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    Clinical Trial Results:
    A Phase 2b open-label, single-arm study to evaluate pharmacokinetics, efficacy, safety and tolerability of letermovir in pediatric participants from birth to less than 18 years of age at risk of developing CMV infection and/or disease following allogeneic haematopoietic stem cell transplantation (HSCT)

    Summary
    EudraCT number
    		 2018-001326-25
    Trial protocol
    		 DE   ES   Outside EU/EEA   FR   PL  
    Global end of trial date
    25 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2024
    First version publication date
    15 Feb 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    8228-030
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03940586
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, Rahway, NJ, United States, P.O. Box 2000
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001631-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    04 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the pharmacokinetics (PK) of letermovir (LET) in pediatric participants. Participants were enrolled in the following 3 age groups: Age Group 1: From 12 to <18 years of age (adolescents); Age Group 2: From 2 to <12 years of age (children); and Age Group 3: From birth to <2 years of age (neonates, infants and toddlers). All participants received open label LET for 14 weeks (~100 days) post-transplant, with doses based on body weight and 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Aug 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Türkiye: 6
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    65
    EEA total number of subjects
    19
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    8
    Children (2-11 years)
    29
    Adolescents (12-17 years)
    28
    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
    		 Male and female recipients of a first allogeneic hematopoietic stem cell transplant (HSCT), between the ages of birth and <18 years of age, who were at risk for cytomegalovirus (CMV) infection and/or disease, and who had undetectable CMV deoxyribonucleic acid (DNA) collected within 5 days before enrollment. were enrolled in this study.

    Period 1
    Period 1 title
    Randomized
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 12 - <18 Years
    Arm description
    		 Letermovir (LET) 480 mg without cyclosporin (CsA), or 240 mg with CsA, administered either orally as tablets or in granular form, or by intravenous (IV) infusion, once daily (QD) through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir tablet
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Arm title
    		 2 - <12 Years
    Arm description
    		 Participants ≥30 kg body weight (BW): LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Arm title
    		 Birth - <2 Years
    Arm description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Number of subjects in period 1
    		12 - <18 Years 2 - <12 Years Birth - <2 Years
    Started
    28
    29
    8
    Completed
    28
    27
    8
    Not completed
    0
    2
    0
         Not Treated
    -
    2
    -
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 12 - <18 Years
    Arm description
    		 Letermovir (LET) 480 mg without cyclosporin (CsA), or 240 mg with CsA, administered either orally as tablets or in granular form, or by intravenous (IV) infusion, once daily (QD) through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir tablet
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Arm title
    		 2 - <12 Years
    Arm description
    		 Participants ≥30 kg body weight (BW): LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Arm title
    		 Birth - <2 Years
    Arm description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir oral granules
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Investigational medicinal product name
    Letermovir intravenous
    Investigational medicinal product code
    Other name
    MK-8228 AIC246 AIC001
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1, the number of participants randomized, is not the baseline period. Rather Period 2, the number of participants treated is the baseline period.
    Number of subjects in period 2 [2]
    		12 - <18 Years 2 - <12 Years Birth - <2 Years
    Started
    28
    27
    8
    Completed
    21
    21
    6
    Not completed
    7
    6
    2
         Adverse event, serious fatal
    3
    2
    -
         Physician decision
    1
    -
    1
         Withdrawal By Parent/Guardian
    3
    4
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of participants reported to in the baseline period are not the same as the worldwide number enrolled in the trial because the number of participants in the baseline period are instead the number of participants treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    12 - <18 Years
    Reporting group description
    		 Letermovir (LET) 480 mg without cyclosporin (CsA), or 240 mg with CsA, administered either orally as tablets or in granular form, or by intravenous (IV) infusion, once daily (QD) through week 14 (~ 100 days) post-transplant.

    Reporting group title
    2 - <12 Years
    Reporting group description
    		 Participants ≥30 kg body weight (BW): LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Reporting group title
    Birth - <2 Years
    Reporting group description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Reporting group values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years Total
    Number of subjects
    		 28 27 8 63
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 8 8
        Children (2-11 years)
    		 0 27 0 27
        Adolescents (12-17 years)
    		 28 0 0 28
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 14.1 ( 1.5 ) 6.6 ( 3.2 ) 0.7 ( 0.3 ) -
    Sex: Female, Male
    Units:
        Female
    		 13 5 1 19
        Male
    		 15 22 7 44
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 6 3 0 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 3 0 0 3
        White
    		 15 22 7 44
        More than one race
    		 4 2 1 7
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 4 1 14
        Not Hispanic or Latino
    		 14 21 6 41
        Unknown or Not Reported
    		 5 2 1 8

    End points

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    End points reporting groups
    Reporting group title
    12 - <18 Years
    Reporting group description
    		 Letermovir (LET) 480 mg without cyclosporin (CsA), or 240 mg with CsA, administered either orally as tablets or in granular form, or by intravenous (IV) infusion, once daily (QD) through week 14 (~ 100 days) post-transplant.

    Reporting group title
    2 - <12 Years
    Reporting group description
    		 Participants ≥30 kg body weight (BW): LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Reporting group title
    Birth - <2 Years
    Reporting group description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.
    Reporting group title
    12 - <18 Years
    Reporting group description
    		 Letermovir (LET) 480 mg without cyclosporin (CsA), or 240 mg with CsA, administered either orally as tablets or in granular form, or by intravenous (IV) infusion, once daily (QD) through week 14 (~ 100 days) post-transplant.

    Reporting group title
    2 - <12 Years
    Reporting group description
    		 Participants ≥30 kg body weight (BW): LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Reporting group title
    Birth - <2 Years
    Reporting group description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    12 - <18 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET 480 mg without CsA as tablets or in granular form, was administered orally, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET administered orally in granular form without CsA within 28 days post-transplant, QD through week 14 (approximately 100 days). Dosing varied based on weight.

    Subject analysis set title
    Birth - <2 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET administered orally in granular form without CsA within 28 days post-transplant, QD through week 14 (approximately 100 days). Dosing varied based on weight.

    Subject analysis set title
    2 - <12 Years, 18 to <30 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 18 to <30 kg BW)received LET 240 mg without CsA orally in granular form QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    Birth - <2 Years, 5 to <7.5 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 5 to <7.5 kg BW received LET 60 mg orally without CsA, in granular form, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years, 10 to <18 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 10 to <18 kg BW received LET 120 mg without CsA orally in granular form QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    Birth - <2 Years, 7.5 to <10 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 7.5 to <10 kg BW received LET 40 mg orally without CsA, in granular form, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    Birth - <2 Years, 5 to <7.5 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 5 to <7.5 kg BW received LET 60 mg orally without CsA, in granular form, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    12 - <18 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET 480 mg without CsA was administered by IV, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years, ≥30 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants ≥30 kg BW received LET 240 mg without CsA orally by IV QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years, 18 to <30 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 18 to <30 kg BW received LET 120 mg without CsA, by IV QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years, 18 to <30 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 18 to <30 kg BW received LET 240 mg without CsA by IV QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years, 10 to <18 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 10 to <18 kg BW received LET 60 mg without CsA by IV QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    Birth - <2 Years, 5 to <7.5 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 5.0 to <7.5 kg BW received LET 40 mg without CsA, by IV QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    Birth - <2 Years, 7.5 to <10 kg BW
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants 7.5 to <10 kg BW received LET 40 mg without CsA, by IV, QD through week 14 (~ 100 days) post-transplant.

    Subject analysis set title
    2 - <12 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET administered by IV within 28 days post-transplant, QD without CsA through week 14 (approximately 100 days). Dosing varied based on weight.

    Subject analysis set title
    Birth - <2 Years
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LET administered by IV without CsA within 28 days post-transplant, QD through week 14 (approximately 100 days). Dosing varied based on weight.

    Primary: Area under the concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir taken as oral formulation by ages 2 - <18 years

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    End point title
    		 Area under the concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir taken as oral formulation by ages 2 - <18 years [1]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    5
    4
    0 [2]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    80300 ( 74.9 )
    62900 ( 37.4 )
    ( )
    Notes
    [2] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as oral formulation by ages 2 to <12 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as oral formulation by ages 2 to <12 years [3]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years Birth - <2 Years, 5 to <7.5 kg BW 2 - <12 Years, 10 to <18 kg BW
    Number of subjects analysed
    0 [4]
    0 [5]
    2
    Units: hr*ng/mL
        geometric mean (full range (min-max))
    ( to )
    ( to )
    39500 (23900 to 65200)
    Notes
    [4] - data analysis resulted in a different measure type and method of dispersion.
    [5] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as oral formulation by ages <2 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as oral formulation by ages <2 years [6]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [7]
    0 [8]
    1
    Units: hr*ng/mL
        number (not applicable)
    26200
    Notes
    [7] - Data analysis resulted in a different measure type and method of dispersion.
    [8] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Maximal concentration (Cmax) of plasma letermovir taken as oral formulation by ages 2 - <18 years

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    End point title
    		 Maximal concentration (Cmax) of plasma letermovir taken as oral formulation by ages 2 - <18 years [9]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure type is geometric least squares mean. Participants aged < 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    5
    4
    0 [10]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    7410 ( 70.1 )
    10800 ( 17.4 )
    ( )
    Notes
    [10] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Cmax of plasma letermovir taken as oral formulation by ages 2 to <12 years

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    End point title
    		 Cmax of plasma letermovir taken as oral formulation by ages 2 to <12 years [11]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged <2 and >12 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 10 to <18 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [12]
    2
    0 [13]
    Units: ng/mL
        geometric mean (full range (min-max))
    ( to )
    5500 (5430 to 5580)
    ( to )
    Notes
    [12] - Data analysis resulted in a different measure type and method of dispersion.
    [13] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Cmax of plasma letermovir taken as oral formulation by ages < 2 years

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    End point title
    		 Cmax of plasma letermovir taken as oral formulation by ages < 2 years [14]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged 2 - <18 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [15]
    0 [16]
    1
    Units: ng/mL
        number (not applicable)
    2950
    Notes
    [15] - Data analysis resulted in a different measure type and method of dispersion.
    [16] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Minimum concentration of plasma letermovir observed before next dose (Ctrough) taken as oral formulation by ages 2 - <18 years

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    End point title
    		 Minimum concentration of plasma letermovir observed before next dose (Ctrough) taken as oral formulation by ages 2 - <18 years [17]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure type is geometric least squares mean. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    5
    4
    0 [18]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    845 ( 107.5 )
    171 ( 2046.8 )
    ( )
    Notes
    [18] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as oral formulation by ages 2 to <12 years

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    End point title
    		 Ctrough of plasma letermovir taken as oral formulation by ages 2 to <12 years [19]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged <2 and >12 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 10 to <18 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [20]
    2
    0 [21]
    Units: ng/mL
        geometric mean (full range (min-max))
    ( to )
    481 (207 to 1120)
    ( to )
    Notes
    [20] - Data analysis resulted in a different measure type and method of dispersion.
    [21] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as oral formulation by ages < 2 years

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    End point title
    		 Ctrough of plasma letermovir taken as oral formulation by ages < 2 years [22]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged 2 - <18 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [23]
    0 [24]
    1
    Units: ng/mL
        number (not applicable)
    61.7
    Notes
    [23] - Data analysis resulted in a different measure type and method of dispersion.
    [24] - Data analysis resulted in a different measure type and method of dispersion.
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as intravenous (IV) formulation by ages 12 - <18 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as intravenous (IV) formulation by ages 12 - <18 years [25]
    End point description
    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    3
    0 [26]
    0 [27]
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    114000 ( 37.8 )
    ( )
    ( )
    Notes
    [26] - Data analysis resulted in a different measure type and method of dispersion
    [27] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as IV formulation by ages 2 to <12 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as IV formulation by ages 2 to <12 years [28]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    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: Statistical comparisons between treatment groups were neither planned or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [29]
    2
    2
    0 [30]
    Units: hr*ng/mL
        geometric mean (full range (min-max))
    ( to )
    36200 (21000 to 62100)
    31500 (20300 to 48900)
    ( to )
    Notes
    [29] - Data analysis resulted in a different measure type and method of dispersion
    [30] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as IV formulation by ages 2 to <12 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as IV formulation by ages 2 to <12 years [31]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [31] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 10 to <18 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [32]
    1
    0 [33]
    Units: hr*ng/mL
        number (not applicable)
    25300
    Notes
    [32] - Data analysis resulted in a different measure type and method of dispersion
    [33] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Concentration at the end of infusion (Ceoi) of plasma letermovir taken as IV formulation by ages 12 - <18 years

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    End point title
    		 Concentration at the end of infusion (Ceoi) of plasma letermovir taken as IV formulation by ages 12 - <18 years [34]
    End point description
    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model .The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [34] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    3
    0 [35]
    0 [36]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    30600 ( 16.4 )
    ( )
    ( )
    Notes
    [35] - Data analysis resulted in a different measure type and method of dispersion
    [36] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: AUC0-24 of plasma letermovir taken as IV formulation by ages <2 years

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    End point title
    		 AUC0-24 of plasma letermovir taken as IV formulation by ages <2 years [37]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [37] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [38]
    0 [39]
    1
    Units: hr*ng/mL
        number (not applicable)
    37300
    Notes
    [38] - Data analysis resulted in a different measure type and method of dispersion
    [39] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ceoi of plasma letermovir taken as IV formulation by ages 2 to <12 years

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    End point title
    		 Ceoi of plasma letermovir taken as IV formulation by ages 2 to <12 years [40]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [40] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    0 [41]
    2
    2
    0 [42]
    Units: ng/mL
        geometric mean (full range (min-max))
    ( to )
    16800 (14900 to 19000)
    8200 (7580 to 8870)
    ( to )
    Notes
    [41] - Data analysis resulted in a different measure type and method of dispersion
    [42] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ceoi of plasma letermovir taken as IV formulation by ages s 2 to <12 years

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    End point title
    		 Ceoi of plasma letermovir taken as IV formulation by ages s 2 to <12 years [43]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model. A measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [43] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 10 to <18 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [44]
    1
    0 [45]
    Units: ng/mL
        number (not applicable)
    8630
    Notes
    [44] - Data analysis resulted in a different measure type and method of dispersion
    [45] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ceoi of plasma letermovir taken as IV formulation by ages <2 years

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    End point title
    		 Ceoi of plasma letermovir taken as IV formulation by ages <2 years [46]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear modelA measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [46] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [47]
    0 [48]
    1
    Units: ng/mL
        number (not applicable)
    11700
    Notes
    [47] - Data analysis resulted in a different measure type and method of dispersion
    [48] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as IV formulation by ages 2 to <12 years

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    End point title
    		 Ctrough of plasma letermovir taken as IV formulation by ages 2 to <12 years [49]
    End point description
    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    Notes
    [49] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    0 [50]
    2
    2
    0 [51]
    Units: ng/mL
        geometric mean (full range (min-max))
    ( to )
    71.6 (12.9 to 397)
    318 (134 to 754)
    ( to )
    Notes
    [50] - Data analysis resulted in a different measure type and method of dispersion
    [51] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as IV formulation by ages 12 - <18 years

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    End point title
    		 Ctrough of plasma letermovir taken as IV formulation by ages 12 - <18 years [52]
    End point description
    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    Notes
    [52] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 18 to <30 kg BW Birth - <2 Years, 7.5 to <10 kg BW
    Number of subjects analysed
    3
    0 [53]
    0 [54]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    709 ( 256.8 )
    ( )
    ( )
    Notes
    [53] - Data analysis resulted in a different measure type and method of dispersion
    [54] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as IV formulation by ages 2 to <12 years

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    End point title
    		 Ctrough of plasma letermovir taken as IV formulation by ages 2 to <12 years [55]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [55] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, 10 to <18 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [56]
    1
    0 [57]
    Units: ng/mL
        number (not applicable)
    216
    Notes
    [56] - Data analysis resulted in a different measure type and method of dispersion
    [57] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken as IV formulation by ages <2 years

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    End point title
    		 Ctrough of plasma letermovir taken as IV formulation by ages <2 years [58]
    End point description
    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. The measure type is Geometric Mean, and a measure of dispersion is not determined when N <2. The population analyzed was all participants with at least one measurable PK sample who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.
    End point type
    Primary
    End point timeframe
    Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
    Notes
    [58] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years, ≥30 kg BW Birth - <2 Years, 5 to <7.5 kg BW
    Number of subjects analysed
    0 [59]
    0 [60]
    1
    Units: ng/mL
        number (not applicable)
    98.3
    Notes
    [59] - Data analysis resulted in a different measure type and method of dispersion
    [60] - Data analysis resulted in a different measure type and method of dispersion
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken during sparse PK for oral formulation

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    End point title
    		 Ctrough of plasma letermovir taken during sparse PK for oral formulation [61]
    End point description
    Blood was collected on treatment Day 7 in order to determine the Ctrough of plasma letermovir during sparse PK for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    Notes
    [61] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    0 [62]
    0 [63]
    0 [64]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    Notes
    [62] - As sparse PK data were instead used in population PK model development, they were not summarized
    [63] - As sparse PK data were instead used in population PK model development, they were not summarized
    [64] - As sparse PK data were instead used in population PK model development, they were not summarized
    No statistical analyses for this end point

    Primary: Ctrough of plasma letermovir taken during sparse PK as IV formulation

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    End point title
    		 Ctrough of plasma letermovir taken during sparse PK as IV formulation [65]
    End point description
    Blood was collected on treatment Day 7 in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation during sparse PK. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant.
    End point type
    Primary
    End point timeframe
    Day 7: 24 hours post-dose
    Notes
    [65] - 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 or performed for this primary endpoint.
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    0 [66]
    0 [67]
    0 [68]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    Notes
    [66] - As sparse PK data were instead used in population PK model development, they were not summarized
    [67] - As sparse PK data were instead used in population PK model development, they were not summarized
    [68] - As sparse PK data were instead used in population PK model development, they were not summarized
    No statistical analyses for this end point

    Secondary: Percentage of participants with one or more adverse event (AE)

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    End point title
    		 Percentage of participants with one or more adverse event (AE)
    End point description
    .An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The 95% confidence interval (CI) is based on the exact binomial method proposed by Clopper and Pearson. The population analyzed was all participants who received ≥1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to Week 48 post-transplant (up to 52 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    28
    27
    8
    Units: Percentage of participants
        number (confidence interval 95%)
    100.0 (87.7 to 100.0)
    100.0 (87.7 to 100.0)
    100.0 (63.1 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants who discontinued study medication due to an AE.

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    End point title
    		 Percentage of participants who discontinued study medication due to an AE.
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The 95% CI is based on the exact binomial method proposed by Clopper and Pearson. The population analyzed was all participants who received ≥1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to Week 14 post-transplant (up to 18 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    28
    27
    8
    Units: Percentage of participants
        number (confidence interval 95%)
    17.9 (6.1 to 36.9)
    7.4 (0.9 to 24.3)
    12.5 (0.3 to 52.7)
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinically significant CMV infection through Week 14 post-transplant

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    End point title
    		 Percentage of participants with clinically significant CMV infection through Week 14 post-transplant
    End point description
    Clinically significant cytomegalovirus (CMV) infection is defined as CMV end organ disease (proven or probable) or initiation of pre-emptive therapy (PET) based on documented CMV viremia and the clinical condition of the participant. The 95% confidence interval (CI) was based on the exact binomial method proposed by Clopper and Pearson. Missing values: were handled by the Non-Completer=Failure (NC=F) approach. where failure was defined as all participants who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through week 14 post-transplant visit window. The population analyzed was participants who received ≥1 dose of study intervention, had no detectable CMV viral DNA on the day study intervention was initiated, had not prematurely discontinued from the study and had an outcome through week 14 post-transplant.
    End point type
    Secondary
    End point timeframe
    Up to Week 14 post-transplant (up to 18 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    25
    24
    7
    Units: Percentage of participants
        number (confidence interval 95%)
    20.0 (6.8 to 40.7)
    16.7 (4.7 to 37.4)
    28.5 (3.7 to 71.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinically significant CMV infection through Week 24 post-transplant

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    End point title
    		 Percentage of participants with clinically significant CMV infection through Week 24 post-transplant
    End point description
    Clinically significant CMV infection is defined as CMV end organ disease (proven or probable) or initiation of PET based on documented CMV viremia and the clinical condition of the participant. The 95% confidence interval (CI) was based on the exact binomial method proposed by Clopper and Pearson. Missing values: were handled by the Non-Completer=Failure (NC=F) approach. where failure was defined as all participants who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through week 24 post-transplant visit window. The population analyzed was participants who received ≥1 dose of study intervention, had no detectable CMV viral DNA on the day study intervention was initiated, had not prematurely discontinued from the study and had an outcome through week 14 post-transplant.
    End point type
    Secondary
    End point timeframe
    Up to Week 24 post-transplant (up to 28 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    25
    24
    7
    Units: Percentage of participants
        number (confidence interval 95%)
    24.0 (9.4 to 45.1)
    25.0 (9.8 to 46.7)
    28.6 (3.7 to 71.0)
    No statistical analyses for this end point

    Secondary: Number of participants receiving oral granules with palatability response, based on taste of medication on the first day of administration of oral formulation

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    End point title
    		 Number of participants receiving oral granules with palatability response, based on taste of medication on the first day of administration of oral formulation
    End point description
    Palatability was measured by response to a questionnaire on the taste of medication , with responses from very good, good, neither good nor bad, bad or very bad. The population analyzed was participants who received ≥1 dose of study intervention, and completed palatability questionnaire.
    End point type
    Secondary
    End point timeframe
    Day 1 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    4
    27
    7
    Units: Participants
        Very good
    0
    3
    0
        Good
    1
    5
    3
        Neither good nor bad
    1
    8
    1
        Bad
    1
    8
    3
        Very bad
    1
    3
    0
    No statistical analyses for this end point

    Secondary: Number of participants receiving oral granules with palatability response, based on taste of medication on the eighth day of administration of oral formulation

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    End point title
    		 Number of participants receiving oral granules with palatability response, based on taste of medication on the eighth day of administration of oral formulation
    End point description
    Palatability was measured by response to a questionnaire on the taste of medication , with responses from very good, good, neither good nor bad, bad or very bad. The population analyzed was participants who received ≥1 dose of study intervention, and completed palatability questionnaire.
    End point type
    Secondary
    End point timeframe
    Day 8 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)
    End point values
    		 12 - <18 Years 2 - <12 Years Birth - <2 Years
    Number of subjects analysed
    2
    23
    7
    Units: Participants
        Very good
    0
    3
    0
        Good
    1
    4
    3
        Neither good nor bad
    1
    8
    4
        Bad
    0
    5
    0
        Very bad
    0
    3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality (ACM): from allocation/randomization (i.e. prior to treatment) up to Week 48 post-transplant (up to 52 weeks). AEs: From first treatment up to Week 48 post-transplant (up to 52 weeks)
    Adverse event reporting additional description
    ACMs: the population analyzed was all allocated/randomized participants. AEs: the population analyzed was all allocated/randomized participants who received ≥1 dose of study intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    12 - <18 Years
    Reporting group description
    		 LET 480 mg without CsA, or 240 mg with CsA, administered either orally as tablets or in granular form, or by iIV infusion, QD through week 14 (~ 100 days) post-transplant.

    Reporting group title
    <2 Years
    Reporting group description
    		 10 to ≤15 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA; 7.5 to <10 kg BW: LET 80 mg orally without CsA, or 40 mg with CsA, either in granular form, or 40 mg IV with or without CsA; 5.0 to <7.5 kg BW: LET 40 mg orally without CsA, or 20 mg with CsA, in granular form, or 20 mg IV with or without CsA; 2.5 to <5.0 kg BW: LET 20 mg orally without CsA, or 10 mg with CsA, in granular form, or 10 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Reporting group title
    2 - <12 Years
    Reporting group description
    		 Participants ≥30 kg BW: LET 480 mg orally without CsA, or 240 mg with CsA, in granular form, or 240 mg IV with or without CsA; 18 to <30 kg BW: LET 240 mg orally without CsA, or 120 mg with CsA, either in granular form, or 120 mg IV with or without CsA; 10 to <18 kg BW: LET 120 mg orally without CsA, or 60 mg with CsA, in granular form, or 60 mg IV with or without CsA, all QD through week 14 (~ 100 days) post-transplant.

    Serious adverse events
    		 12 - <18 Years <2 Years 2 - <12 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 28 (42.86%)
    6 / 8 (75.00%)
    17 / 27 (62.96%)
         number of deaths (all causes)
    4
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Venoocclusive disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Graft versus host disease
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute graft versus host disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Respiratory distress
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Epstein-Barr virus test positive
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Humerus fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Engraft failure
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Nervous system disorders
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Polyneuropathy
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Endocrine disorders
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Candida infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cystitis viral
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Bronchitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BK virus infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (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
    Febrile infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Epstein-Barr virus infection reactivation
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 8 (25.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Septic shock
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Klebsiella bacteraemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatosplenic candidiasis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    0 / 27 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 12 - <18 Years <2 Years 2 - <12 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 28 (96.43%)
    8 / 8 (100.00%)
    27 / 27 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    3
    Flushing
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    7 / 28 (25.00%)
    0 / 8 (0.00%)
    9 / 27 (33.33%)
         occurrences all number
    8
    0
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    3
    0
    4
    Catheter site erythema
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Fatigue
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    3
    Face oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    4 / 27 (14.81%)
         occurrences all number
    0
    1
    4
    Pyrexia
         subjects affected / exposed
    10 / 28 (35.71%)
    4 / 8 (50.00%)
    12 / 27 (44.44%)
         occurrences all number
    17
    4
    21
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    3
    Engraftment syndrome
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Graft versus host disease
         subjects affected / exposed
    10 / 28 (35.71%)
    2 / 8 (25.00%)
    10 / 27 (37.04%)
         occurrences all number
    13
    2
    13
    Graft versus host disease in skin
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Pulmonary mass
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    5
    0
    4
    Hypoxia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    5
    Dyspnoea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Cough
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    4
    0
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 28 (17.86%)
    1 / 8 (12.50%)
    3 / 27 (11.11%)
         occurrences all number
    6
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 8 (12.50%)
    1 / 27 (3.70%)
         occurrences all number
    5
    1
    1
    BK polyomavirus test positive
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Cytomegalovirus test positive
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    7
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    3
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Contusion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    4
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Headache
         subjects affected / exposed
    6 / 28 (21.43%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    8
    0
    4
    Tremor
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    0
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    4
    0
    6
    Anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    4
    0
    15
    Lymphopenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    2
    0
    3
    Leukopenia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 8 (0.00%)
    9 / 27 (33.33%)
         occurrences all number
    8
    0
    9
    Neutropenia
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 8 (12.50%)
    8 / 27 (29.63%)
         occurrences all number
    4
    2
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 28 (39.29%)
    1 / 8 (12.50%)
    6 / 27 (22.22%)
         occurrences all number
    14
    1
    10
    Abdominal pain upper
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    7
    Anal fissure
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    2
    Constipation
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    4
    0
    4
    Diarrhoea
         subjects affected / exposed
    12 / 28 (42.86%)
    1 / 8 (12.50%)
    12 / 27 (44.44%)
         occurrences all number
    16
    1
    15
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Haematochezia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    Nausea
         subjects affected / exposed
    12 / 28 (42.86%)
    0 / 8 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    23
    0
    7
    Oesophagitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    0
    3
    Stomatitis
         subjects affected / exposed
    7 / 28 (25.00%)
    0 / 8 (0.00%)
    9 / 27 (33.33%)
         occurrences all number
    7
    0
    9
    Vomiting
         subjects affected / exposed
    13 / 28 (46.43%)
    3 / 8 (37.50%)
    20 / 27 (74.07%)
         occurrences all number
    41
    5
    48
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    3
    Nail pigmentation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Macule
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Erythema
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    5
    Eczema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    2
    Dry skin
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Rash macular
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    4
    0
    6
    Pruritus
         subjects affected / exposed
    6 / 28 (21.43%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    7
    0
    3
    Palmar erythema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    3
    0
    3
    Hypercalciuria
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Haematuria
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    4
    0
    2
    Dysuria
         subjects affected / exposed
    6 / 28 (21.43%)
    0 / 8 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    6
    0
    3
    Acute kidney injury
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    1
    Infections and infestations
    Streptococcal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Adenovirus infection
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    BK virus infection
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Bacteraemia
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    1
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Device related bacteraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Device related infection
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    3 / 27 (11.11%)
         occurrences all number
    1
    1
    3
    Epstein-Barr virus infection reactivation
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Febrile infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 8 (12.50%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Pneumonia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Polyomavirus viraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Sepsis
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 8 (12.50%)
    2 / 27 (7.41%)
         occurrences all number
    3
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    8 / 27 (29.63%)
         occurrences all number
    4
    0
    10
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Hypervolaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 8 (0.00%)
    5 / 27 (18.52%)
         occurrences all number
    7
    0
    8
    Hypokalaemia
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 8 (12.50%)
    4 / 27 (14.81%)
         occurrences all number
    5
    1
    5
    Hypomagnesaemia
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 8 (12.50%)
    3 / 27 (11.11%)
         occurrences all number
    6
    1
    4
    Hypophosphataemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    3
    Malnutrition
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 8 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Neonatal diabetes mellitus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Sodium retention
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 8 (12.50%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2019
    Amendment 01: Testicular toxicity testing was removed, and creatinine clearance monitoring every 2 weeks was added to the protocol.
    03 Apr 2019
    Amendment 02: The description of the coating of the oral granule formulation to be used in this study provided in Section 2.2.4 was incorrect in the original protocol. This amendment provides the correct description of the coating of the oral granule formulation being used (Opadry coating without Surelease) and provides the rationale for selection of this oral granule formulation. Additional minor changes have been made to incorporate changes communicated in prior protocol clarification letters.
    27 Sep 2019
    Amendment 03: To add the requirement that the IV formulation of LET supplied by the Sponsor to sites as study medication must be administered through a sterile 0.2-micron or 0.22-micron polyethersulfone (PES) in-line filter and using diethylhexyl phthalate (DEHP)-free IV bags and infusion set materials. This requirement is being added to prevent the possible administration of product-related particulate matter. The presence of visible product-related particulate matter is an expected characteristic of new clinical supplies of the IV formulation of LET. This requirement is being implemented to allow for the release of new clinical supplies of IV LET, and, as a precaution, it must be applied regardless of whether the clinical site considers its current clinical supply to be impacted.
    01 Oct 2021
    Amendment 07: To provide the initial dose of oral and IV LET for Age Group 3, which has been determined by interim pharmacokinetics (PK) analyses using data from participants in Age Group 1 and Age Group 2 of this study. To add a requirement for PK sampling of hydroxypropyl-beta-cyclodextrin (HPCD), an excipient in the IV LET formulation, for Age Group 3 participants receiving the IV formulation for at least 4 consecutive days. In addition, the 10-mg oral capsule of LET is now available for use in Spain.
    21 Oct 2022
    Amendment 08:The primary reason was Sponsor underwent entity name change and update to the address.

    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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