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    1 / 3 (33.33%)
         occurrences all number
    3
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    1 / 3 (33.33%)
         occurrences all number
    3
    0
    1
    1
    Injection site pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 1 (0.00%)
    4 / 14 (28.57%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    7
    0
    Nasal congestion
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Nasal mucosal disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    skin laceratio
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    1
    1
    Headache
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    1
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dermatitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nephropathy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    4
    0
    Ear infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 1 (100.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post-acute COVID-19 syndrome
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Varicella
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Obesity
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2020
    AM01: the primary purposes of this amendment were to include a new cohort of ART-naïve participants; to remove the Week 12 visit and add visits at Weeks 8 and 16; to remove the 12-year-old lower age limit; to remove DOR PK assessments; and to extend the overall duration of the study to a total of 96 weeks.
    12 Mar 2021
    AM02: the primary purposes of this amendment were to include an assessment of the palatability of a split tablet, and to update inclusion criteria to include only participants who have no prior history of treatment failure.
    08 Feb 2022
    AM03: The primary purposes of the amendment were to discontinue dosing of study intervention in all participants based on Sponsor’s acceptance of recommendations by the eDMC for pediatric HIV treatment trials, and to specify plans for detection and follow-up of participants with specified decreases in CD4+ T-cell and/or total lymphocyte counts.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Dec 2021
    Decreases in CD4+ T-cell and total lymphocyte counts were observed in some participants. Based on the totality of these changes noted across the ISL program occurring at doses of 0.75 mg and above, the pediatric external data monitoring committee (eDMC) recommended discontinuation of study intervention administration for all participants and to initiate safety monitoring.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Premature discontinuation of the study limits data interpretation of Week 48 endpoints.
    For support, Contact us.
    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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