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    Clinical Trial Results:
    A Phase III Randomized, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-8228 (Letermovir) for the Prevention of Clinically Significant Human Cytomegalovirus (CMV) Infection in Adult, CMV Seropositive Allogeneic Hematopoietic Stem Cell Transplant Recipient

    Summary
    EudraCT number
    		 2013-003831-31
    Trial protocol
    		 SE   LT   IT   FI   AT   ES   BE   PL   GB  
    Global end of trial date
    21 Nov 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Dec 2017
    First version publication date
    19 Oct 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    8228-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02137772
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    21 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study evaluated the efficacy and safety of letermovir (MK-8228) for the prevention of clinically-significant CMV infection in adult, CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT). The hypothesis being tested was that MK-8228 is superior to placebo in the prevention of clinically-significant CMV infection through Week 24 post-transplant.
    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
    06 Jun 2014
    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
    Austria: 28
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Turkey: 36
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 203
    Country: Number of subjects enrolled
    Sweden: 20
    Worldwide total number of subjects
    570
    EEA total number of subjects
    249
    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)
    482
    From 65 to 84 years
    88
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants had documented seropositivity for CMV within 1 year before transplant. A total of 738 participants were screened, 570 were randomized 2:1 letermovir:placebo, and 565 received at least one dose of study medication.

    Pre-assignment
    Screening details
    		 Screening could occur up to 15 days before transplant and no more than 28 days post-transplant. From the time of screening to randomization, participants were tested weekly for CMV viremia; a positive test resulted in exclusion from the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Letermovir
    Arm description
    		 Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letermovir Intravenous
    Investigational medicinal product code
    Other name
    MK-8228
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Letermovir 240 mg once daily for up to 14 weeks beginning up to Day 28 post-transplant for participants receiving concomitant cyclosporin A and 480 mg once daily for 14 weeks beginning up to Day 28 post-transplant for participants not receiving cyclosporine A. IV infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets. Infusion was administered in 250 mL over 60 minutes.

    Investigational medicinal product name
    Letermovir Oral
    Investigational medicinal product code
    Other name
    MK-8228
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letermovir 240 mg once daily for up to 14 weeks beginning up to Day 28 post-transplant for participants receiving concomitant cyclosporin A and 480 mg once daily for 14 weeks beginning up to Day 28 post-transplant for participants not receiving cyclosporin A.

    Arm title
    		 Placebo
    Arm description
    		 Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Intravenous
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo once daily for up to 14 weeks beginning up to Day 28 post-transplant. IV infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets. Infusion was administered in 250 mL over 60 minutes.

    Investigational medicinal product name
    Placebo Oral
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo once daily for up to 14 weeks beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status.

    Number of subjects in period 1
    		Letermovir Placebo
    Started
    376
    194
    Treated participants
    373
    192
    Completed
    244
    119
    Not completed
    132
    75
         Adverse event, serious fatal
    71
    44
         Physician decision
    15
    5
         Consent withdrawn by subject
    28
    17
         Adverse event, non-fatal
    6
    3
         Non-compliance with study drug
    1
    -
         Lost to follow-up
    8
    4
         Not treated
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Letermovir
    Reporting group description
    		 Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Reporting group values
    		 Letermovir Placebo Total
    Number of subjects
    		 376 194 570
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 320 162 482
        From 65-84 years
    		 56 32 88
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.8 ( 13.4 ) 50.8 ( 14.8 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 162 77 239
        Male
    		 214 117 331
    Risk Stratum for CMV Reactivation
    High risk: Participants meeting one or more of the following criteria at randomization: 1) Human leukocyte antigen (HLA)-related (sibling) donor with at least one mismatch at an HLA-A, -B or -DR gene loci 2) Haploidentical donor, 3) Unrelated donor with at least one mismatch at HLA- HLA-A, -B, -C or -DRB1 gene loci 4) Use of umbilical cord blood as stem cell source, 5) Use of ex vivo T-cell-depleted grafts, 6) Grade 2 or greater graft-versus-host disease requiring the use of systemic corticosteroids. Low risk: All other participants
    Units: Subjects
        High risk
    		 122 54 176
        Low risk
    		 254 140 394

    End points

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    End points reporting groups
    Reporting group title
    Letermovir
    Reporting group description
    		 Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Primary: Percentage of Participants with Clinically-significant CMV Infection up to Week 24 Post-transplant

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    End point title
    		 Percentage of Participants with Clinically-significant CMV Infection up to Week 24 Post-transplant
    End point description
    Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed. The Full Analysis Set (FAS) was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. Participants who prematurely discontinued from the study or had a missing outcome through the 24-week visit window were considered treatment failure (i.e. Non-completers equal failure [NC=F] approach was used).
    End point type
    Primary
    End point timeframe
    Up to Week 24 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (not applicable)
    37.5
    60.6
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -23.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.5
         upper limit
    		 -14.6
    Notes
    [1] - A 1-sided p-value ≤0.0249 for the risk difference was used for declaring statistical significance

    Secondary: Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants with a Qualifying Event at Week 24 Post-transplant)

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    End point title
    		 Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants with a Qualifying Event at Week 24 Post-transplant)
    End point description
    Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically-significant CMV infection was defined from the day of transplantation to the day the participant developed clinically-significant CMV infection, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not develop clinically-significant CMV infection. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated.
    End point type
    Secondary
    End point timeframe
    Up to Week 24 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (confidence interval 95%)
    18.9 (14.4 to 23.5)
    44.3 (36.4 to 52.1)
    Statistical analysis title
    		 Log Rank
    Statistical analysis description
    The log rank test was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Nominal 2-sided p-value

    Secondary: Percentage of Participants with Clinically-significant CMV Infection up to Week 14 Post-transplant

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    End point title
    		 Percentage of Participants with Clinically-significant CMV Infection up to Week 14 Post-transplant
    End point description
    Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. Participants who prematurely discontinued from the study or had a missing outcome through the 14-week visit window were considered treatment failure (i.e. NC=F approach was used).
    End point type
    Secondary
    End point timeframe
    Up to Week 14 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (not applicable)
    19.1
    50.0
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [3]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -31.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.9
         upper limit
    		 -22.6
    Notes
    [3] - Nominal 1-sided p-value

    Secondary: Percentage of Participants with CMV End-organ Disease up to Week 24 Post-transplant

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    End point title
    		 Percentage of Participants with CMV End-organ Disease up to Week 24 Post-transplant
    End point description
    CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. A participant with a missing value was excluded from the analysis (i.e., Data as observed [DAO] approach was used).
    End point type
    Secondary
    End point timeframe
    Up to Week 24 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    254
    123
    Units: Percentage of participants
        number (not applicable)
    2.0
    2.4
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4056 [4]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 3.2
    Notes
    [4] - Nominal 1-sided p-value

    Secondary: Percentage of Participants with CMV End-organ Disease up to Week 14 Post-transplant

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    End point title
    		 Percentage of Participants with CMV End-organ Disease up to Week 14 Post-transplant
    End point description
    CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. A participant with a missing value was excluded from the analysis (i.e., DAO approach was used).
    End point type
    Secondary
    End point timeframe
    Up to Week 14 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    285
    145
    Units: Percentage of participants
        number (not applicable)
    0.4
    1.4
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2258 [5]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.5
    Notes
    [5] - Nominal 1-sided p-value

    Secondary: Percentage of Participants with Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant

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    End point title
    		 Percentage of Participants with Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant
    End point description
    Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. Participants who prematurely discontinued from the study or had a missing outcome through the 14-week visit window were considered treatment failure (i.e. NC=F approach was used).
    End point type
    Secondary
    End point timeframe
    Up to Week 14 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (not applicable)
    18.8
    49.4
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [6]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.6
         upper limit
    		 -22.4
    Notes
    [6] - Nominal 1-sided p-value

    Secondary: Percentage of Participants with Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant

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    End point title
    		 Percentage of Participants with Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant
    End point description
    Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated. Participants who prematurely discontinued from the study or had a missing outcome through the 24-week visit window were considered treatment failure (i.e. NC=F approach was used).
    End point type
    Secondary
    End point timeframe
    Up to Week 24 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (not applicable)
    36.6
    59.4
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The Mantel Haenszel analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [7]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -23.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.3
         upper limit
    		 -14.3
    Notes
    [7] - Nominal 1-sided p-value

    Secondary: Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants with a Qualifying Event at Week 24 Post-transplant)

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    End point title
    		 Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants with a Qualifying Event at Week 24 Post-transplant)
    End point description
    The need for anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The outcome was calculated from the day of transplantation to the start of anti-CMV pre-emptive therapy, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not initiate pre-emptive therapy. The FAS was all randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated.
    End point type
    Secondary
    End point timeframe
    Up to Week 24 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    325
    170
    Units: Percentage of participants
        number (confidence interval 95%)
    17.2 (12.8 to 21.6)
    42.4 (34.7 to 50.2)
    Statistical analysis title
    		 Log Rank
    Statistical analysis description
    The log rank test analysis was adjusted for sample size for each stratum (high or low risk for CMV reactivation)
    Comparison groups
    Letermovir v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [8]
    Method
    		 Logrank
    Confidence interval
    Notes
    [8] - Nominal 2-sided p-value

    Other pre-specified: Percentage of Participants with One or More Adverse Events up to Week 48 Post-transplant

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    End point title
    		 Percentage of Participants with One or More Adverse Events up to Week 48 Post-transplant
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an adverse event. The All Subjects as Treated population (ASaT) was all randomized participants who received at least one dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Up to Week 48 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    373
    192
    Units: Percentage of participants
        number (not applicable)
    98.4
    100.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants Discontinued from Study Medication Due to an Adverse Event

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    End point title
    		 Percentage of Participants Discontinued from Study Medication Due to an Adverse Event
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an adverse event. The ASaT was all randomized participants who received at least one dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Up to Week 14 post-transplant
    End point values
    		 Letermovir Placebo
    Number of subjects analysed
    373
    192
    Units: Percentage of participants
        number (not applicable)
    19.6
    51.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 48 post-transplant
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Letermovir
    Reporting group description
    		 Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

    Serious adverse events
    		 Letermovir Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    202 / 373 (54.16%)
    115 / 192 (59.90%)
         number of deaths (all causes)
    81
    47
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    6 / 373 (1.61%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Acute myeloid leukaemia
         subjects affected / exposed
    7 / 373 (1.88%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    23 / 373 (6.17%)
    17 / 192 (8.85%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 17
         deaths causally related to treatment / all
    0 / 15
    0 / 11
    B-cell lymphoma recurrent
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diffuse large B-cell lymphoma recurrent
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Mantle cell lymphoma
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Mantle cell lymphoma recurrent
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycosis fungoides
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mycosis fungoides recurrent
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 373 (0.54%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Natural killer-cell leukaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-Hodgkin's lymphoma recurrent
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma recurrent
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Primary myelofibrosis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 373 (0.54%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Pyrexia
         subjects affected / exposed
    10 / 373 (2.68%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    45 / 373 (12.06%)
    29 / 192 (15.10%)
         occurrences causally related to treatment / all
    0 / 49
    0 / 31
         deaths causally related to treatment / all
    0 / 9
    0 / 7
    Transplant rejection
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse alveolar damage
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 373 (1.88%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Tonsillar disorder
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (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
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed engraftment
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    3 / 373 (0.80%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 373 (1.88%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukopenia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 373 (1.07%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (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
    3 / 373 (0.80%)
    5 / 192 (2.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (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
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stomatitis haemorrhagic
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 373 (0.80%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 373 (0.54%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    2 / 373 (0.54%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 373 (1.88%)
    9 / 192 (4.69%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis haemorrhagic
         subjects affected / exposed
    3 / 373 (0.80%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral haemorrhagic cystitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atypical pneumonia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    BK virus infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchiolitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    4 / 373 (1.07%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cellulitis
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral toxoplasmosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium bacteraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 373 (0.80%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis viral
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    14 / 373 (3.75%)
    15 / 192 (7.81%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr viraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fusarium infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal candidiasis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site cellulitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis viral
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    15 / 373 (4.02%)
    6 / 192 (3.13%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 7
    0 / 2
    Pneumonia adenoviral
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (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
    3 / 373 (0.80%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia viral
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinitis viral
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 373 (2.14%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Septic shock
         subjects affected / exposed
    5 / 373 (1.34%)
    7 / 192 (3.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Sinusitis
         subjects affected / exposed
    4 / 373 (1.07%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    4 / 373 (1.07%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 373 (1.07%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    3 / 373 (0.80%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral haemorrhagic cystitis
         subjects affected / exposed
    3 / 373 (0.80%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gout
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactose intolerance
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tetany
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Letermovir Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    360 / 373 (96.51%)
    186 / 192 (96.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    34 / 373 (9.12%)
    23 / 192 (11.98%)
         occurrences all number
    38
    24
    Hypotension
         subjects affected / exposed
    16 / 373 (4.29%)
    11 / 192 (5.73%)
         occurrences all number
    16
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 373 (7.77%)
    9 / 192 (4.69%)
         occurrences all number
    36
    13
    Chest pain
         subjects affected / exposed
    20 / 373 (5.36%)
    5 / 192 (2.60%)
         occurrences all number
    21
    5
    Fatigue
         subjects affected / exposed
    55 / 373 (14.75%)
    26 / 192 (13.54%)
         occurrences all number
    63
    30
    Mucosal inflammation
         subjects affected / exposed
    45 / 373 (12.06%)
    24 / 192 (12.50%)
         occurrences all number
    47
    24
    Oedema peripheral
         subjects affected / exposed
    60 / 373 (16.09%)
    23 / 192 (11.98%)
         occurrences all number
    74
    27
    Pyrexia
         subjects affected / exposed
    85 / 373 (22.79%)
    50 / 192 (26.04%)
         occurrences all number
    112
    60
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    147 / 373 (39.41%)
    74 / 192 (38.54%)
         occurrences all number
    173
    91
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    62 / 373 (16.62%)
    27 / 192 (14.06%)
         occurrences all number
    70
    28
    Dyspnoea
         subjects affected / exposed
    36 / 373 (9.65%)
    9 / 192 (4.69%)
         occurrences all number
    38
    10
    Epistaxis
         subjects affected / exposed
    25 / 373 (6.70%)
    13 / 192 (6.77%)
         occurrences all number
    29
    13
    Oropharyngeal pain
         subjects affected / exposed
    32 / 373 (8.58%)
    19 / 192 (9.90%)
         occurrences all number
    34
    20
    Rhinorrhoea
         subjects affected / exposed
    15 / 373 (4.02%)
    10 / 192 (5.21%)
         occurrences all number
    18
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    23 / 373 (6.17%)
    5 / 192 (2.60%)
         occurrences all number
    23
    5
    Insomnia
         subjects affected / exposed
    35 / 373 (9.38%)
    12 / 192 (6.25%)
         occurrences all number
    37
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 373 (6.97%)
    17 / 192 (8.85%)
         occurrences all number
    31
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 373 (5.63%)
    13 / 192 (6.77%)
         occurrences all number
    24
    16
    Blood creatinine increased
         subjects affected / exposed
    39 / 373 (10.46%)
    14 / 192 (7.29%)
         occurrences all number
    43
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    29 / 373 (7.77%)
    16 / 192 (8.33%)
         occurrences all number
    30
    16
    Dysgeusia
         subjects affected / exposed
    19 / 373 (5.09%)
    10 / 192 (5.21%)
         occurrences all number
    19
    10
    Headache
         subjects affected / exposed
    58 / 373 (15.55%)
    24 / 192 (12.50%)
         occurrences all number
    68
    26
    Tremor
         subjects affected / exposed
    29 / 373 (7.77%)
    13 / 192 (6.77%)
         occurrences all number
    30
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    24 / 373 (6.43%)
    12 / 192 (6.25%)
         occurrences all number
    39
    13
    Febrile neutropenia
         subjects affected / exposed
    28 / 373 (7.51%)
    19 / 192 (9.90%)
         occurrences all number
    28
    20
    Neutropenia
         subjects affected / exposed
    18 / 373 (4.83%)
    11 / 192 (5.73%)
         occurrences all number
    20
    12
    Thrombocytopenia
         subjects affected / exposed
    27 / 373 (7.24%)
    13 / 192 (6.77%)
         occurrences all number
    32
    13
    Eye disorders
    Dry eye
         subjects affected / exposed
    24 / 373 (6.43%)
    12 / 192 (6.25%)
         occurrences all number
    24
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    49 / 373 (13.14%)
    19 / 192 (9.90%)
         occurrences all number
    53
    21
    Abdominal pain upper
         subjects affected / exposed
    23 / 373 (6.17%)
    17 / 192 (8.85%)
         occurrences all number
    30
    20
    Constipation
         subjects affected / exposed
    30 / 373 (8.04%)
    22 / 192 (11.46%)
         occurrences all number
    30
    24
    Diarrhoea
         subjects affected / exposed
    108 / 373 (28.95%)
    51 / 192 (26.56%)
         occurrences all number
    139
    64
    Dry mouth
         subjects affected / exposed
    21 / 373 (5.63%)
    11 / 192 (5.73%)
         occurrences all number
    22
    11
    Dyspepsia
         subjects affected / exposed
    21 / 373 (5.63%)
    6 / 192 (3.13%)
         occurrences all number
    22
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 373 (1.61%)
    11 / 192 (5.73%)
         occurrences all number
    6
    11
    Nausea
         subjects affected / exposed
    106 / 373 (28.42%)
    53 / 192 (27.60%)
         occurrences all number
    141
    64
    Stomatitis
         subjects affected / exposed
    24 / 373 (6.43%)
    14 / 192 (7.29%)
         occurrences all number
    25
    14
    Vomiting
         subjects affected / exposed
    79 / 373 (21.18%)
    35 / 192 (18.23%)
         occurrences all number
    93
    40
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    31 / 373 (8.31%)
    16 / 192 (8.33%)
         occurrences all number
    32
    19
    Erythema
         subjects affected / exposed
    34 / 373 (9.12%)
    12 / 192 (6.25%)
         occurrences all number
    37
    13
    Pruritus
         subjects affected / exposed
    31 / 373 (8.31%)
    12 / 192 (6.25%)
         occurrences all number
    35
    14
    Rash
         subjects affected / exposed
    90 / 373 (24.13%)
    51 / 192 (26.56%)
         occurrences all number
    109
    62
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    35 / 373 (9.38%)
    22 / 192 (11.46%)
         occurrences all number
    37
    25
    Dysuria
         subjects affected / exposed
    17 / 373 (4.56%)
    11 / 192 (5.73%)
         occurrences all number
    17
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 373 (8.04%)
    15 / 192 (7.81%)
         occurrences all number
    31
    18
    Back pain
         subjects affected / exposed
    24 / 373 (6.43%)
    20 / 192 (10.42%)
         occurrences all number
    26
    22
    Muscle spasms
         subjects affected / exposed
    12 / 373 (3.22%)
    10 / 192 (5.21%)
         occurrences all number
    13
    12
    Myalgia
         subjects affected / exposed
    21 / 373 (5.63%)
    4 / 192 (2.08%)
         occurrences all number
    21
    4
    Pain in extremity
         subjects affected / exposed
    20 / 373 (5.36%)
    16 / 192 (8.33%)
         occurrences all number
    24
    17
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    21 / 373 (5.63%)
    4 / 192 (2.08%)
         occurrences all number
    24
    5
    Cytomegalovirus infection
         subjects affected / exposed
    55 / 373 (14.75%)
    77 / 192 (40.10%)
         occurrences all number
    65
    93
    Nasopharyngitis
         subjects affected / exposed
    19 / 373 (5.09%)
    8 / 192 (4.17%)
         occurrences all number
    22
    8
    Viraemia
         subjects affected / exposed
    12 / 373 (3.22%)
    12 / 192 (6.25%)
         occurrences all number
    12
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    43 / 373 (11.53%)
    26 / 192 (13.54%)
         occurrences all number
    48
    26
    Hyperglycaemia
         subjects affected / exposed
    31 / 373 (8.31%)
    13 / 192 (6.77%)
         occurrences all number
    31
    14
    Hyperkalaemia
         subjects affected / exposed
    28 / 373 (7.51%)
    5 / 192 (2.60%)
         occurrences all number
    29
    5
    Hypokalaemia
         subjects affected / exposed
    23 / 373 (6.17%)
    12 / 192 (6.25%)
         occurrences all number
    25
    13
    Hypomagnesaemia
         subjects affected / exposed
    24 / 373 (6.43%)
    15 / 192 (7.81%)
         occurrences all number
    24
    16
    Hyponatraemia
         subjects affected / exposed
    23 / 373 (6.17%)
    10 / 192 (5.21%)
         occurrences all number
    24
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2014
    Amendment 001: Changes to plasma collection times, clarification that plasma sampling for CMV DNA polymerase chain reaction (PCR) testing was to be confirmatory, change to definition of documented viremia on a confirmatory sample, and revision of guidance regarding viral load threshold for initiation of pre-emptive therapy.
    01 Sep 2014
    Amendment 002: Added an exclusion criterion to define and exclude participants of Asian descent, change to allow a participant to reinitiate protocol-defined study therapy under the instance where the confirmatory central laboratory test result for CMV DNA PCR obtained on the day of pre-emptive therapy initiation is negative and pre-emptive therapy is stopped.
    16 Mar 2015
    Amendment 003: Addition of a 480-mg oral tablet formulation of letermovir, and removal of the exclusion criterion that excluded participants of Asian descent.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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