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    Clinical Trial Results:
    A Phase 3, Randomized, Adaptive Study Comparing the Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients Undergoing Hematopoietic Stem Cell Transplant

    Summary
    EudraCT number
    		 2016-002004-10
    Trial protocol
    		 ES   GB   BE   DE   FR   IT  
    Global end of trial date
    20 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 May 2021
    First version publication date
    06 May 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    15-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02851407
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 62,118
    Sponsors
    Sponsor organisation name
    Jazz Pharmaceuticals Inc.
    Sponsor organisation address
    3170 Porter Drive, Palo Alto, United States, 94304
    Public contact
    Director, Clinical Trial Disclosure & Transparency, Jazz Pharmaceuticals, Inc., +1 2158709177, ClinicalTrialDisclosure@JazzPharma.com
    Scientific contact
    Director, Clinical Trial Disclosure & Transparency, Jazz Pharmaceuticals, Inc., +1 2158709177, ClinicalTrialDisclosure@jazzpharma.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the efficacy of defibrotide vs Best Supportive Care for the prevention of Veno-Occlusive Disease (VOD) as measured by VOD-free survival by Day +30 post-hematopoietic stem cell transplant (HSCT) in participants who are at high risk or very high risk for developing VOD.
    Protection of trial subjects
    All participants provided their written informed consent or assent, as applicable, before any study-related procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    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
    Turkey: 24
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Japan: 48
    Country: Number of subjects enrolled
    New Zealand: 2
    Worldwide total number of subjects
    372
    EEA total number of subjects
    110
    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)
    34
    Children (2-11 years)
    135
    Adolescents (12-17 years)
    38
    Adults (18-64 years)
    149
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants, their parents/legal guardians, or representatives were required to sign a statement of informed consent.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Defibrotide
    Arm description
    		 Eligible participants were randomly assigned to receive Defibrotide in addition to best supportive care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Defibrotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously at a dose of 25 mg/kg/day in addition to best supportive care within 24 hours prior to the start of the first dose of the conditioning regimen and continued (for those participants without a VOD diagnosis) for a recommended minimum of 21 days and end no later than Day +30 post HSCT.

    Arm title
    		 Best Supportive Care
    Arm description
    		 Eligible participants were randomly assigned to receive best supportive care alone.
    Arm type
    		 Reference therapy

    Investigational medicinal product name
    Best Supportive Care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Best supportive care alone (without the addition of defibrotide) according to institutional guidelines and participant need, was administered on the first day of conditioning and continued until Day +30 post HSCT or hospital discharge, whichever was sooner, or diagnosis of VOD, if applicable.

    Number of subjects in period 1
    		Defibrotide Best Supportive Care
    Started
    190
    182
    Completed
    120
    121
    Not completed
    70
    61
         Adverse event, serious fatal
    6
    8
         Physician decision
    7
    6
         Enrolled in an investigational study
    -
    1
         Transferred to hospital closer to home
    -
    1
         Disease relapse
    9
    6
         Screen failure
    2
    1
         Withdrawal by parent/guardian
    2
    7
         Transferred to another hospital to continue
    1
    -
         Consent withdrawn by subject
    5
    3
         Adverse event, non-fatal
    7
    5
         Early recovery
    1
    -
         Lost to follow-up
    -
    2
         Other Death
    30
    20
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Defibrotide
    Reporting group description
    		 Eligible participants were randomly assigned to receive Defibrotide in addition to best supportive care.

    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Eligible participants were randomly assigned to receive best supportive care alone.

    Reporting group values
    		 Defibrotide Best Supportive Care Total
    Number of subjects
    		 190 182 372
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.7 ± 21.87 23.2 ± 21.73 -
    Gender categorical
    Units: Subjects
        Female
    		 90 82 172
        Male
    		 100 100 200

    End points

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    End points reporting groups
    Reporting group title
    Defibrotide
    Reporting group description
    		 Eligible participants were randomly assigned to receive Defibrotide in addition to best supportive care.

    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Eligible participants were randomly assigned to receive best supportive care alone.

    Primary: Number of Participants Experiencing Veno-occlusive Disease (VOD)-Free Survival by Day +30 Post-Hematopoietic Stem Cell Transplant (HSCT)

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    End point title
    		 Number of Participants Experiencing Veno-occlusive Disease (VOD)-Free Survival by Day +30 Post-Hematopoietic Stem Cell Transplant (HSCT)
    End point description
    End point type
    Primary
    End point timeframe
    Day +30 post-HSCT
    End point values
    		 Defibrotide Best Supportive Care
    Number of subjects analysed
    190
    182
    Units: number of participants with No VOD/Death
    112
    113
    Statistical analysis title
    		 P-value from log rank statistics
    Statistical analysis description
    P-value was calculated for the combined Stage 1 and Stage 2 log rank statistics stratified by risk status and age group using the method described by Cui, Hung, and Wang (1999).
    Comparison groups
    Best Supportive Care v Defibrotide
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8504
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Participants Experiencing VOD-Free survival by Day +100 post HSCT

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    End point title
    		 Number of Participants Experiencing VOD-Free survival by Day +100 post HSCT
    End point description
    End point type
    Secondary
    End point timeframe
    Day +100 Post-HSCT
    End point values
    		 Defibrotide Best Supportive Care
    Number of subjects analysed
    190
    182
    Units: number of participants with No VOD/Death
    74
    81
    Statistical analysis title
    		 P-value from log rank statistics
    Statistical analysis description
    Based on the pre-planned hierarchical testing strategy, the key secondary efficacy endpoint hypothesis was not evaluated because the primary endpoint was not met. P-values are nominal.
    Comparison groups
    Defibrotide v Best Supportive Care
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8156
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were reported from date of consent through the end of protocol-specific reporting period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Defibrotide
    Reporting group description
    		 Defibrotide is administered intravenously at a dose of 25 mg/kg/day in addition to best supportive care within 24 hours prior to the first dose of conditioning regimen and will continued (for those patients without a VOD diagnosis) for a recommended minimum of 21 days and end no later than Day +30 post HSCT.

    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Best supportive care alone (without the addition of defibrotide) according to institutional guidelines and patient need, is administered on the first day of conditioning and will continue until Day +30 post HSCT or hospital discharge, whichever is sooner, or diagnosis of VOD, if applicable.

    Serious adverse events
    		 Defibrotide Best Supportive Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    82 / 181 (45.30%)
    74 / 174 (42.53%)
         number of deaths (all causes)
    35
    29
         number of deaths resulting from adverse events
    22
    18
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Burkitt's lymphoma
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemia recurrent
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Air embolism
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Capillary leak syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    9 / 181 (4.97%)
    5 / 174 (2.87%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 5
         deaths causally related to treatment / all
    0 / 4
    1 / 2
    Immune system disorders
    Acute graft versus host disease in intestine
         subjects affected / exposed
    3 / 181 (1.66%)
    4 / 174 (2.30%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute graft versus host disease in liver
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute graft versus host disease in skin
         subjects affected / exposed
    4 / 181 (2.21%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         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 pulmonary oedema
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 181 (2.21%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngospasm
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 181 (3.31%)
    6 / 174 (3.45%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper airway obstruction
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus test positive
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella test positive
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Norovirus test positive
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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
    Airway complication of anaesthesia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis postoperative
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         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
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Engraft failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Headache
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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
    3 / 181 (1.66%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histiocytosis haematophagic
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    2 / 181 (1.10%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Anal inflammation
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 181 (0.00%)
    5 / 174 (2.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Pneumatosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    10 / 181 (5.52%)
    14 / 174 (8.05%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    2 / 181 (1.10%)
    4 / 174 (2.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 181 (1.66%)
    4 / 174 (2.30%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular dysfunction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    BK virus infection
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis viral
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 181 (1.10%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 181 (1.10%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 181 (0.00%)
    4 / 174 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 181 (3.31%)
    5 / 174 (2.87%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin candida
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         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 / 181 (0.55%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 174 (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
    2 / 181 (1.10%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 Defibrotide Best Supportive Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    180 / 181 (99.45%)
    174 / 174 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    71 / 181 (39.23%)
    55 / 174 (31.61%)
         occurrences all number
    92
    80
    Hypotension
         subjects affected / exposed
    28 / 181 (15.47%)
    26 / 174 (14.94%)
         occurrences all number
    30
    32
    Venoocclusive disease
         subjects affected / exposed
    8 / 181 (4.42%)
    20 / 174 (11.49%)
         occurrences all number
    8
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 181 (5.52%)
    7 / 174 (4.02%)
         occurrences all number
    11
    7
    Chills
         subjects affected / exposed
    11 / 181 (6.08%)
    14 / 174 (8.05%)
         occurrences all number
    16
    16
    Face oedema
         subjects affected / exposed
    10 / 181 (5.52%)
    12 / 174 (6.90%)
         occurrences all number
    10
    16
    Fatigue
         subjects affected / exposed
    24 / 181 (13.26%)
    23 / 174 (13.22%)
         occurrences all number
    35
    28
    Malaise
         subjects affected / exposed
    7 / 181 (3.87%)
    11 / 174 (6.32%)
         occurrences all number
    12
    16
    Oedema peripheral
         subjects affected / exposed
    27 / 181 (14.92%)
    30 / 174 (17.24%)
         occurrences all number
    33
    38
    Pain
         subjects affected / exposed
    22 / 181 (12.15%)
    19 / 174 (10.92%)
         occurrences all number
    24
    20
    Pyrexia
         subjects affected / exposed
    113 / 181 (62.43%)
    113 / 174 (64.94%)
         occurrences all number
    201
    202
    Immune system disorders
    Acute graft versus host disease in intestine
         subjects affected / exposed
    13 / 181 (7.18%)
    19 / 174 (10.92%)
         occurrences all number
    15
    19
    Acute graft versus host disease in skin
         subjects affected / exposed
    31 / 181 (17.13%)
    34 / 174 (19.54%)
         occurrences all number
    39
    41
    Engraftment syndrome
         subjects affected / exposed
    14 / 181 (7.73%)
    15 / 174 (8.62%)
         occurrences all number
    14
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 181 (13.26%)
    23 / 174 (13.22%)
         occurrences all number
    29
    26
    Dyspnoea
         subjects affected / exposed
    12 / 181 (6.63%)
    11 / 174 (6.32%)
         occurrences all number
    15
    11
    Epistaxis
         subjects affected / exposed
    41 / 181 (22.65%)
    46 / 174 (26.44%)
         occurrences all number
    52
    68
    Hypoxia
         subjects affected / exposed
    13 / 181 (7.18%)
    10 / 174 (5.75%)
         occurrences all number
    15
    10
    Nasal congestion
         subjects affected / exposed
    10 / 181 (5.52%)
    4 / 174 (2.30%)
         occurrences all number
    13
    4
    Oropharyngeal pain
         subjects affected / exposed
    20 / 181 (11.05%)
    20 / 174 (11.49%)
         occurrences all number
    21
    26
    Pleural effusion
         subjects affected / exposed
    15 / 181 (8.29%)
    7 / 174 (4.02%)
         occurrences all number
    16
    9
    Tachypnoea
         subjects affected / exposed
    10 / 181 (5.52%)
    8 / 174 (4.60%)
         occurrences all number
    10
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    14 / 181 (7.73%)
    19 / 174 (10.92%)
         occurrences all number
    14
    20
    Depression
         subjects affected / exposed
    11 / 181 (6.08%)
    3 / 174 (1.72%)
         occurrences all number
    11
    4
    Insomnia
         subjects affected / exposed
    17 / 181 (9.39%)
    31 / 174 (17.82%)
         occurrences all number
    19
    35
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    17 / 181 (9.39%)
    13 / 174 (7.47%)
         occurrences all number
    33
    33
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 181 (9.94%)
    28 / 174 (16.09%)
         occurrences all number
    31
    48
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 181 (8.29%)
    28 / 174 (16.09%)
         occurrences all number
    31
    50
    Blood bilirubin increased
         subjects affected / exposed
    26 / 181 (14.36%)
    20 / 174 (11.49%)
         occurrences all number
    61
    36
    Blood creatinine increased
         subjects affected / exposed
    10 / 181 (5.52%)
    11 / 174 (6.32%)
         occurrences all number
    25
    16
    Cytomegalovirus test positive
         subjects affected / exposed
    16 / 181 (8.84%)
    9 / 174 (5.17%)
         occurrences all number
    19
    15
    International normalised ratio increased
         subjects affected / exposed
    10 / 181 (5.52%)
    12 / 174 (6.90%)
         occurrences all number
    22
    16
    Lymphocyte count decreased
         subjects affected / exposed
    6 / 181 (3.31%)
    10 / 174 (5.75%)
         occurrences all number
    13
    24
    Neutrophil count decreased
         subjects affected / exposed
    19 / 181 (10.50%)
    25 / 174 (14.37%)
         occurrences all number
    42
    74
    Platelet count decreased
         subjects affected / exposed
    34 / 181 (18.78%)
    43 / 174 (24.71%)
         occurrences all number
    168
    161
    Weight decreased
         subjects affected / exposed
    5 / 181 (2.76%)
    11 / 174 (6.32%)
         occurrences all number
    10
    14
    Weight increased
         subjects affected / exposed
    22 / 181 (12.15%)
    17 / 174 (9.77%)
         occurrences all number
    33
    21
    White blood cell count decreased
         subjects affected / exposed
    22 / 181 (12.15%)
    17 / 174 (9.77%)
         occurrences all number
    41
    68
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    15 / 181 (8.29%)
    12 / 174 (6.90%)
         occurrences all number
    20
    16
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    37 / 181 (20.44%)
    24 / 174 (13.79%)
         occurrences all number
    47
    30
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 181 (27.62%)
    36 / 174 (20.69%)
         occurrences all number
    77
    60
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 181 (27.62%)
    52 / 174 (29.89%)
         occurrences all number
    163
    158
    Febrile neutropenia
         subjects affected / exposed
    52 / 181 (28.73%)
    59 / 174 (33.91%)
         occurrences all number
    57
    70
    Leukopenia
         subjects affected / exposed
    5 / 181 (2.76%)
    10 / 174 (5.75%)
         occurrences all number
    9
    22
    Neutropenia
         subjects affected / exposed
    31 / 181 (17.13%)
    27 / 174 (15.52%)
         occurrences all number
    52
    44
    Thrombocytopenia
         subjects affected / exposed
    31 / 181 (17.13%)
    27 / 174 (15.52%)
         occurrences all number
    56
    77
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    17 / 181 (9.39%)
    4 / 174 (2.30%)
         occurrences all number
    21
    4
    Abdominal pain
         subjects affected / exposed
    57 / 181 (31.49%)
    48 / 174 (27.59%)
         occurrences all number
    87
    70
    Abdominal pain upper
         subjects affected / exposed
    12 / 181 (6.63%)
    11 / 174 (6.32%)
         occurrences all number
    16
    11
    Constipation
         subjects affected / exposed
    40 / 181 (22.10%)
    39 / 174 (22.41%)
         occurrences all number
    44
    40
    Diarrhoea
         subjects affected / exposed
    110 / 181 (60.77%)
    108 / 174 (62.07%)
         occurrences all number
    176
    178
    Haemorrhoids
         subjects affected / exposed
    12 / 181 (6.63%)
    13 / 174 (7.47%)
         occurrences all number
    14
    15
    Nausea
         subjects affected / exposed
    109 / 181 (60.22%)
    101 / 174 (58.05%)
         occurrences all number
    166
    149
    Oral pain
         subjects affected / exposed
    13 / 181 (7.18%)
    8 / 174 (4.60%)
         occurrences all number
    14
    10
    Proctalgia
         subjects affected / exposed
    7 / 181 (3.87%)
    9 / 174 (5.17%)
         occurrences all number
    8
    11
    Stomatitis
         subjects affected / exposed
    105 / 181 (58.01%)
    114 / 174 (65.52%)
         occurrences all number
    167
    188
    Vomiting
         subjects affected / exposed
    106 / 181 (58.56%)
    91 / 174 (52.30%)
         occurrences all number
    208
    179
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    21 / 181 (11.60%)
    11 / 174 (6.32%)
         occurrences all number
    26
    13
    Erythema
         subjects affected / exposed
    13 / 181 (7.18%)
    14 / 174 (8.05%)
         occurrences all number
    15
    16
    Pruritus
         subjects affected / exposed
    13 / 181 (7.18%)
    24 / 174 (13.79%)
         occurrences all number
    14
    26
    Pruritus generalised
         subjects affected / exposed
    13 / 181 (7.18%)
    11 / 174 (6.32%)
         occurrences all number
    17
    13
    Rash
         subjects affected / exposed
    32 / 181 (17.68%)
    20 / 174 (11.49%)
         occurrences all number
    43
    26
    Rash generalised
         subjects affected / exposed
    12 / 181 (6.63%)
    6 / 174 (3.45%)
         occurrences all number
    13
    8
    Rash maculo-papular
         subjects affected / exposed
    13 / 181 (7.18%)
    12 / 174 (6.90%)
         occurrences all number
    15
    16
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 181 (4.42%)
    14 / 174 (8.05%)
         occurrences all number
    11
    18
    Haematuria
         subjects affected / exposed
    21 / 181 (11.60%)
    13 / 174 (7.47%)
         occurrences all number
    23
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 181 (3.31%)
    10 / 174 (5.75%)
         occurrences all number
    9
    11
    Back pain
         subjects affected / exposed
    18 / 181 (9.94%)
    8 / 174 (4.60%)
         occurrences all number
    20
    8
    Pain in extremity
         subjects affected / exposed
    19 / 181 (10.50%)
    15 / 174 (8.62%)
         occurrences all number
    25
    18
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    26 / 181 (14.36%)
    23 / 174 (13.22%)
         occurrences all number
    29
    24
    Cytomegalovirus viraemia
         subjects affected / exposed
    6 / 181 (3.31%)
    9 / 174 (5.17%)
         occurrences all number
    7
    9
    Device related infection
         subjects affected / exposed
    15 / 181 (8.29%)
    9 / 174 (5.17%)
         occurrences all number
    17
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    51 / 181 (28.18%)
    51 / 174 (29.31%)
         occurrences all number
    75
    72
    Fluid overload
         subjects affected / exposed
    13 / 181 (7.18%)
    8 / 174 (4.60%)
         occurrences all number
    16
    12
    Fluid retention
         subjects affected / exposed
    14 / 181 (7.73%)
    16 / 174 (9.20%)
         occurrences all number
    15
    18
    Hyperglycaemia
         subjects affected / exposed
    22 / 181 (12.15%)
    17 / 174 (9.77%)
         occurrences all number
    31
    35
    Hyperkalaemia
         subjects affected / exposed
    12 / 181 (6.63%)
    12 / 174 (6.90%)
         occurrences all number
    16
    18
    Hypoalbuminaemia
         subjects affected / exposed
    29 / 181 (16.02%)
    23 / 174 (13.22%)
         occurrences all number
    60
    55
    Hypocalcaemia
         subjects affected / exposed
    19 / 181 (10.50%)
    24 / 174 (13.79%)
         occurrences all number
    28
    48
    Hypokalaemia
         subjects affected / exposed
    75 / 181 (41.44%)
    63 / 174 (36.21%)
         occurrences all number
    114
    111
    Hypomagnesaemia
         subjects affected / exposed
    71 / 181 (39.23%)
    59 / 174 (33.91%)
         occurrences all number
    123
    123
    Hyponatraemia
         subjects affected / exposed
    17 / 181 (9.39%)
    13 / 174 (7.47%)
         occurrences all number
    24
    19
    Hypophosphataemia
         subjects affected / exposed
    20 / 181 (11.05%)
    23 / 174 (13.22%)
         occurrences all number
    34
    40

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2017
    Changes to master ICF (Version 2), Assent Form 7-9 years of age (Version 2), Assent Form 10-12 years of age (Version 2), Assent Form 13-15 years of age (Version 2), Parent Information Sheet and ICF (Version 2), Intensive Pharmacokinetic Testing Consent (Version 2). Protocol 15-007 Data Monitoring Committee (DMC) Charter (Version 2).
    24 Feb 2017
    Changes to master ICF (Version 3), Assent Form 7-9 years of age (Version 3), Assent Form 10-12 years of age (Version 3), Assent Form 13-15 years of age (Version 3), Parent Information Sheet and ICF (Version 3 and 3.1), Intensive Pharmacokinetic Testing Consent (Version 3). Protocol 15-007 Data Monitoring Committee (DMC) Charter (Version 3).
    20 Aug 2018
    Changes to master ICF (Version 4), Assent Form 7-9 years of age (Version 4), Assent Form 10-12 years of age (Version 4), Assent Form 13-15 years of age (Version 4), Parent Information Sheet and ICF (Version 4), Intensive Pharmacokinetic Testing Consent (Version 4).

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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