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    Clinical Trial Results:
    A Phase 3 randomized, double-blind, placebocontrolled clinical trial to evaluate the safety and efficacy of letermovir (LET) prophylaxis when extended from 100 days to 200 days post-transplant in cytomegalovirus (CMV) seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT)

    Summary
    EudraCT number
    		 2018-001038-17
    Trial protocol
    		 GB   DE   ES   FR   IT  
    Global end of trial date
    16 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2023
    First version publication date
    15 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8228-040
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03930615
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck: MK-8228-040
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the safety and efficacy of letermovir (LET) versus placebo when cytomegalovirus (CMV) prophylaxis was extended from 100 days to 200 days post-transplant in CMV seropositive participants who received an allogenic hematopoietic stem cell transplant (HSCT). It was hypothesized that LET is superior to placebo in the prevention of clinically-significant CMV infection when LET prophylaxis is extended from 100 to 200 days.
    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
    21 Jun 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
    France: 28
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Italy: 61
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    220
    EEA total number of subjects
    119
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    176
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Cytomegalovirus (CMV)-seropositive recipients (R+) of a hematopoietic stem cell transplant (HSCT) who had received letermovir (LET) prophylaxis through Week 14 (~100 days) post-transplant and were at high risk for CMV infection and/or disease were enrolled in this study.

    Period 1
    Period 1 title
    Randomized
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Letermovir
    Arm description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir
    Investigational medicinal product code
    Other name
    PREVYMIS™, MK-8228
    Pharmaceutical forms
    Buccal tablet, Infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Participants who received hematopoietic stem cell transplant (HSCT) transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Arm title
    		 Placebo
    Arm description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet, Infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment (inactive saline or dextrose).

    Number of subjects in period 1
    		Letermovir Placebo
    Started
    145
    75
    Completed
    144
    74
    Not completed
    1
    1
         Not treated
    1
    1
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Letermovir
    Arm description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir
    Investigational medicinal product code
    Other name
    PREVYMIS™, MK-8228
    Pharmaceutical forms
    Buccal tablet, Infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Participants who received hematopoietic stem cell transplant (HSCT) transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Arm title
    		 Placebo
    Arm description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet, Infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment (inactive saline or dextrose).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Instead of the randomized/enrolled population in period 1, the baseline period was the treated population in period 2.
    Number of subjects in period 2 [2]
    		Letermovir Placebo
    Started
    144
    74
    Completed
    118
    63
    Not completed
    26
    11
         Adverse event, serious fatal
    9
    3
         Physician decision
    3
    4
         Consent withdrawn by subject
    13
    2
         Lost to follow-up
    1
    2
    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 worldwide number randomized/enrolled in the trial was different from the number at baseline, which was the treated population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Letermovir
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.

    Reporting group values
    		 Letermovir Placebo Total
    Number of subjects
    		 144 74 218
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 112 63 175
        From 65-84 years
    		 32 11 43
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.9 ( 14.3 ) 62.7 ( 12.9 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 52 31 83
        Male
    		 92 43 135
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 16 8 24
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        Black or African American
    		 3 1 4
        White
    		 113 60 173
        More than one race
    		 2 1 3
        Unknown or Not Reported
    		 8 4 12
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 8 21
        Not Hispanic or Latino
    		 106 53 159
        Unknown or Not Reported
    		 25 13 38
    Donor Stratum
    Units: Subjects
        Haploidentical
    		 45 22 67
        Non-haploidentical
    		 99 52 151

    End points

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    End points reporting groups
    Reporting group title
    Letermovir
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
    Reporting group title
    Letermovir
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.

    Primary: Percentage of participants with clinically significant CMV infection from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant

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    End point title
    		 Percentage of participants with clinically significant CMV infection from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant
    End point description
    Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV preemptive therapy (PET) with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the observed failure (OF) approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 28 post-transplant. It was hypothesized that LET is superior to placebo in the prevention of clinically significant CMV infection when LET prophylaxis is extended from 100 to 200 days. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    2.8
    18.9
    Statistical analysis title
    		 Treatment differences in percent response
    Statistical analysis description
    It was hypothesized that LET is superior to placebo in the prevention of clinically significant CMV infection.
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0005 [2]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -16.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.8
         upper limit
    		 -6.5
    Notes
    [1] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).
    [2] - A one-sided p-value ≤0.0249 was used for declaring statistical significance

    Secondary: Percentage of participants experiencing ≥1 adverse events (AEs) from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant

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    End point title
    		 Percentage of participants experiencing ≥1 adverse events (AEs) from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant
    End point description
    An adverse event (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. The population analyzed was all randomized participants who received at least 1 dose of study intervention according to the study intervention they received.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    88.9
    93.2
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    Miettinen & Nurminen method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 4.7
    Notes
    [3] - Letermovir minus Placebo

    Secondary: Percentage of participants withdrawing from study drug due to an AE from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant

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    End point title
    		 Percentage of participants withdrawing from study drug due to an AE from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant
    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. The population analyzed was all randomized participants who received at least 1 dose of study intervention according to the study intervention they received.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    4.9
    1.4
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    Miettinen & Nurminen method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 8.6
    Notes
    [4] - Letermovir minus placebo

    Secondary: Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 28 post-transplant

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    End point title
    		 Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 28 post-transplant
    End point description
    Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144 [5]
    74 [6]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [5] - 9999 means the median time was not reached.
    [6] - 9999 means the median time was not reached.
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 48 post-transplant

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    End point title
    		 Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 48 post-transplant
    End point description
    Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 48 post-transplant. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    14.6
    20.3
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1591
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.8
         upper limit
    		 5.4
    Notes
    [7] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 38 post-transplant

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    End point title
    		 Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 38 post-transplant
    End point description
    Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 38 post-transplant. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 38 post-transplant (approximately 24 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    14.6
    20.3
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.1591
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.8
         upper limit
    		 5.4
    Notes
    [8] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 48 post-transplant

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    End point title
    		 Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 48 post-transplant
    End point description
    Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144 [9]
    74 [10]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [9] - 9999 means the median time was not reached.
    [10] - 9999 means the median time was not reached.
    No statistical analyses for this end point

    Secondary: Percentage of participants with CMV viremia who started PET from Week 14 post-transplant to Week 48 post-transplant

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    End point title
    		 Percentage of participants with CMV viremia who started PET from Week 14 post-transplant to Week 48 post-transplant
    End point description
    The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 48 post-transplant. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    13.2
    18.9
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.1494
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 5.1
    Notes
    [11] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Percentage of participants with CMV viremia who started PET from Week 14 post-transplant to Week 28 post-transplant

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    End point title
    		 Percentage of participants with CMV viremia who started PET from Week 14 post-transplant to Week 28 post-transplant
    End point description
    The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 28 post-transplant. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    2.1
    16.2
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0012
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    -14.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.3
         upper limit
    		 -5
    Notes
    [12] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 48 post-transplant

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    End point title
    		 Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 48 post-transplant
    End point description
    The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 48 was determined. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    8.3
    8.1
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.5264
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9
         upper limit
    		 8.4
    Notes
    [13] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 28 post-transplant

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    End point title
    		 Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 28 post-transplant
    End point description
    The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 28 was determined. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144
    74
    Units: Percentage of participants
        number (not applicable)
    2.1
    1.4
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    Mantel Haenszel method
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.6244
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 5.3
    Notes
    [14] - 95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

    Secondary: Time to all-cause mortality from Week 14 post-transplant to Week 28 post-transplant

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    End point title
    		 Time to all-cause mortality from Week 14 post-transplant to Week 28 post-transplant
    End point description
    Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144 [15]
    74 [16]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [15] - 9999 means there was insufficient time to reach a median survival time.
    [16] - 9999 means there was insufficient time to reach a median survival time.
    No statistical analyses for this end point

    Secondary: Time to all-cause mortality from Week 14 post-transplant to Week 48 post-transplant

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    End point title
    		 Time to all-cause mortality from Week 14 post-transplant to Week 48 post-transplant
    End point description
    Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data. The population analyzed was all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    144 [17]
    74 [18]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [17] - 9999 means there was insufficient time to reach a median survival time.
    [18] - 9999 means there was insufficient time to reach a median survival time.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and serious.adverse events (SAEs): From 14 weeks post-transplant up to 48 weeks post-transplant (approximately 34 weeks); adverse events (AEs): From 14 weeks post-transplant up to 30 weeks post-transplant (approximately 16 weeks).
    Adverse event reporting additional description
    The population analyzed for all-cause mortality (death due to any cause) was all randomized participants. The population analyzed for AEs was all randomized participants who received at least 1 dose of study intervention according to the study intervention they received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment

    Reporting group title
    Letermovir
    Reporting group description
    		 Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

    Serious adverse events
    		 Placebo Letermovir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 74 (36.49%)
    49 / 144 (34.03%)
         number of deaths (all causes)
    8
    16
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large granular lymphocytosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    3 / 74 (4.05%)
    8 / 144 (5.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral T-cell lymphoma unspecified recurrent
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Plasma cell myeloma recurrent
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 144 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    6 / 74 (8.11%)
    9 / 144 (6.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Escherichia test positive
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombotic microangiopathy
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pure white cell aplasia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis subacute
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral haemorrhagic cystitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral toxoplasmosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 144 (2.78%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rhinovirus infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 144 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 144 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoproteinaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 144 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Letermovir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 74 (78.38%)
    100 / 144 (69.44%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 144 (2.78%)
         occurrences all number
    6
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 144 (3.47%)
         occurrences all number
    5
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 74 (5.41%)
    10 / 144 (6.94%)
         occurrences all number
    4
    11
    Dizziness
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 144 (2.08%)
         occurrences all number
    5
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 74 (4.05%)
    8 / 144 (5.56%)
         occurrences all number
    3
    9
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 74 (12.16%)
    12 / 144 (8.33%)
         occurrences all number
    13
    13
    Oedema peripheral
         subjects affected / exposed
    9 / 74 (12.16%)
    12 / 144 (8.33%)
         occurrences all number
    10
    12
    Fatigue
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 144 (3.47%)
         occurrences all number
    5
    6
    Oedema
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 144 (0.00%)
         occurrences all number
    4
    0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    22 / 74 (29.73%)
    45 / 144 (31.25%)
         occurrences all number
    34
    61
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 74 (4.05%)
    9 / 144 (6.25%)
         occurrences all number
    4
    10
    Nausea
         subjects affected / exposed
    15 / 74 (20.27%)
    17 / 144 (11.81%)
         occurrences all number
    17
    19
    Diarrhoea
         subjects affected / exposed
    11 / 74 (14.86%)
    16 / 144 (11.11%)
         occurrences all number
    12
    19
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 74 (8.11%)
    9 / 144 (6.25%)
         occurrences all number
    7
    10
    Cough
         subjects affected / exposed
    9 / 74 (12.16%)
    8 / 144 (5.56%)
         occurrences all number
    11
    8
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 74 (2.70%)
    11 / 144 (7.64%)
         occurrences all number
    3
    11
    Rash
         subjects affected / exposed
    8 / 74 (10.81%)
    9 / 144 (6.25%)
         occurrences all number
    8
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 74 (6.76%)
    6 / 144 (4.17%)
         occurrences all number
    5
    6
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 144 (2.08%)
         occurrences all number
    4
    4
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    5 / 74 (6.76%)
    6 / 144 (4.17%)
         occurrences all number
    6
    6
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 74 (6.76%)
    6 / 144 (4.17%)
         occurrences all number
    5
    7
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 144 (3.47%)
         occurrences all number
    4
    5
    Decreased appetite
         subjects affected / exposed
    11 / 74 (14.86%)
    6 / 144 (4.17%)
         occurrences all number
    13
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2019
    Amendment 01: Added the requirement that the intravenous (IV) formulation of letermovir (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.
    05 Feb 2020
    Amendment 02: Limited enrollment of participants who have anti-thymocyte globulin as the only high-risk category for CMV reactivation to =< 20% of the total trial population.

    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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