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    Clinical Trial Results:
    A Phase 1 Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in Human Immunodeficiency Virus-1 (HIV-1)-Exposed Neonates at High Risk of Acquiring HIV-1 Infection

    Summary
    EudraCT number
    2016-003248-34
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    20 Apr 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Oct 2020
    First version publication date
    25 Aug 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    0518-080
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01780831
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Protocol number: IMPAACT P1110
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hills 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-000279-PIP01-08
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of raltegravir (RAL) when given to HIV-1-exposed, normal birth weight newborn infants at risk of acquiring HIV-1 infection. (PK is the study of the time course of absorption, distribution, metabolism, and excretion of drugs in the body.) The primary goal of this study was to determine a dose of RAL that was safe and met the PK targets for infants when administered during the first 6 weeks of life in addition to standard of care antiretroviral (ARV) agents for prevention of perinatal transmission.
    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. At the end of the study, HIV infected infants (if any) who continue to receive raltegravir as part of their combination antiretroviral therapy (cART) regimen may have access to raltegravir through Merck Pediatric Compassionate Use program.
    Background therapy
    All enrolled neonates also received standard of care antiretroviral (ARV) for prevention of mother-to-child transmission (PMTCT) prophylaxis. Choice of the ARV regimen will be left to the discretion of the site investigator.
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Jan 2014
    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
    South Africa: 5
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Brazil: 25
    Worldwide total number of subjects
    52
    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)
    52
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Cohort 1 participants were from 2 sites in Brazil, 1 site in South Africa, and 7 sites in the USA. Enrollment period was January 2014 - December 2015. Cohort 2 participants were from 3 sites in Brazil, 2 sites in South Africa, 1 site in Thailand, and 4 sites in the USA. Enrollment period was September 2015 - November 2017.

    Period 1
    Period 1 title
    All enrolled (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Raltegravir-naive
    Arm description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.
    Arm type
    Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    MK-0518, Isentress
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Raltegravir granules for suspension (GFS) 2 or 3 mg/kg as a single dose within 48 hours of birth. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Arm title
    Cohort 1: Raltegravir-exposed
    Arm description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.
    Arm type
    Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    MK-0518, Isentress
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Raltegravir granules for suspension (GFS) 1.5 mg/kg as a single dose within 48 hours of birth. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Arm title
    Cohort 2: Raltegravir-naive
    Arm description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
    Arm type
    Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    MK-0518, Isentress
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Raltegravir 1.5 mg/kg once daily during Days 1 to 7 of age (Week 1), Raltegravir 3 mg/kg twice daily during Days 8 to 28 of age (Weeks 2 to 4) and Raltegravir 6 mg/kg twice daily during Days 29 to 42 of age (Weeks 5 and 6).

    Arm title
    Cohort 2: Raltegravir-exposed
    Arm description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
    Arm type
    Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    MK-0518, Isentress
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Raltegravir 1.5 mg/kg once daily during Days 1 to 7 of age (Week 1), Raltegravir 3 mg/kg twice daily during Days 8 to 28 of age (Weeks 2 to 4) and Raltegravir 6 mg/kg twice daily during Days 29 to 42 of age (Weeks 5 and 6).

    Number of subjects in period 1
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed
    Started
    10
    6
    26
    10
    Completed
    10
    6
    22
    9
    Not completed
    0
    0
    4
    1
         Consent withdrawn by parent/guardian
    -
    -
    4
    -
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Raltegravir-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Reporting group title
    Cohort 1: Raltegravir-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Reporting group title
    Cohort 2: Raltegravir-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Reporting group title
    Cohort 2: Raltegravir-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Reporting group values
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed Total
    Number of subjects
    10 6 26 10 52
    Age Categorical
    Units: Subjects
        <=18 years
    10 6 26 10 52
        Between 18 and 65 years
    0 0 0 0 0
        >=65 years
    0 0 0 0 0
    Age Continuous
    Gestational age at birth
    Units: weeks
        median (full range (min-max))
    39 (38 to 40) 38 (37 to 40) 38 (37 to 41) 39 (38 to 41) -
    Gender Categorical
    Units: Subjects
        Female
    6 2 12 4 24
        Male
    4 4 14 6 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    3 3 19 5 30
        Not Hispanic or Latino
    7 2 7 4 20
        Unknown or Not Reported
    0 1 0 1 2
    Birth weight
    Units: Grams
        median (full range (min-max))
    3020 (2385 to 4200) 2948 (2320 to 3385) 2930 (2390 to 3745) 3085 (2090 to 4130) -
    Apgar score at 1 minute
    The Apgar score is an evaluation typically done at 1 minute and 5 minutes after birth to describe an infant’s health. It ranges from 0 – 10, where 10 is the best possible score. Baseline table includes Apgar Score at 1 minute after birth.
    Units: Score on a scale
        median (full range (min-max))
    8 (8 to 9) 9 (8 to 9) 9 (6 to 10) 9 (8 to 10) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Raltegravir-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Reporting group title
    Cohort 1: Raltegravir-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Reporting group title
    Cohort 2: Raltegravir-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Reporting group title
    Cohort 2: Raltegravir-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 1: Raltegravir-naive
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 1: Raltegravir-exposed
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 1 Total
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 2: Raltegravir-naive
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 2: Raltegravir-exposed
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 2 Total
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1- 7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days Go to daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 1 RAL-naive: 3 mg/kg for First Dose
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single RAL doses: first dose (3 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 1 RAL-naive: 2 mg/kg for First Dose
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single RAL doses: first dose (2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 1 RAL-exposed 1.5 mg/kg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.

    Subject analysis set title
    Cohort 2 RAL-naive: 1.5 mg/kg Once Daily on Days 1-7 of Life
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 2 RAL-exposed: 1.5mg/kg Once Daily on Days 1-7 of Life
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 2 RAL-naive: 3 mg/kg Twice Daily on Days 8-18 of Life
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 2 RAL-exposed: 3 mg/kg Twice Daily on Days 8-28 of Life
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting between 12 to 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Subject analysis set title
    Cohort 1 (TA)5(TA)6
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose UGT1A1 genotype were (TA)5(TA)6.

    Subject analysis set title
    Cohort 1 (TA)6(TA)6
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).

    Subject analysis set title
    Cohort 1 (TA)6(TA)7
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose UGT1A1 genotype were (TA)6(TA)7.

    Subject analysis set title
    Cohort 2 (TA)6(TA)6 Wildtype
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).

    Subject analysis set title
    Cohort 2 Mutation
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were mutation: (TA)5(TA)5, (TA)5(TA)6, (TA)5(TA)7, (TA)6(TA)7, or (TA)7(TA)7.

    Subject analysis set title
    Cohort 2 (TA)5(TA)5
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were mutation (TA)5(TA)5

    Subject analysis set title
    Cohort 2 (TA)5(TA)6
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were (TA)5(TA)6.

    Subject analysis set title
    Cohort 2 (TA)5(TA)7
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were (TA)5(TA)7.

    Subject analysis set title
    Cohort 2 (TA)6(TA)7
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)7.

    Subject analysis set title
    Cohort 2 (TA)7(TA)7
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose UGT1A1 genotype were (TA)7(TA)7.

    Subject analysis set title
    Cohort 1 C/C
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose SLCO1B3 genotype were C/C (wildtype).

    Subject analysis set title
    Cohort 1 C/T
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose SLCO1B3 genotype were C/T.

    Subject analysis set title
    Cohort 1 T/T
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 1 infants whose SLCO1B3 genotype were T/T.

    Subject analysis set title
    Cohort 2 C/C
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose SLCO1B3 genotype were C/C (wildtype).

    Subject analysis set title
    Cohort 2 C/T
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose SLCO1B3 genotype were C/T.

    Subject analysis set title
    Cohort 2 T/T
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Cohort 2 infants whose SLCO1B3 genotype were T/T

    Primary: Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life

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    End point title
    Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life [1]
    End point description
    Number of infants who died or had adverse events (AEs) of Grade 3 or 4 as defined in Division of AIDS (DAIDS) AE Grading Table. Events with onset dates prior to first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. The population analyzed were all infants who received at least one dose of RAL. Excluded one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.
    End point type
    Primary
    End point timeframe
    From first dosing of RAL through 6 weeks of life
    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: As statistical analyses were performed separately on individual arms, they were not included.
    End point values
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 1 Total Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed Cohort 2 Total
    Number of subjects analysed
    10
    6
    16
    25
    10
    35
    Units: Participants
    2
    2
    4
    7
    4
    11
    No statistical analyses for this end point

    Primary: AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)

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    End point title
    AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [2]
    End point description
    Area Under the Concentration-time Curve at 24-hour interval (AUC24) based on intensive PK sampling around Cohort 1 RAL dose #1 (within 48 hours of birth). The population analyzed were all Cohort 1 infants who received the first RAL dosing within 48 hours of birth and had AUC24 data for the dosing. AUC24 was missing for one Cohort 1 RAL-naive infant whose PK samples were possibly switched.
    End point type
    Primary
    End point timeframe
    Cohort 1 RAL dose #1 (within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.
    Notes
    [2] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 1 RAL-naive: 3 mg/kg for First Dose Cohort 1 RAL-naive: 2 mg/kg for First Dose Cohort 1 RAL-exposed 1.5 mg/kg
    Number of subjects analysed
    6
    3
    6
    Units: mg*h/L
        geometric mean (geometric coefficient of variation)
    53.88 ± 34.6
    44.26 ± 71.9
    37.42 ± 92.7
    No statistical analyses for this end point

    Primary: Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)

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    End point title
    Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [3]
    End point description
    Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth). The population analyzed were all Cohort 1 infants who received the first RAL dosing within 48 hours of birth and had Cmax data for the dosing. Cmax was missing for one Cohort 1 RAL-naive infant whose PK samples were possibly switched.
    End point type
    Primary
    End point timeframe
    Cohort 1 dose #1(within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours postdose.
    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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 1 RAL-naive: 3 mg/kg for First Dose Cohort 1 RAL-naive: 2 mg/kg for First Dose Cohort 1 RAL-exposed 1.5 mg/kg
    Number of subjects analysed
    6
    3
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3360.89 ± 35.5
    3405.24 ± 38.1
    2188.82 ± 73.3
    No statistical analyses for this end point

    Primary: AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)

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    End point title
    AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively) [4]
    End point description
    Area Under the Concentration-time Curve at the 24-hour interval (AUC24) for Cohort 2 initial RAL dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively). The population analyzed were all Cohort 2 infants who had AUC24 data for the initial RAL dosing. AUC24 were missing for 2 Cohort 2 RAL-naive infants: one was off-study right after study entry and had incomplete PK specimen collection; and one whose AUC24 could not be estimated due to possible administration of next dose before the 24 hr sample was collected.
    End point type
    Primary
    End point timeframe
    Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.
    Notes
    [4] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 2 RAL-naive: 1.5 mg/kg Once Daily on Days 1-7 of Life Cohort 2 RAL-exposed: 1.5mg/kg Once Daily on Days 1-7 of Life
    Number of subjects analysed
    24
    10
    Units: mg*h/L
        geometric mean (geometric coefficient of variation)
    38.2 ± 42
    42.89 ± 25.3
    No statistical analyses for this end point

    Primary: Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively)

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    End point title
    Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively) [5]
    End point description
    Last concentration of the drug (Clast) at 24 hour interval post dosing for the Cohort 2 initial RAL dose (within 48 and at 12-60 hours of birth for RAL-naive and RAL-exposed, respectively). This is the plasma RAL concentration from a sample collected at or close to 24 hours post dose. The population analyzed were all Cohort 2 infants who had Clast data for the initial RAL dosing. Clast was missing for one Cohort 2 RAL-naive infant who was off-study right after study entry and had incomplete PK specimen collection.
    End point type
    Primary
    End point timeframe
    Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed groups, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.
    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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 2 RAL-naive: 1.5 mg/kg Once Daily on Days 1-7 of Life Cohort 2 RAL-exposed: 1.5mg/kg Once Daily on Days 1-7 of Life
    Number of subjects analysed
    25
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    947.90 ± 84
    946.24 ± 74
    No statistical analyses for this end point

    Primary: RAL AUC12 for Cohort 2 at 15-18 Days of Life

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    End point title
    RAL AUC12 for Cohort 2 at 15-18 Days of Life [6]
    End point description
    Area Under the Concentration-time Curve at 12-hour interval (AUC12) of RAL for Cohort 2 at 15-18 days of life. The population analyzed were all infants who continued to receive RAL at or beyond Day 15-18 study visit and had AUC12 for the dosing. AUC12 were missing for 2 RAL-naive infants taken off study prior to Day 15-18 visit; 1 RAL-naive infant with delayed absorption for whom AUC12 could not be estimated; and 1 RAL-exposed infant who had incomplete PK sample collection.
    End point type
    Primary
    End point timeframe
    Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.
    Notes
    [6] - 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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 2 RAL-naive: 3 mg/kg Twice Daily on Days 8-18 of Life Cohort 2 RAL-exposed: 3 mg/kg Twice Daily on Days 8-28 of Life
    Number of subjects analysed
    23
    9
    Units: mg*h/L
        geometric mean (geometric coefficient of variation)
    14.3 ± 49.5
    18.25 ± 62.8
    No statistical analyses for this end point

    Primary: RAL C12 for Cohort 2 at 15-18 Days of Life

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    End point title
    RAL C12 for Cohort 2 at 15-18 Days of Life [7]
    End point description
    RAL concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life. The population analyzed were all infants who continued to receive RAL at or beyond Day 15-18 study visit and had C12 for the dosing. C12 were missing for 2 RAL-naive infants taken off study prior to Day 15-18 visit; 1 RAL-naive infant with delayed absorption for whom C12 could not be estimated; and 1 RAL-exposed infant who had incomplete PK sample collection.
    End point type
    Primary
    End point timeframe
    Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.
    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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    Cohort 2 RAL-naive: 3 mg/kg Twice Daily on Days 8-18 of Life Cohort 2 RAL-exposed: 3 mg/kg Twice Daily on Days 8-28 of Life
    Number of subjects analysed
    23
    9
    Units: mg*h/L
        geometric mean (geometric coefficient of variation)
    176.11 ± 162.1
    273.59 ± 176.4
    No statistical analyses for this end point

    Secondary: Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life

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    End point title
    Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life
    End point description
    Number of infants who died or had adverse events (AEs) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. The population analyzed were all infants who received at least one dose of RAL. Excluded was one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.
    End point type
    Secondary
    End point timeframe
    From first RAL dose through 24 weeks of life
    End point values
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 1 Total Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed Cohort 2 Total
    Number of subjects analysed
    10
    6
    16
    25
    10
    35
    Units: Participants
    2
    2
    4
    11
    4
    15
    No statistical analyses for this end point

    Secondary: Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life

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    End point title
    Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life
    End point description
    Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL. The population analyzed were all infants who received at least one dose of RAL. Excluded was one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.
    End point type
    Secondary
    End point timeframe
    From first RAL dose through 6 weeks of life
    End point values
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 1 Total Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed Cohort 2 Total
    Number of subjects analysed
    10
    6
    16
    25
    10
    35
    Units: Participants
    1
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life

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    End point title
    Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life
    End point description
    Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL. The population analyzed were all infants who received at least one dose of RAL. Excluded was one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.
    End point type
    Secondary
    End point timeframe
    From first RAL dose through 24 weeks of life
    End point values
    Cohort 1: Raltegravir-naive Cohort 1: Raltegravir-exposed Cohort 1 Total Cohort 2: Raltegravir-naive Cohort 2: Raltegravir-exposed Cohort 2 Total
    Number of subjects analysed
    10
    6
    16
    25
    10
    35
    Units: Participants
    1
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group

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    End point title
    Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
    End point description
    Cohort 1 Dose #1 neonatal RAL elimination was represented by Clearance (CL/F), which is the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional). The population analyzed were all Cohort 1 infants with data on CL/F (for dose #1) and UGT1A1 genotype. Excluded were: 1 Cohort 1 RAL-naive infant with missing CL/F due to possible PK specimen switch; 2 Cohort 1 RAL-naive infants with no specimen for genotype testing; 1 Cohort 1 RAL-exposed infant with CL/F and genotype data but was the only infant with (TA)5(TA)6 genotype.
    End point type
    Secondary
    End point timeframe
    Cohort 1 Dose #1 Intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12, 24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.
    End point values
    Cohort 1 (TA)6(TA)6 Cohort 1 (TA)6(TA)7
    Number of subjects analysed
    6
    6
    Units: L/hr
        median (inter-quartile range (Q1-Q3))
    0.11 (0.10 to 0.13)
    0.06 (0.04 to 0.15)
    Statistical analysis title
    Wild type vs Mutation
    Comparison groups
    Cohort 1 (TA)6(TA)6 v Cohort 1 (TA)6(TA)7
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.298
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group

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    End point title
    Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
    End point description
    Cohort 2 initial dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional). The population analyzed were all Cohort 2 infants with data on initial dose CL/F and UGT1A1 genotype. Exclusions: 1 RAL-naive infant who was off-study right after entry w/ incomplete PK specimens; 1 RAL-naive infant's CL/F can't be estimated due to possible administration of next dose before 24 hr sample collection; 3 RAL-naive and 4 exposed infants without genotype specimen.
    End point type
    Secondary
    End point timeframe
    Intensive PK sampling for Cohort 2 initial dose: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.
    End point values
    Cohort 2 (TA)6(TA)6 Wildtype Cohort 2 Mutation
    Number of subjects analysed
    15
    12
    Units: L/hr
        median (inter-quartile range (Q1-Q3))
    0.1 (0.1 to 0.2)
    0.1 (0.1 to 0.1)
    Statistical analysis title
    Wild type vs Mutation
    Comparison groups
    Cohort 2 (TA)6(TA)6 Wildtype v Cohort 2 Mutation
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.37
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group

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    End point title
    Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group
    End point description
    Cohort 2 15-18 days of life dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time at 15-18 days of life when RAL dosing would have been 3 mg/kg twice daily. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians(i.e. genotyping was optional). The population analyzed were all Cohort 2 infants with data on CL/F for Day 15-18 visit and UGT1A1 genotype. Exclusions: 1 RAL-naive infant off-study right after entry w/ incomplete PK specimens; consent withdrawn for 1 RAL-naive infant; 1 RAL-naive infant stopped RAL after wk 4; 1 RAL-exposed infant w/ incomplete PK specimens; 3 RAL-naive and 4 exposed infants w/o genotype specimen.
    End point type
    Secondary
    End point timeframe
    Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2 hours post-dose, 4-6, 8-12 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.
    End point values
    Cohort 2 (TA)6(TA)6 Wildtype Cohort 2 Mutation
    Number of subjects analysed
    14
    11
    Units: L/hr
        median (inter-quartile range (Q1-Q3))
    0.5 (0.4 to 1)
    0.5 (0.4 to 0.8)
    Statistical analysis title
    Wild type vs Mutation
    Comparison groups
    Cohort 2 (TA)6(TA)6 Wildtype v Cohort 2 Mutation
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.98
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype

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    End point title
    Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype
    End point description
    The intent of this endpoint was to investigate the association between UGT1A1 genotypes with hyperbilirubinemia. Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
    End point type
    Secondary
    End point timeframe
    Specimens for bilirubin testing were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at entry.
    End point values
    Cohort 1 (TA)5(TA)6 Cohort 1 (TA)6(TA)6 Cohort 1 (TA)6(TA)7
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Participants
    Notes
    [8] - No infants had hyperbilirubinemia.
    [9] - No infants had hyperbilirubinemia.
    [10] - No infants had hyperbilirubinemia.
    No statistical analyses for this end point

    Secondary: Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype

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    End point title
    Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype
    End point description
    The intent of this endpoint was to investigate the association between UGT1A1 genotypes with hyperbilirubinemia. Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
    End point type
    Secondary
    End point timeframe
    Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry.
    End point values
    Cohort 2 (TA)6(TA)6 Wildtype Cohort 2 (TA)5(TA)5 Cohort 2 (TA)5(TA)6 Cohort 2 (TA)5(TA)7 Cohort 2 (TA)6(TA)7 Cohort 2 (TA)7(TA)7
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    Units: Participants
    Notes
    [11] - No infants had hyperbilirubinemia.
    [12] - No infants had hyperbilirubinemia
    [13] - No infants had hyperbilirubinemia
    [14] - No infants had hyperbilirubinemia
    [15] - No infants had hyperbilirubinemia
    [16] - No infants had hyperbilirubinemia
    No statistical analyses for this end point

    Secondary: Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype

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    End point title
    Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
    End point description
    The intent of this Outcome Measure was to investigate the association between SLCO1B3 genotypes with hyperbilirubinemia. Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
    End point type
    Secondary
    End point timeframe
    Specimens for bilirubin test were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at study entry.
    End point values
    Cohort 1 C/C Cohort 1 C/T Cohort 1 T/T
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: Participants
    Notes
    [17] - No infants had hyperbilirubinemia.
    [18] - No infants had hyperbilirubinemia.
    [19] - No infants had hyperbilirubinemia.
    No statistical analyses for this end point

    Secondary: Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype

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    End point title
    Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
    End point description
    The intent of this endpoint was to investigate the association between SLCO1B3 genotypes with hyperbilirubinemia. Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.
    End point type
    Secondary
    End point timeframe
    Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry.
    End point values
    Cohort 2 C/C Cohort 2 C/T Cohort 2 T/T
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    Units: Participants
    Notes
    [20] - No infants had hyperbilirubinemia.
    [21] - No infants had hyperbilirubinemia.
    [22] - No infants had hyperbilirubinemia.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first RAL dose through 24 weeks of life.
    Adverse event reporting additional description
    All Adverse Events (AEs) including diagnoses, signs/symptoms and abnormal laboratory test results. Events with onset dates prior to first RAL dose and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Cohort 1 RAL-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1infection. Raltegravir: RAL was given as oral granules for suspension. Two single RAL doses: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7- 10 days of life.

    Reporting group title
    Cohort 1 RAL-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1infection. Raltegravir: RAL was given as oral granules for suspension. Two single RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7- 10 days of life.

    Reporting group title
    Cohort 2 RAL-naive
    Reporting group description
    Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Reporting group title
    Cohort 2 RAL-exposed
    Reporting group description
    Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting between 12 to 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

    Serious adverse events
    Cohort 1 RAL-naive Cohort 1 RAL-exposed Cohort 2 RAL-naive Cohort 2 RAL-exposed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 6 (16.67%)
    7 / 25 (28.00%)
    2 / 10 (20.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypertension neonatal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (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
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematocrit decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital syphilis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (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
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Cohort 1 RAL-naive Cohort 1 RAL-exposed Cohort 2 RAL-naive Cohort 2 RAL-exposed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    24 / 25 (96.00%)
    9 / 10 (90.00%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Pregnancy, puerperium and perinatal conditions
    Jaundice neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    4 / 25 (16.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    4
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    7 / 25 (28.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    7
    1
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Breast induration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Penile erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    4 / 25 (16.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    1
    4
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    6 / 25 (24.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    6
    1
    Blood glucose decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Haemoglobin decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 6 (83.33%)
    20 / 25 (80.00%)
    7 / 10 (70.00%)
         occurrences all number
    4
    5
    20
    7
    Neutrophil count decreased
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 6 (66.67%)
    10 / 25 (40.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    4
    10
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Congenital umbilical hernia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    3 / 25 (12.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Craniosynostosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Laryngomalacia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pulmonary artery stenosis congenital
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    9 / 25 (36.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    9
    1
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nasal congestion
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 6 (0.00%)
    5 / 25 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    0
    5
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Cyanosis neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal plaque
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Hypertonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fontanelle bulging
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Eye discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    0
    2
    3
    Infantile vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Oral mucosal discolouration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Umbilical hernia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    3 / 25 (12.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    3
    1
    Infantile spitting up
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Hepatobiliary disorders
    Hyperbilirubinaemia neonatal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Jaundice
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Papule
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    3 / 25 (12.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Seborrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    4 / 25 (16.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Rash erythematous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Rash generalised
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Genital candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    3 / 25 (12.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    3
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    8 / 25 (32.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    8
    1
    Otitis media acute
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Skin candida
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    5 / 25 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    5
    1
    Tinea versicolour
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2014
    Amendment 1: Primary reason for amendment was to change the initial dose regimen for Raltegravir-exposed neonates in Cohort 1 to single dose of 1.5 mg/kg. Second dose regimen was not changed.
    09 Jul 2015
    Amendment 2: Primary reason for the amendment was to define the 3 doses of MK-0518 for Raltegravir-unexposed neonates in Cohort 2.
    26 May 2016
    Amendment 3: Primary reason for the amendment was to change inclusion criterion regarding multi-class resistant virus to permit inclusion of mothers with at least one class of resistant HIV.

    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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