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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

    Results information
    Results version number
    		 v1
    This version publication date
    25 Aug 2017
    First version publication date
    25 Aug 2017
    Other versions
    		 v2

    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
    Interim
    Date of interim/final analysis
    06 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to evaluate the safety and tolerability through 6 weeks of age of raltegravir oral granules for suspension (GFS) when administered during the first 6 weeks of age with standard prevention of mother-to-child transmission (PMTCT) antiretroviral prophylaxis to human immunodeficiency virus Type 1 (HIV-1)-exposed infants assessed at high risk of HIV-1 infection, to evaluate the pharmacokinetics (PK) of raltegravir GFS during the first 6 weeks of age along with standard PMTCT antiretroviral therapy prophylaxis, and to determine an appropriate dose of raltegravir GFS for use in neonates and infants during the first 6 weeks of age.
    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 will have access to raltegravir through Merck Pediatric Compassionate Use program.
    Background therapy
    		 All enrolled neonates also received standard of care antiretroviral (ARV) for 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
    04 Apr 2013
    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
    Brazil: 21
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    42
    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)
    42
    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
    		 Mother/infant pairs were enrolled. Mother was known to be HIV-1 infected. Infants were HIV-1 exposed full-term neonates aged ≤48 hours who may have received up to 48 hours of standard of care ARV prophylaxis before enrollment and either had been exposed to raltegravir in utero or not exposed to raltegravir in utero.

    Pre-assignment
    Screening details
    		 Neonates enrolled in Cohort I received 3 mg/kg raltegravir GFS as a single dose within 48 hours of birth. Assessment of the PK and safety data from the 1st 6 enrolled raltegravir-unexposed neonates resulted in lowering of the first dose to 2 mg/kg for subsequent enrolled Cohort I neonates and the 2nd dose remained unchanged.

    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 Exposed
    Arm description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.
    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 in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Arm title
    		 Cohort 1: Raltegravir Unexposed
    Arm description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.
    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 in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Arm title
    		 Cohort 2: Raltegravir Unexposed
    Arm description
    		 Raltegravir GFS in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. Participants received Raltegravir 1.5 mg/kg once daily during Days 1 to 7 of age (Week 1), Raltegravir 3 mg/kg twice daily (BID) 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 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). All doses administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Number of subjects in period 1
    		Cohort 1: Raltegravir Exposed Cohort 1: Raltegravir Unexposed Cohort 2: Raltegravir Unexposed
    Started
    6
    10
    26
    Completed Study Treatment
    6
    10
    23
    Completed
    6
    10
    22
    Not completed
    0
    0
    4
         Consent withdrawn by subject
    -
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Raltegravir Exposed
    Reporting group description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Reporting group title
    Cohort 1: Raltegravir Unexposed
    Reporting group description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Reporting group title
    Cohort 2: Raltegravir Unexposed
    Reporting group description
    		 Raltegravir GFS in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. Participants received Raltegravir 1.5 mg/kg once daily during Days 1 to 7 of age (Week 1), Raltegravir 3 mg/kg twice daily (BID) 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)

    Reporting group values
    		 Cohort 1: Raltegravir Exposed Cohort 1: Raltegravir Unexposed Cohort 2: Raltegravir Unexposed Total
    Number of subjects
    		 6 10 26 42
    Age Categorical
    Units: Subjects
    Age Continuous
    Age reported is the age of the first dose was administered.
    Units: days
        arithmetic mean (standard deviation)
    		 1.7 ± 0.5 0.8 ± 0.6 1.5 ± 0.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 2 6 12 20
        Male
    		 4 4 14 22

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Raltegravir Exposed
    Reporting group description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Reporting group title
    Cohort 1: Raltegravir Unexposed
    Reporting group description
    		 Raltegravir granules for suspension (GFS) 3 mg/kg as a single dose within 48 hours of birth in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. A second dose of raltegravir 3 mg/kg administered at 7 to 10 days of age.

    Reporting group title
    Cohort 2: Raltegravir Unexposed
    Reporting group description
    		 Raltegravir GFS in addition to standard of care antiretroviral therapy for PMTCT prophylaxis. Participants received Raltegravir 1.5 mg/kg once daily during Days 1 to 7 of age (Week 1), Raltegravir 3 mg/kg twice daily (BID) 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)

    Subject analysis set title
    Cohort 1: Raltegravir Exposed - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants previously exposed to Raltegravir who received 1.5 mg/kg of Raltegravir in Cohort 1. A second dose of Raltegravir 3 mg/kg administered at 7 to 10 days of age. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 1: Raltegravir Unexposed - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants not previously exposed to Raltegravir who received either 2.0 or 3.0 mg/kg of Raltegravir in Cohort 1. A second dose of Raltegravir 3 mg/kg administered at 7 to 10 days of age. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 2: Raltegravir Unexposed - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participant not previously exposed to Raltegravir who received 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). Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants not previously exposed to Raltegravir who received 2.0 mg/kg of Raltegravir in Cohort 1. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants not previously exposed to Raltegravir who received 3.0 mg/kg of Raltegravir in Cohort 1. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 2: Raltegravir Unexposed - PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants not previously exposed to Raltegravir who received 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). Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Subject analysis set title
    Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants previously exposed to Raltegravir who received 1.5 mg/kg of Raltegravir in Cohort 1. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Primary: Percentage of Participants Who Experience 1 or More Grade 3 or 4 Adverse Event: Week 6 - Cohorts 1 and 2

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    End point title
    		 Percentage of Participants Who Experience 1 or More Grade 3 or 4 Adverse Event: Week 6 - Cohorts 1 and 2 [1]
    End point description
    An adverse event (AE) was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Adverse events were graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). Participants that experienced AEs that were reported as either Grade 3 or 4 in intensity were summarized.
    End point type
    Primary
    End point timeframe
    up to Week 6 of Cohort 1 and Cohort 2
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Exposed - Safety Cohort 1: Raltegravir Unexposed - Safety Cohort 2: Raltegravir Unexposed - Safety
    Number of subjects analysed
    6
    10
    26
    Units: Percentage of Participants
        number (not applicable)
    33.3
    20
    23.1
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experience a Suspected Adverse Drug Reaction (ADR) of Grade 3 or 4: Week 6 - Cohorts 1 and 2

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    End point title
    		 Percentage of Participants Who Experience a Suspected Adverse Drug Reaction (ADR) of Grade 3 or 4: Week 6 - Cohorts 1 and 2 [2]
    End point description
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Adverse events were graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). Suspected Adverse Drug Reaction (ADR) was an AE that was an AE that was reported as possibly, probably or definitely related to the study drug. Participants that experienced suspected ADR that were reported as either Grade 3 or 4 in intensity were summarized.
    End point type
    Primary
    End point timeframe
    up to Week 6 of Cohort 1 and Cohort 2
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Exposed - Safety Cohort 1: Raltegravir Unexposed - Safety Cohort 2: Raltegravir Unexposed - Safety
    Number of subjects analysed
    6
    10
    26
    Units: Percentage of Participants
        number (not applicable)
    0
    10
    0
    No statistical analyses for this end point

    Primary: Apparent Terminal Half-life (t1/2) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Apparent Terminal Half-life (t1/2) of Raltegravir – Single Dose: Cohort 1 [3]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours post-dose on day of 1st dose to determine the t1/2 of Raltegravir. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose, which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hours
        geometric mean (geometric coefficient of variation)
    17.15 ± 63.92
    11.82 ± 25.5
    12.6 ± 39.86
    No statistical analyses for this end point

    Primary: Maximum Concentration (Cmax) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Maximum Concentration (Cmax) of Raltegravir – Single Dose: Cohort 1 [4]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the Cmax of Raltegravir. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3405.24 ± 32.41
    3360.89 ± 33.33
    2188.82 ± 49.5
    No statistical analyses for this end point

    Primary: Time to Maximum Concentration (Tmax) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Time to Maximum Concentration (Tmax) of Raltegravir – Single Dose: Cohort 1 [5]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the Tmax of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hours
        geometric mean (geometric coefficient of variation)
    4.42 ± 4.44
    6.51 ± 93.89
    5.23 ± 69.87
    No statistical analyses for this end point

    Primary: Last Observed Quantifiable Concentration (Clast) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Last Observed Quantifiable Concentration (Clast) of Raltegravir – Single Dose: Cohort 1 [6]
    End point description
    Blood samples taken at Predose, 1 to 2 hours post-dose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the Clast of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    704.49 ± 92.25
    66.81 ± 122.64
    201.6 ± 98.6
    No statistical analyses for this end point

    Primary: Time to Last Observed Quantifiable Concentration (Tlast) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Time to Last Observed Quantifiable Concentration (Tlast) of Raltegravir – Single Dose: Cohort 1 [7]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the Tlast of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hours
        geometric mean (geometric coefficient of variation)
    28.56 ± 0.66
    74.79 ± 40.93
    45.87 ± 37.37
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir – Single Dose: Cohort 1 [8]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the V/F of Raltegravir in the neonates not exposed to Raltegravir in-utero. V/F is a measure of the amount of the Raltegravir enters circulation. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    Notes
    [8] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: Liters (L)
        geometric mean (geometric coefficient of variation)
    2 ± 57.51
    1.72 ± 37.08
    1.37 ± 83.2
    No statistical analyses for this end point

    Primary: Apparent Clearance Following Dosing (CL/F) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Apparent Clearance Following Dosing (CL/F) of Raltegravir – Single Dose: Cohort 1 [9]
    End point description
    Blood samples taken at Predose, 1 to 2 hours post-dose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the Cl/F of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: Liters/hour
        geometric mean (geometric coefficient of variation)
    0.08 ± 98.28
    0.1 ± 28.88
    0.08 ± 139.57
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve From 0 to 12 Hours (AUC12) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Area Under the Concentration-time Curve From 0 to 12 Hours (AUC12) of Raltegravir – Single Dose: Cohort 1 [10]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, and 12 (±1) hours postdose on day of 1st dose to determine the AUC12 of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1 to 2 hours post-dose, 4 to 8 hours postdose, and 12 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    Notes
    [10] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    28.11 ± 44.2
    29.48 ± 34.98
    20.33 ± 53.06
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve From 0 to 24 Hours (AUC24) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Area Under the Concentration-time Curve From 0 to 24 Hours (AUC24) of Raltegravir – Single Dose: Cohort 1 [11]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the AUC24 of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    44.26 ± 59.17
    53.88 ± 30.96
    37.42 ± 54.63
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve From 0 to infinity (AUCinf) of Raltegravir – Single Dose: Cohort 1

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    End point title
    		 Area Under the Concentration-time Curve From 0 to infinity (AUCinf) of Raltegravir – Single Dose: Cohort 1 [12]
    End point description
    Blood samples taken at Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours postdose, and 24 (±1) hours postdose on day of 1st dose to determine the AUCinf of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant who received 3 mg/kg was excluded from pharmacokinetic analyses. Another participant was scheduled to receive 2 mg/kg but was administered a 3 mg/kg dose in error and thus is included in the 3 mg/kg arm.
    End point type
    Primary
    End point timeframe
    Predose, 1 to 2 hours postdose, 4 to 8 hours postdose, 12 (±1) hours post-dose, and 24 (±1) hours postdose on day of 1st dose which was to administered within 48 hours after birth
    Notes
    [12] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 1: Raltegravir Unexposed - 2 mg/kg - PK Cohort 1: Raltegravir Unexposed - 3 mg/kg - PK Cohort 1: Raltegravir - Exposed- 1.5 mg/kg - PK
    Number of subjects analysed
    3
    6
    6
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    78.26 ± 73.98
    98.67 ± 33.45
    62.5 ± 62.74
    No statistical analyses for this end point

    Primary: Apparent Terminal Half-life (t1/2) of Raltegravir - 1.5 mg/kg Once Daily (QD): Cohort 2

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    End point title
    		 Apparent Terminal Half-life (t1/2) of Raltegravir - 1.5 mg/kg Once Daily (QD): Cohort 2 [13]
    End point description
    Blood samples taken within 1 hour pre-dose, and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post 1st dose to determine the t1/2 of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: Hours
        geometric mean (geometric coefficient of variation)
    15.79 ± 174.79
    No statistical analyses for this end point

    Primary: Maximum Concentration (Cmax) of Raltegravir – 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Maximum Concentration (Cmax) of Raltegravir – 1.5 mg/kg QD: Cohort 2 [14]
    End point description
    Blood samples taken within1 hour pre-dose, and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-post-dose on day of 1st dose to determine the Cmax of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    Notes
    [14] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    25
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2349.91 ± 35.02
    No statistical analyses for this end point

    Primary: Time to Maximum Concentration (Tmax) of Raltegravir – 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Time to Maximum Concentration (Tmax) of Raltegravir – 1.5 mg/kg QD: Cohort 2 [15]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose post-dose on day of 1st dose to determine the Tmax of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    25
    Units: Hours
        geometric mean (geometric coefficient of variation)
    5.37 ± 57.49
    No statistical analyses for this end point

    Primary: Last Observed Quantifiable Concentration (Clast) of Raltegravir – 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Last Observed Quantifiable Concentration (Clast) of Raltegravir – 1.5 mg/kg QD: Cohort 2 [16]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose, and 24 (±1) hours post-dose on day of 1st dose to determine the Clast of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    Notes
    [16] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    25
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    947.9 ± 64.23
    No statistical analyses for this end point

    Primary: Area Under the Time-concentration Curve for All Values (AUCall) - 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Area Under the Time-concentration Curve for All Values (AUCall) - 1.5 mg/kg QD: Cohort 2 [17]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose on day of 1st dose to determine the AUCall of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    25
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    36.74 ± 36.16
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir- 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir- 1.5 mg/kg QD: Cohort 2 [18]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post 1st dose to determine the V/F of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    Notes
    [18] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: Liters (L)
        geometric mean (geometric coefficient of variation)
    1.63 ± 41.22
    No statistical analyses for this end point

    Primary: Apparent Clearance Following Dosing (CL/F) of Raltegravir – 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Apparent Clearance Following Dosing (CL/F) of Raltegravir – 1.5 mg/kg QD: Cohort 2 [19]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose on day of 1st dose to determine the Cl/F of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: Liters/hour
        geometric mean (geometric coefficient of variation)
    0.07 ± 62.39
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve From 0 to 24 Hours (AUC24) of Raltegravir – 1.5 mg/kg QD: Cohort 2

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    End point title
    		 Area Under the Concentration-time Curve From 0 to 24 Hours (AUC24) of Raltegravir – 1.5 mg/kg QD: Cohort 2 [20]
    End point description
    Blood samples taken within 1 hour pre-dose and at 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose on day of 1st dose to determine the AUC24 of Raltegravir in the neonates not exposed to Raltegravir in-utero.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1 to 2 hours, 6 to 10 hours, 20 to 24 hours post-dose. Dose administered within 48 hours after birth.
    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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    38.2 ± 38.35
    No statistical analyses for this end point

    Primary: Apparent Terminal Half-life (t1/2) of Raltegravir – 3 mg/kg Twice Daily (BID): Cohort 2

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    End point title
    		 Apparent Terminal Half-life (t1/2) of Raltegravir – 3 mg/kg Twice Daily (BID): Cohort 2 [21]
    End point description
    Blood samples taken Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the t1/2 of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed. Another participant could not have all PK parameters calculated due to issues related to drug concentration increasing.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [21] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    23
    Units: Hours
        geometric mean (geometric coefficient of variation)
    2.45 ± 33.49
    No statistical analyses for this end point

    Primary: Maximum Concentration (Cmax) of Raltegravir – 3 mg/kg BID: Cohort 2

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    End point title
    		 Maximum Concentration (Cmax) of Raltegravir – 3 mg/kg BID: Cohort 2 [22]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the Cmax of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [22] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2849.48 ± 41.9
    No statistical analyses for this end point

    Primary: Time to Maximum Concentration (Tmax) of Raltegravir – 3 mg/kg BID: Cohort 2

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    End point title
    		 Time to Maximum Concentration (Tmax) of Raltegravir – 3 mg/kg BID: Cohort 2 [23]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the Tmax of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [23] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: Hours
        geometric mean (geometric coefficient of variation)
    2.34 ± 67.12
    No statistical analyses for this end point

    Primary: Last Observed Quantifiable Concentration (Clast) of Raltegravir – 3 mg/kg BID: Cohort 2

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    End point title
    		 Last Observed Quantifiable Concentration (Clast) of Raltegravir – 3 mg/kg BID: Cohort 2 [24]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the Clast of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [24] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    557.99 ± 83.74
    No statistical analyses for this end point

    Primary: Time to Last Observed Quantifiable Concentration (Tlast) of Raltegravir – 3 mg/kg BID: Cohort 2

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    End point title
    		 Time to Last Observed Quantifiable Concentration (Tlast) of Raltegravir – 3 mg/kg BID: Cohort 2 [25]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the Tlast of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [25] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: Hours
        geometric mean (geometric coefficient of variation)
    8.42 ± 7.34
    No statistical analyses for this end point

    Primary: Area Under the Time-concentration Curve for All Values (AUCall) of Raltegravir - 3 mg/kg BID: Cohort 2

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    End point title
    		 Area Under the Time-concentration Curve for All Values (AUCall) of Raltegravir - 3 mg/kg BID: Cohort 2 [26]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the AUCall of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [26] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    24
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    13.23 ± 42.3
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir - 3 mg/kg BID: Cohort 2

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    End point title
    		 Apparent Volume of Distribution During the Terminal Phase (V/F) of Raltegravir - 3 mg/kg BID: Cohort 2 [27]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the V/F of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed. Another participant could not have all PK parameters calculated due to issues related to drug concentration increasing.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [27] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    23
    Units: Liters
        geometric mean (geometric coefficient of variation)
    2.32 ± 64.02
    No statistical analyses for this end point

    Primary: Apparent Clearance Following Dosing (CL/F) of Raltegravir - 3 mg/kg BID: Cohort 2

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    End point title
    		 Apparent Clearance Following Dosing (CL/F) of Raltegravir - 3 mg/kg BID: Cohort 2 [28]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the CL/F of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed. Another participant could not have all PK parameters calculated due to issues related to drug concentration increasing.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [28] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    23
    Units: Liters/hour
        geometric mean (geometric coefficient of variation)
    0.66 ± 54.98
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve From 0 to 12 Hours (AUC12) of Raltegravir - 3 mg/kg BID: Cohort 2

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    End point title
    		 Area Under the Concentration-time Curve From 0 to 12 Hours (AUC12) of Raltegravir - 3 mg/kg BID: Cohort 2 [29]
    End point description
    Blood samples taken within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to determine the AUC12 of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed. Another participant could not have all PK parameters calculated due to issues related to drug concentration increasing.
    End point type
    Primary
    End point timeframe
    Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [29] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    23
    Units: hr*mg/L
        geometric mean (geometric coefficient of variation)
    14.3 ± 43.25
    No statistical analyses for this end point

    Primary: Concentration of Raltegravir at Hour 12 (C12) – 3 mg/kg BID: Cohort 2

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    End point title
    		 Concentration of Raltegravir at Hour 12 (C12) – 3 mg/kg BID: Cohort 2 [30]
    End point description
    Blood samples 8-12 hours post-dose on Day 15 (Day 15-18 after birth) to estimate the C12 of Raltegravir in the neonates not exposed to Raltegravir in-utero. One participant's mother withdrew consent after 1.5 mg QD dosing thus no 3 mg/kg BID PK analyses were performed. Another participant could not have all PK parameters calculated due to issues related to drug concentration increasing.
    End point type
    Primary
    End point timeframe
    12 hours post-dose on Day 15 (Day 15-18 after birth)
    Notes
    [30] - 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: No statistical analysis was planned for the endpoint
    End point values
    		 Cohort 2: Raltegravir Unexposed - PK
    Number of subjects analysed
    23
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    176.11 ± 93.75
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 28 weeks for both Cohort 1 and Cohort 2
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort 1 RAL Unexposed
    Reporting group description
    		 Participants not previously exposed to Raltegravir who received either 2.0 or 3.0 mg/kg of Raltegravir in Cohort 1. A second dose of Raltegravir 3 mg/kg administered at 7 to 10 days of age. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Reporting group title
    Cohort 1 RAL Exposed
    Reporting group description
    		 Participants previously exposed to Raltegravir who received 1.5 mg/kg of Raltegravir in Cohort 1. A second dose of Raltegravir 3 mg/kg administered at 7 to 10 days of age. Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Reporting group title
    Cohort 2 RAL Unexposed
    Reporting group description
    		 Participant not previously exposed to Raltegravir who received 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). Study drug administered in addition to standard of care antiretroviral therapy for PMTCT prophylaxis.

    Serious adverse events
    		 Cohort 1 RAL Unexposed Cohort 1 RAL Exposed Cohort 2 RAL Unexposed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    7 / 26 (26.92%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    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 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital syphilis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    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 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 RAL Unexposed Cohort 1 RAL Exposed Cohort 2 RAL Unexposed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 6 (100.00%)
    24 / 26 (92.31%)
    Vascular disorders
    Hypertension neonatal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Pallor
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    2 / 26 (7.69%)
         occurrences all number
    0
    4
    4
    Pregnancy, puerperium and perinatal conditions
    Jaundice neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    4 / 26 (15.38%)
         occurrences all number
    0
    0
    4
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Mucosal discolouration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    7 / 26 (26.92%)
         occurrences all number
    1
    0
    9
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Breast induration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Penile erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    8 / 26 (30.77%)
         occurrences all number
    2
    1
    10
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    4
    Nasal congestion
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 6 (0.00%)
    5 / 26 (19.23%)
         occurrences all number
    6
    0
    7
    Rales
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Snoring
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    5 / 26 (19.23%)
         occurrences all number
    1
    1
    6
    Blood calcium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    5 / 26 (19.23%)
         occurrences all number
    1
    0
    6
    Blood glucose decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    Blood pressure increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 6 (83.33%)
    19 / 26 (73.08%)
         occurrences all number
    7
    11
    60
    Neutrophil count decreased
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 6 (66.67%)
    7 / 26 (26.92%)
         occurrences all number
    12
    5
    15
    Injury, poisoning and procedural complications
    Scar
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Congenital megaureter
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Congenital renal cyst
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Congenital umbilical hernia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Craniosynostosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Laryngomalacia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary artery stenosis congenital
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Talipes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Hypertonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    0
    4
    2
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Eye discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Infantile colic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    Infantile vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Oral mucosal discolouration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Umbilical hernia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    3 / 26 (11.54%)
         occurrences all number
    1
    1
    4
    Hepatobiliary disorders
    Hyperbilirubinaemia neonatal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Jaundice
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Dermatitis atopic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Dermatitis bullous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Milia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Neurodermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Papule
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    1
    0
    3
    Scab
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Seborrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    4 / 26 (15.38%)
         occurrences all number
    0
    0
    6
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Body tinea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Genital candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Impetigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    8 / 26 (30.77%)
         occurrences all number
    0
    1
    9
    Otitis media acute
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    Skin candida
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    5 / 26 (19.23%)
         occurrences all number
    0
    0
    8
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    Failure to thrive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    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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