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    Clinical Trial Results:
    Clinical phase 2 trial to compare treosulfan-based conditioning therapy with busulfan-based conditioning prior to allogeneic haematopoietic stem cell transplantation (HSCT) in paediatric patients with non-malignant diseases.

    Summary
    EudraCT number
    2013-005508-33
    Trial protocol
    DE   AT   CZ   PL   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Apr 2022
    First version publication date
    03 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MC-FludT.16/NM
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02349906
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    medac Gesellschaft fuer klinische Spezialpraeparate mbH
    Sponsor organisation address
    Theaterstrasse 6, Wedel, Germany, 22880
    Public contact
    Dr Jochen Kehne, medac Gesellschaft fuer klinische Spezialpräparate mbH, 0049 41038006388, j.kehne@medac.de
    Scientific contact
    Medical Expert, medac Gesellschaft fuer klinische Spezialpräparate mbH, 0049 410380060, medwiss@medac.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000088-PIP01-10
    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
    Interim
    Date of interim/final analysis
    07 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 May 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial was to describe the safety and efficacy of i.v. treosulfan compared to the conventional (myeloablative) dose of i.v. busulfan, each administered as part of a standardised fludarabine-containing conditioning regimen and to contribute to a PK model, which permits - in conjunction with data comparing treosulfan and busulfan in adults with malignant diseases - to extend the use of treosulfan in the paediatric population by extrapolating efficacy The primary objective of this trial was the comparative evaluation of freedom from transplantation (treatment)-related mortality, defined as death from any transplantation (treatment)-related cause from start of conditioning treatment (visit Day -7) until day +100 after HSCT.
    Protection of trial subjects
    The study was conducted in accordance with ICH GCP guidelines, applicable local laws and in compliance with the ethical principles originating in the Declaration of Helsinki. Regulatory authorities were informed of the study and amendments in accordance with national regulations and, where necessary, the appropriate approval was obtained. Due to the life-threatening diseases to be treated, an independent Data Monitoring Committee (DMC) was set up. All available safety and efficacy data were subjected to thorough review.
    Background therapy
    This trial allowed administration of 2 different background conditioning regimens in addition to treosulfan or busulfan: one background conditioning regimen consisted of an intensified fludarabine-containing regimen with additional thiotepa (Stratum A) whereas the other consisted of the standard regimen with fludarabine only (Stratum B). Other concomitant medication could be administered according to the hospital practice.
    Evidence for comparator
    Busilvex® (i.v. busulfan) was selected as reference regimen within this trial. This reference treatment regimen was confirmed by EMA. The drug is registered in Europe for conditioning treatment prior to conventional haematopoietic progenitor cell Transplantation.
    Actual start date of recruitment
    20 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Regulatory reason
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Italy: 22
    Worldwide total number of subjects
    106
    EEA total number of subjects
    106
    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)
    29
    Children (2-11 years)
    61
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    106 subjects were enrolled at 18 sites in 4 countries. The first subject was enrolled in the study on 20 April 2015.

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the study to ensure that all subjects met all inclusion and exclusion criteria. A total of 106 subjects were randomised of which 101 subjects received Investigational medicinal product (IMP) and were included in the efficacy and safety analyses.

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Due to the different treatment schedules of the test arm (treosulfan) and the reference arm (busulfan) with regard to the different infusion regimens, blinding of the IMP was not considered feasible within the orphan indication of paediatric subjects with a non-malignant indication for allogeneic HSCT.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Busulfan
    Arm description
    This arm comprises all subjects randomised to Busulfan.
    Arm type
    Active comparator

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilvex
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan was administered i.v. on 4 consecutive days (days -7, -6, -5, and -4) prior to Hematopoietic stem-cell transplantation (HSCT) (day 0). Busulfan was to be infused in accordance with the respective hospital standard, ie, 1, 2, or 4 times daily. The required total dose was calculated on basis of the actual body weight based on the summary of product characteristics (SmPC).

    Arm title
    Treosulfan
    Arm description
    This arm comprises all subjects randomised to Treosulfan.
    Arm type
    Experimental

    Investigational medicinal product name
    Treosulfan
    Investigational medicinal product code
    Other name
    Trecondi
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan was administered i.v. over 2 hours on 3 consecutive days (days -6, -5, and -4) prior to HSCT (day 0). The required total dose of treosulfan was calculated on basis of the subject’s body surface area (BSA).

    Number of subjects in period 1
    Busulfan Treosulfan
    Started
    54
    52
    Completed
    50
    51
    Not completed
    4
    1
         Withdrawal prior to start of treatment with IMP
    4
    1
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    Yes [1]
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Busulfan
    Arm description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to busulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).
    Arm type
    Active comparator

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilvex
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan was administered i.v. on 4 consecutive days (days -7, -6, -5, and -4) prior to Hematopoietic stem-cell transplantation (HSCT) (day 0). Busulfan was to be infused in accordance with the respective hospital standard, ie, 1, 2, or 4 times daily. The required total dose was calculated on basis of the actual body weight based on the summary of product characteristics (SmPC) for Busilvex.

    Arm title
    Treosulfan
    Arm description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to treosulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).
    Arm type
    Experimental

    Investigational medicinal product name
    Treosulfan
    Investigational medicinal product code
    Other name
    Trecondi
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan was administered i.v. over 2 hours on 3 consecutive days (days -6, -5, and -4) prior to HSCT (day 0). The required total dose of treosulfan was calculated on basis of the subject’s body surface area (BSA).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: To be able to document the reason for "not complete" between randomization and treatment for both treatment arms separately, an additional pretreatment (“Randomization”) period was created.
    Number of subjects in period 2 [2]
    Busulfan Treosulfan
    Started
    50
    51
    Completed
    43
    47
    Not completed
    7
    4
         Death
    7
    2
         Lost to follow-up
    -
    2
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects in the baseline period is based on the subjects treated (Full Analysis set).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Busulfan
    Reporting group description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to busulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).

    Reporting group title
    Treosulfan
    Reporting group description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to treosulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).

    Reporting group values
    Busulfan Treosulfan Total
    Number of subjects
    50 51 101
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    14 14 28
        Children (2-11 years)
    26 31 57
        Adolescents (12-17 years)
    10 6 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.0 ± 5.3 5.0 ± 4.4 -
    Gender categorical
    Units: Subjects
        Female
    19 15 34
        Male
    31 36 67
    Summary of trial disease characteristics
    Units: Subjects
        Primary immunodeficiencies
    28 23 51
        Inborn errors metabolism
    4 2 6
        Hemoglobinopathies
    13 21 34
        Bone marrow failure syndromes
    5 5 10
    Donor type
    Units: Subjects
        Matched sibling donor (MSD)
    12 9 21
        Matched family donor (MFD)
    5 5 10
        Matched unrelated donor (MUD)
    32 36 68
        Umbilical cord blood (UCB)
    1 1 2
    Body surface area
    Units: square meter
        arithmetic mean (standard deviation)
    0.836 ± 0.396 0.746 ± 0.297 -

    End points

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    End points reporting groups
    Reporting group title
    Busulfan
    Reporting group description
    This arm comprises all subjects randomised to Busulfan.

    Reporting group title
    Treosulfan
    Reporting group description
    This arm comprises all subjects randomised to Treosulfan.
    Reporting group title
    Busulfan
    Reporting group description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to busulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).

    Reporting group title
    Treosulfan
    Reporting group description
    This arm is equal to the Full Analysis Set (FAS) and includes all subjects randomised to treosulfan who received at least one dose of the IMP and with at least one documented efficacy parameter. The subjects within the FAS were analysed in their initial arm of randomisation (intention to treat principle).

    Subject analysis set title
    Treosulfan Pharmacokinetic Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pooled analysis of MC FludT16/NM and MC FludT.17/M. The PK Set included all subjects of the FAS with any treosulfan concentration measurements.

    Primary: Freedom from transplantation (treatment)-related mortality - Number

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    End point title
    Freedom from transplantation (treatment)-related mortality - Number [1]
    End point description
    Freedom from transplantation (treatment)-related mortality, defined as death from any transplantation (treatment)-related cause from start of conditioning treatment (visit Day -7) until day +100 after HSCT. The associated time span of transplantation-related mortality was defined as the interval from end of HSCT to death due to transplantation-related cause whereas the time span of treatment-related mortality was defined as interval from start of conditioning treatment, ie, visit Day -7, until end of HSCT.
    End point type
    Primary
    End point timeframe
    Until day +100 after HSCT
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The data analysis is descriptive in nature. No specific confirmatory statistical hypotheses are specified.
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: Subjects
        With event
    5
    0
        Without event
    45
    51
    No statistical analyses for this end point

    Primary: Freedom from transplantation (treatment)-related mortality - Incidence

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    End point title
    Freedom from transplantation (treatment)-related mortality - Incidence
    End point description
    Incidence of freedom from transplantation (treatment)-related mortality, defined as death from any transplantation (treatment)-related cause from start of conditioning treatment (visit Day -7) until day +100 after HSCT. The associated time span of transplantation-related mortality was defined as the interval from end of HSCT to death due to transplantation-related cause whereas the time span of treatment-related mortality was defined as interval from start of conditioning treatment, ie, visit Day -7, until end of HSCT.
    End point type
    Primary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
        number (confidence interval 90%)
    90.0 (80.1 to 96.0)
    100.0 (94.3 to 100.0)
    Statistical analysis title
    Diff. incidences
    Comparison groups
    Busulfan v Treosulfan
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0528
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -10
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -19.9
         upper limit
    -3.4

    Secondary: Engraftment - reconstitution of granulopoiesis

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    End point title
    Engraftment - reconstitution of granulopoiesis
    End point description
    Neutrophilic granulocytes engraftment was assessed by reconstitution of granulopoiesis. Engraftment was defined as the first of 3 consecutive days with an absolute neutrophilic granulocytes count of more than 0.5 x10^9/L. The term “consecutive days” was defined as 3 consecutive blood samples if taken on different days. The date of reaching engraftment was the documented “date of engraftment”. Death from any cause, relapse/progression or use of rescue therapies until the date of primary graft failure or documentation of engraftment status (whatever occurred first) were competing events. The maximum conditional cumulative incidence is reported.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
        number (confidence interval 90%)
    100.0 (94.1 to 100.0)
    97.3 (88.7 to 100.0)
    No statistical analyses for this end point

    Secondary: Engraftment - reconstitution of leukopoiesis

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    End point title
    Engraftment - reconstitution of leukopoiesis
    End point description
    Leukocyte engraftment was assessed by reconstitution of leukopoiesis. Engraftment was defined as the first of 3 consecutive days with a total leucocyte of more than 1 x 10^9/L. The term “consecutive days” was defined as 3 consecutive blood samples if taken on different days. The date of reaching engraftment was the documented “date of engraftment”. Death from any cause, relapse/progression or use of rescue therapies until the date of primary graft failure or documentation of engraftment status (whatever occurred first) were competing events. The maximum conditional cumulative incidence is reported.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
        number (confidence interval 90%)
    100.0 (94.1 to 100.0)
    96.8 (87.1 to 100.0)
    No statistical analyses for this end point

    Secondary: Engraftment - reconstitution of thrombopoiesis > 20 x10^9/L

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    End point title
    Engraftment - reconstitution of thrombopoiesis > 20 x10^9/L
    End point description
    Platelet (PLT) engraftment was assessed by reconstitution of thrombopoiesis. Engraftment was defined as the first of 3 consecutive days with PLT count of at least 20 x10^9/L in the absence of PLT transfusion. The term “consecutive days” was defined as 3 consecutive blood samples if taken on different days. The date of reaching engraftment was the documented “date of engraftment”. Death from any cause, relapse/progression or use of rescue therapies until the date of primary graft failure or documentation of engraftment status (whatever occurred first) were competing events. The maximum conditional cumulative incidence is reported.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
        number (confidence interval 90%)
    96.8 (86.6 to 100.0)
    100.0 (93.8 to 100.0)
    No statistical analyses for this end point

    Secondary: Engraftment - reconstitution of thrombopoiesis > 50 x10^9/L

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    End point title
    Engraftment - reconstitution of thrombopoiesis > 50 x10^9/L
    End point description
    Platelet (PLT) engraftment was assessed by reconstitution of thrombopoiesis. Engraftment was defined as the first of 3 consecutive days with PLT count of at least 50 x10^9/L in the absence of PLT transfusion. The term “consecutive days” was defined as 3 consecutive blood samples if taken on different days. The date of reaching engraftment was the documented “date of engraftment”. Death from any cause, relapse/progression or use of rescue therapies until the date of primary graft failure or documentation of engraftment status (whatever occurred first) were competing events. The maximum conditional cumulative incidence is reported.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
        number (confidence interval 90%)
    97.1 (87.9 to 100.0)
    94.8 (86.3 to 100.0)
    No statistical analyses for this end point

    Secondary: HSOS, lung toxicity, hepatic toxicity, early toxicity (until day +28) and infections of any CTCAE grade

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    End point title
    HSOS, lung toxicity, hepatic toxicity, early toxicity (until day +28) and infections of any CTCAE grade
    End point description
    Incidence of all treatment emergent significant adverse events. Evaluation of hepatic sinusoidal obstruction syndrome (“HSOS”, according to Jones et al), “Lung toxicity” (CTCAE term “Pulmonary fibrosis”), “Hepatic toxicity” (according to Bearman’s criteria), Early toxicity defined as any AE occurring until day +28 and “Infections of any CTCAE grade” (non-serious and serious) until day +100.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        HSOS according to Jones (1987)
    10.0 (4.0 to 19.9)
    2.0 (0.1 to 9.0)
        Early toxicity (any AE occurring until day +28)
    96.0 (87.9 to 99.3)
    94.1 (85.5 to 98.4)
        Hepatic toxicity according to Bearman (1988)
    54.0 (41.5 to 66.2)
    51.0 (38.7 to 63.2)
        Lung toxicity (CTCAE term "Pulmonary fibrosis")
    0.0 (0.0 to 5.8)
    0.0 (0.0 to 5.7)
        Infections (SOC "Infections and infestations")
    70.0 (57.6 to 80.5)
    60.8 (48.3 to 72.3)
    No statistical analyses for this end point

    Secondary: Incidence of complete donor type chimerism

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    End point title
    Incidence of complete donor type chimerism
    End point description
    Evaluation of donor-type chimerism on day +28, day +100, and 12 months after HSCT. Chimerism was analysed in Peripheral blood or Bone marrow samples at visits Day +28, Day +100, Month 12. Complete donor-type chimerism was defined if a value of >= 95% was detected. The incidences of complete donor-type chimerism were estimated as the number of subjects with complete chimerism divided by the total number of subjects at risk.
    End point type
    Secondary
    End point timeframe
    28 days, 100 days and 12 months after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50 [2]
    51 [3]
    Units: percent
    number (confidence interval 90%)
        Day +28
    82.0 (70.7 to 90.3)
    84.3 (73.5 to 91.9)
        Day +100
    84.8 (73.3 to 92.6)
    66.7 (54.3 to 77.5)
        Month 12
    76.7 (63.8 to 86.8)
    49.0 (36.5 to 61.5)
    Notes
    [2] - Subjects at risk: Day +28 = 50 Day +100 = 46 Month 12 = 43
    [3] - Subjects at risk: Day +28 = 51 Day +100 = 51 Month 12 = 49
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival (OS) after HSCT was defined as the probability of surviving. Survival time was defined as the time period between end of HSCT and the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    12, 24 and 36 months after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        Month 12
    88.0 (77.9 to 93.7)
    96.1 (88.0 to 98.8)
        Month 24
    88.0 (77.9 to 93.7)
    96.1 (88.0 to 98.8)
        Month 36
    84.0 (71.4 to 91.4)
    96.1 (88.0 to 98.8)
    No statistical analyses for this end point

    Secondary: Incidence of graft failure

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    End point title
    Incidence of graft failure
    End point description
    The incidence of graft failure was defined as the probability of having a graft failure (primary or secondary) and being alive without using “stem cell infusion (re-transplant) with conditioning” rescue therapy (ie, second allogenic transplantations) between the end of HSCT and the end of the longer term follow up phase. The associated time span was defined as the interval from day 0 to graft failure.
    End point type
    Secondary
    End point timeframe
    12, 24 and 36 months after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        Month 12
    4.0 (0.0 to 8.6)
    15.8 (7.4 to 24.3)
        Month 24
    4.0 (0.0 to 8.6)
    21.0 (11.2 to 30.9)
        Month 36
    4.0 (0.0 to 8.6)
    24.8 (13.6 to 35.9)
    No statistical analyses for this end point

    Secondary: Acute GvHD grade I-IV - number

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    End point title
    Acute GvHD grade I-IV - number
    End point description
    Acute graft versus host disease of grades I to IV - number of subjects with and without event. Time to aGvHD was defined as the time between end of HSCT and the date of first occurrence of aGvHD. Subjects alive with no occurrence of aGvHD at 100 days after end of HSCT and no competing event were censored. Death and graft failure within 100 days after HSCT were competing events.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: Subjects
        With event
    21
    28
        Without event
    29
    23
    No statistical analyses for this end point

    Secondary: Acute GvHD grade I-IV - cumulative incidence

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    End point title
    Acute GvHD grade I-IV - cumulative incidence
    End point description
    Acute graft versus host disease of grades I to IV - cumulative incidence. Time to aGvHD was defined as the time between end of HSCT and the date of first occurrence of aGvHD. Subjects alive with no occurrence of aGvHD at 100 days after end of HSCT and no competing event were censored. Death and graft failure within 100 days after HSCT were competing events.
    End point type
    Secondary
    End point timeframe
    14, 28 and 100 days after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        Day 14
    2.0 (0.0 to 5.3)
    13.7 (5.8 to 21.7)
        Day 28
    30.0 (19.3 to 40.7)
    37.3 (26.1 to 48.4)
        Day 100
    42.0 (30.5 to 53.5)
    54.9 (43.4 to 66.4)
    No statistical analyses for this end point

    Secondary: Acute GvHD grade III-IV - number

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    End point title
    Acute GvHD grade III-IV - number
    End point description
    Acute graft versus host disease of grades III to IV - number of subjects with and without Event. Time to aGvHD was defined as the time between end of HSCT and the date of first occurrence of aGvHD. Subjects alive with no occurrence of aGvHD at 100 days after end of HSCT and no competing event were censored. Death and graft failure within 100 days after HSCT were competing events.
    End point type
    Secondary
    End point timeframe
    Until day +100 after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: subjects
        With event
    4
    7
        Without event
    46
    44
    No statistical analyses for this end point

    Secondary: Acute GvHD grade III-IV - cumulative incidence

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    End point title
    Acute GvHD grade III-IV - cumulative incidence
    End point description
    Acute graft versus host disease of grades III to IV - cumulative incidence. Time to acute GvHD (aGvHD) was defined as the time between end of HSCT and the date of first occurrence of acute GvHD. Death, relapse/progression and graft failure within 100 days after end of HSCT were competing events.
    End point type
    Secondary
    End point timeframe
    14, 28 and 100 days after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        Day 14
    2.0 (0.0 to 5.3)
    2.0 (0.0 to 5.2)
        Day 28
    4.0 (0.0 to 8.6)
    2.0 (0.0 to 5.2)
        Day 100
    8.0 (1.7 to 14.3)
    13.7 (5.8 to 21.7)
    No statistical analyses for this end point

    Secondary: Overall chronic GvHD - number

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    End point title
    Overall chronic GvHD - number
    End point description
    Overall chronic graft versus host disease - number of subjects with and without event. Chronic GvHD was evaluated from 100 days after transplantation until the end of the longer term follow-up. Time to cGvHD was defined as the time between 100 days after end of HSCT and the first episode of cGvHD. Subjects were at risk (evaluable) for cGvHD if they had survived graft failure-free until 100 days after end of HSCT. In addition, subjects with premature trial termination at visit Day +100 were excluded from the risk set. Subjects alive with no cGvHD at the last follow-up were censored. Death and graft failure were competing events.
    End point type
    Secondary
    End point timeframe
    From day +100 to last follow-up visit
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    44
    47
    Units: subjects
        With event
    17
    6
        Without event
    27
    41
    No statistical analyses for this end point

    Secondary: Overall chronic GvHD - cumulative incidence

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    End point title
    Overall chronic GvHD - cumulative incidence
    End point description
    Overall chronic graft versus host disease - cumulative incidence Chronic GvHD was evaluated from 100 days after transplantation until the end of the longer term follow-up. Time to cGvHD was defined as the time between 100 days after end of HSCT and the first episode of cGvHD. Subjects were at risk (evaluable) for cGvHD if they had survived graft failure-free until 100 days after end of HSCT. In addition, subjects with premature trial termination at visit Day +100 were excluded from the risk set. Subjects alive with no cGvHD at the last follow-up were censored. Death and graft failure were competing events
    End point type
    Secondary
    End point timeframe
    12, 24 and 36 months after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    44
    47
    Units: percent
    number (confidence interval 90%)
        Month 12
    38.6 (26.6 to 50.7)
    12.8 (4.8 to 20.8)
        Month 24
    38.6 (26.6 to 50.7)
    12.8 (4.8 to 20.8)
        Month 36
    38.6 (26.6 to 50.7)
    12.8 (4.8 to 20.8)
    No statistical analyses for this end point

    Secondary: Moderate/severe chronic GvHD - number

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    End point title
    Moderate/severe chronic GvHD - number
    End point description
    Moderate/severe chronic graft versus host disease - number of subjects with and without event. Chronic GvHD was evaluated from 100 days after transplantation until the end of the longer term follow-up. Time to cGvHD was defined as the time between 100 days after end of HSCT and the first episode of cGvHD. Subjects were at risk (evaluable) for cGvHD if they had survived graft failure-free until 100 days after end of HSCT. In addition, subjects with premature trial termination at visit Day +100 were excluded from the risk set. Subjects alive with no cGvHD at the last follow-up were censored. Death and graft failure were competing events
    End point type
    Secondary
    End point timeframe
    From day +100 to last follow-up visit
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    44
    47
    Units: subjects
        With event
    10
    5
        Without event
    34
    42
    No statistical analyses for this end point

    Secondary: Moderate/severe chronic GvHD - cumulative incidence

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    End point title
    Moderate/severe chronic GvHD - cumulative incidence
    End point description
    Moderate or severe chronic graft versus host disease - cumulative incidence. Chronic GvHD was evaluated from 100 days after transplantation until the end of the longer term follow-up. Time to cGvHD was defined as the time between 100 days after end of HSCT and the first episode of cGvHD. Subjects were at risk (evaluable) for cGvHD if they had survived graft failure-free until 100 days after end of HSCT. In addition, subjects with premature trial termination at visit Day +100 were excluded from the risk set. Subjects alive with no cGvHD at the last follow-up were censored. Death and graft failure were competing events.
    End point type
    Secondary
    End point timeframe
    12, 24 and 36 months after HSCT
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    44
    47
    Units: percent
    number (confidence interval 90%)
        Month 12
    22.7 (12.3 to 33.1)
    10.6 (3.2 to 18.0)
        Month 24
    22.7 (12.3 to 33.1)
    10.6 (3.2 to 18.0)
        Month 36
    22.7 (12.3 to 33.1)
    10.6 (3.2 to 18.0)
    No statistical analyses for this end point

    Secondary: Use of rescue therapies

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    End point title
    Use of rescue therapies
    End point description
    Rescue therapies, cell therapies given in order to treat acute graft failure or relapse of the underlying disease were to be documented as rescue therapies. These included unfractionated or fractionated (eg, allo-depleted or T-cell receptor alpha-beta depleted) donor lymphocyte infusions (DLI) and stem cell infusions (SCI) with or without further conditioning regimens. Re-occurrence of transfusion dependence for red blood cells or PLT was to be documented as rescue therapy.
    End point type
    Secondary
    End point timeframe
    Visit Day 0 (end of HSCT) until the end of the longer term follow up phase.
    End point values
    Busulfan Treosulfan
    Number of subjects analysed
    50
    51
    Units: percent
    number (confidence interval 90%)
        Any rescue therapy
    42.0 (30.1 to 54.6)
    41.2 (29.5 to 53.7)
        DLIs
    4.0 (0.7 to 12.1)
    9.8 (3.9 to 19.5)
        Stem cell boost
    2.0 (0.1 to 9.1)
    3.9 (0.7 to 11.8)
        SCI (re-transplant) with conditioning
    2.0 (0.1 to 9.1)
    0.0 (0.0 to 5.7)
        SCI (re-transplant) without conditioning
    0.0 (0.0 to 5.8)
    0.0 (0.0 to 5.7)
        Transfusion dependence for red blood cells
    34.0 (23.0 to 46.5)
    33.3 (22.5 to 45.7)
        Transfusion dependence for platelets
    28.0 (17.8 to 40.3)
    27.5 (17.4 to 39.5)
        Other rescue therapies
    4.0 (0.7 to 12.1)
    7.8 (2.7 to 17.1)
    No statistical analyses for this end point

    Secondary: PK result _ t1/2term

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    End point title
    PK result _ t1/2term
    End point description
    Pooled analysis of MC FludT16/NM and MC FludT.17/M. Pharmacokinetic Parameter t1/2term = apparent terminal elimination half-life. Analysis of PK parameters was performed in a subset of subjects treated with treosulfan. The calculation of individual treosulfan dose was adapted to the subject’s BSA group.
    End point type
    Secondary
    End point timeframe
    PK samples were taken on day -6 (first day of treatment with treosulfan) at 5 predefined different time points between +/- 5 minutes and 7-8 hours after the end of the infusion.
    End point values
    Treosulfan Pharmacokinetic Set
    Number of subjects analysed
    82 [4]
    Units: hour
    geometric mean (standard deviation)
        BSA group ≤ 0.5 m² (10 g/m² dose group)
    1.27 ± 0.178
        BSA group > 0.5 - ≤ 1.0 m² (12 g/m² dose group)
    1.40 ± 0.173
        BSA group > 1.0 m² (14 g/m² dose group)
    1.58 ± 0.178
    Notes
    [4] - BSA group ≤ 0.5 m²: N = 16 BSA group > 0.5 - ≤ 1.0 m²: N =37 BSA group > 1.0 m²: N = 29
    No statistical analyses for this end point

    Secondary: PK result _ AUC infinity

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    End point title
    PK result _ AUC infinity
    End point description
    Pooled analysis of MC FludT16/NM and MC FludT.17/M. Pharmacokinetic Parameter AUC infinity = AUC from time 0 to infinite time. Analysis of PK parameters was performed in a subset of subjects treated with treosulfan. The calculation of individual treosulfan dose was adapted to the subject’s BSA group.
    End point type
    Secondary
    End point timeframe
    PK samples were taken on day -6 (first day of treatment with treosulfan) at 5 predefined different time points between +/- 5 minutes and 7-8 hours after the end of the infusion.
    End point values
    Treosulfan Pharmacokinetic Set
    Number of subjects analysed
    81 [5]
    Units: μg.h/mL
    geometric mean (standard deviation)
        BSA group ≤ 0.5 m² (10 g/m² dose group)
    1570 ± 482
        BSA group > 0.5 - ≤ 1.0 m² (12 g/m² dose group)
    1672 ± 401
        BSA group > 1.0 m² (14 g/m² dose group)
    1903 ± 310
    Notes
    [5] - BSA group ≤ 0.5 m²: N = 15 BSA group > 0.5 - ≤ 1.0 m²: N =37 BSA group > 1.0 m²: N = 29
    No statistical analyses for this end point

    Other pre-specified: PK result _ Cmax

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    End point title
    PK result _ Cmax
    End point description
    Pooled analysis of MC FludT16/NM and MC FludT.17/M. Pharmacokinetic Parameter Cmax = the maximum observed plasma concentration. Analysis of PK parameters was performed in a subset of subjects treated with treosulfan. The calculation of individual treosulfan dose was adapted to the subject’s BSA group.
    End point type
    Other pre-specified
    End point timeframe
    PK samples were taken on day -6 (first day of treatment with treosulfan) at 5 predefined different time points between +/- 5 minutes and 7-8 hours after the end of the infusion.
    End point values
    Treosulfan Pharmacokinetic Set
    Number of subjects analysed
    82 [6]
    Units: μg/mL
    geometric mean (standard deviation)
        BSA group ≤ 0.5 m² (10 g/m² dose group)
    608 ± 209
        BSA group > 0.5 - ≤ 1.0 m² (12 g/m² dose group)
    662 ± 286
        BSA group > 1.0 m² (14 g/m² dose group)
    652 ± 111
    Notes
    [6] - BSA group ≤ 0.5 m²: N = 15 BSA group > 0.5 - ≤ 1.0 m²: N =38 BSA group > 1.0 m²: N = 29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AE (serious and non serious) occurring between day -7 and day +100 after HSCT were to be reported. Thereafter, only SAE with suspected relatedness (SAR) were to be reported until the end of longer-term follow-up phase.
    Adverse event reporting additional description
    Adverse event reporting was based on the Safety Analysis Set. This includes all subjects enrolled in the trial who have received at least one dose of IMP. All subjects were analysed within their arm of actual treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Busulfan - Safety Analysis Set
    Reporting group description
    This arm comprises all subjects who were randomised to Busulfan and received at least one dose of IMP.

    Reporting group title
    Treosulfan - Safety Analysis Set
    Reporting group description
    This arm comprises all subjects randomised to treosulfan who received at least one dose of the IMP.

    Serious adverse events
    Busulfan - Safety Analysis Set Treosulfan - Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 50 (32.00%)
    18 / 51 (35.29%)
         number of deaths (all causes)
    7
    2
         number of deaths resulting from adverse events
    4
    0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications - Other, specify
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations - Other, specify
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorders - Other, specify
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         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
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders - Other, specify
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders - Other, specify
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 50 (0.00%)
    6 / 51 (11.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 51 (9.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Busulfan - Safety Analysis Set Treosulfan - Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 50 (96.00%)
    49 / 51 (96.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 50 (36.00%)
    19 / 51 (37.25%)
         occurrences all number
    29
    20
    Hematoma
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 51 (5.88%)
         occurrences all number
    8
    4
    Hypotension
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    6
    3
    Capillary leak syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    36 / 50 (72.00%)
    36 / 51 (70.59%)
         occurrences all number
    71
    58
    Infusion related reaction
         subjects affected / exposed
    6 / 50 (12.00%)
    9 / 51 (17.65%)
         occurrences all number
    11
    11
    Chills
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 51 (13.73%)
         occurrences all number
    3
    7
    Localized edema
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 51 (7.84%)
         occurrences all number
    4
    6
    Fatigue
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 51 (5.88%)
         occurrences all number
    8
    3
    Pain
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 51 (7.84%)
         occurrences all number
    7
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 50 (20.00%)
    8 / 51 (15.69%)
         occurrences all number
    13
    9
    Investigations - Other, specify
         subjects affected / exposed
    4 / 50 (8.00%)
    8 / 51 (15.69%)
         occurrences all number
    5
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 51 (7.84%)
         occurrences all number
    9
    6
    GGT increased
         subjects affected / exposed
    6 / 50 (12.00%)
    2 / 51 (3.92%)
         occurrences all number
    6
    2
    Blood bilirubin increased
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    7 / 50 (14.00%)
    5 / 51 (9.80%)
         occurrences all number
    9
    6
    Sinus bradycardia
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    4
    Hemolysis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 50 (26.00%)
    10 / 51 (19.61%)
         occurrences all number
    19
    11
    Epistaxis
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 51 (15.69%)
         occurrences all number
    11
    9
    Hypoxia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 51 (7.84%)
         occurrences all number
    3
    5
    Sore throat
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 51 (9.80%)
         occurrences all number
    2
    5
    Pharyngeal mucositis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 50 (24.00%)
    14 / 51 (27.45%)
         occurrences all number
    18
    20
    Dizziness
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 51 (5.88%)
         occurrences all number
    8
    3
    Eye disorders
    Eye disorders - Other, specify
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Mucositis oral
         subjects affected / exposed
    40 / 50 (80.00%)
    36 / 51 (70.59%)
         occurrences all number
    43
    36
    Vomiting
         subjects affected / exposed
    32 / 50 (64.00%)
    33 / 51 (64.71%)
         occurrences all number
    71
    69
    Diarrhea
         subjects affected / exposed
    23 / 50 (46.00%)
    30 / 51 (58.82%)
         occurrences all number
    45
    46
    Abdominal pain
         subjects affected / exposed
    15 / 50 (30.00%)
    23 / 51 (45.10%)
         occurrences all number
    25
    39
    Nausea
         subjects affected / exposed
    19 / 50 (38.00%)
    15 / 51 (29.41%)
         occurrences all number
    33
    20
    Constipation
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 51 (15.69%)
         occurrences all number
    9
    13
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Gastritis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    4
    Stomach pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    Anal mucositis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify
         subjects affected / exposed
    28 / 50 (56.00%)
    26 / 51 (50.98%)
         occurrences all number
    41
    36
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 51 (9.80%)
         occurrences all number
    6
    5
    Urinary frequency
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 51 (7.84%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 50 (18.00%)
    14 / 51 (27.45%)
         occurrences all number
    11
    22
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    9 / 50 (18.00%)
    13 / 51 (25.49%)
         occurrences all number
    12
    24
    Rash maculo-papular
         subjects affected / exposed
    7 / 50 (14.00%)
    13 / 51 (25.49%)
         occurrences all number
    8
    20
    Alopecia
         subjects affected / exposed
    6 / 50 (12.00%)
    11 / 51 (21.57%)
         occurrences all number
    6
    11
    Dry skin
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 51 (0.00%)
         occurrences all number
    5
    0
    Skin hyperpigmentation
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2
    Urticaria
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Hypertrichosis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 50 (12.00%)
    9 / 51 (17.65%)
         occurrences all number
    10
    11
    Back pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Iron overload
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Hyperkalemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    6
    4
    Hypokalemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    6
    3
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    21 / 50 (42.00%)
    22 / 51 (43.14%)
         occurrences all number
    40
    31
    Rhinitis infective
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 51 (7.84%)
         occurrences all number
    6
    6
    Sepsis
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2
    Lung infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Catheter related infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Skin infection
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2015
    Update of the study timelines due to delayed study start Clarification on withdrawal of patients who violate eligibility criteria prior to administration of IMP, i.e. withdrawals without IMP had to be replaced. To ensure that the inclusion/exclusion criteria remain fulfilled until start of conditioning the most current result had to be used for assessment of eligibility in case of repeated examinations. Exclusion criterion number 8 was revised. Clarification of the period in which the patient registration had to be performed. New safety information was added to the protocol and the patient information for parents. Reference to the document “Development Summary of Product Characteristics” for Treograft was added. A narrower therapeutic window range has been defined for a target AUCday0-4 in order to ensure a dose-adjustment of the full myeloablative dose in case Therapeutic drug monitoring of Busulfan has to be performed. The wording for the administration time of i.v. treosulfan and i.v. fludarabine was changed from “within” 120/30 minutes to “over” 120/30 minutes. In addition to prophylactic also therapeutic treatment of GvHD (eg,glucocorticoids) and anti-infective medication administered for anti-bacterial, antiviral and anti-fungal prophylactic treatment had to be documented on the CRF . Exceptions from expedited SAE/SAR reporting, clarification regarding documentation of laboratory parameters as adverse events, detailed instructions on SAE reporting and Instructions on documentation of “pregnancy” as SAE were added. A separate SAE report form has to be completed for each SAE. A change in the number of patients subjected to blood samples has been implemented in case an interim analysis reveals that the population PK model is not sufficiently accurate, or the DMC recommend dose modifications. The accepted time deviation of the first PK sample has been defined. “Graft failure” has been additionally considered as a competing event for aGvHD and cGvHD.
    23 Jun 2016
    Changes in Sponsor personnel and job titles. Changes in timelines. Up-to-date information regarding safety was provided in the Investigator’s Brochure (approved edition 9.0, released 29-Nov-2015), including the Development SmPC for treosulfan, and in the SmPC for Busilvex. Safety information was deleted from the Clinical Trial Protocol. Additional blood samples were required for the validation of the POP-PK model. Based on a DMC recommendation dated 15-Apr-2016, PK sampling was to be performed until adequate PK data were available for each of the age groups. Editorial changes to improve readability were made and the sentences referring to the pooled statistical analysis and the interim analyses were moved. Subject Information Sheets were updated according to the above mentioned changes.
    13 Feb 2017
    The CRO for regulatory aspects and/or monitoring outside of DE changed. In addition, the outsourcing was extended to all countries involved in the clinical trial and to project management. The Sponsor’s staff changed. In addition, a Medical Expert was named in order to provide a single point of contact to advise on trial related medical questions or problems. Functions of the International Coordinating Investigator and the National Coordinating Investigators were specified. The definition of engraftment after HSCT was clarified in order to avoid misinterpretations. The term “consecutive days” was defined as 3 consecutive blood samples, if these were taken on different days. The second and third samples were required to confirm stable engraftment above the defined thresholds and were to be taken on the next consecutive days whenever possible; however, exceptions were accepted. Update and submission of the Investigational Medicinal Product Dossier.
    06 Jun 2017
    For particular non-malignant diseases like thalassaemia major or combined immunodeficiencies the reoccurrence of disease due to loss of donor cells may require the regular administration of blood products (eg, erythrocytes or PLT) as therapeutic agents. Thus, a return to transfusion dependence associated with the reoccurrence of the underlying disease after allo-HSCT was to be documented as rescue therapy on the CRF. Further, stem cell infusions with or without further conditioning regimens could be used as rescue therapy. A PIP modification was approved requesting to change the requirement to treat the vast majority of subjects (at least 85 out of 100) without additional use of thiotepa. Instead the unlimited use of the thiotepa containing therapy in qualified subjects was permitted. The last regular chimerism documentation (without signs of graft failure) was to be done 12 months after transplantation. The use of rescue therapy and graft failure was to be documented until the end of the longer-term follow-up phase. A donor type chimerism analysis was only required in order to confirm secondary graft failure after sustained decline of neutrophils (≤ 0.5 x 109/L) and leucocytes (≤ 1.0 x 109/L). In some non-malignant diseases like thalassaemia major, graft failure may not manifest as marrow aplasia, but as autologous reconstitution. In these cases, conventional definitions of graft failure based on the detection of cytopaenia could not be applied, but loss of chimerism was the sign of graft failure. Loss of chimerism in the cell compartment of interest led to recurrence of disease symptoms; loss of chimerism in the red cell compartment led to haemolysis and transfusion dependence in thalassaemia. In order to get clear evidence for a late secondary graft failure, the analysis of donor type chimerism was extended to the longer term follow-up phase. The definition of primary graft failure was specified as a donor-type chimerism of < 10% in BM.

    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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