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    Clinical Trial Results:
    A prospective randomized study comparing rapamune and tacrolimus vs. cyclosporine and methotrexate as immune prophylaxis in allogeneic hematopoietic stem cell transplantation, using HLA-A, -B, -DRB1 identical related or unrelated donors. A Nordic multicenter study.

    Summary
    EudraCT number
    		 2006-006577-25
    Trial protocol
    		 SE   FI  
    Global end of trial date
    19 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Feb 2023
    First version publication date
    26 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    070101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00993343
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Solna, Sweden,
    Public contact
    Olle Ringdén, Karolinska Institutet, olle.ringden@ki.se
    Scientific contact
    Olle Ringdén, Karolinska Institutet, olle.ringden@ki.se
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if the immunosuppressive prophylaxis with tacrolimus and sirolimus is better than the established therapy using cyclosporine and methotrexate in preventing graft versus host disease
    Protection of trial subjects
    The study protocol was approved by the Ethical Review Boards in Stockholm (DNR 2006/1430-31/3) and Helsinki (#541/2007, DNR 360/E5/07), and the Swedish and Finnish Medical Products Agencies (DNR 151:2007/38987 and KLNR 57/2008, respectively). The study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient, or from parents/guardians of patients who were under 18 years of age, before the start of HSCT conditioning treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 200
    Country: Number of subjects enrolled
    Finland: 15
    Worldwide total number of subjects
    215
    EEA total number of subjects
    215
    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)
    2
    Children (2-11 years)
    14
    Adolescents (12-17 years)
    9
    Adults (18-64 years)
    169
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled at two participating centers (Stockholm and Turku) between September 2007 and January 2014.

    Pre-assignment
    Screening details
    		 Six patients were excluded from the trial after randomization but before administration of their assigned GvHD prophylaxis. These 6 patients were considered as protocol violations, and they were excluded from further analysis.

    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
    		 CsA/Mtx
    Arm description
    		 graft-versus-host disease (GvHD) prophylaxis regimen using cyclosporine/methotrexate (CsA/Mtx)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    CICLOSPORIN
    Investigational medicinal product code
    Other name
    Sandimmun Neoral, CsA
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the standard arm started CsA on day −1 (the day before graft infusion). CsA was given twice a day (mainly orally). During the first two months, monitored plasma concentration levels were kept between 80-100 ng/mL in patients who received grafts from HLA-identical siblings, and between 150-250 ng/mL in MUD transplants. CsA was discontinued after tapering 3-4 months after HSCT in recipients of HLA-identical sibling grafts, and after six months in recipients of MUD transplants, in the absence of GvHD.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Mtx
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients in the standard arm: Mtx 15 mg/m2 was given on day +1, with consecutive doses of 10 mg/m2 given on days +3, +6, and +11 for all diagnoses.

    Arm title
    		 Tac/Sir
    Arm description
    		 Graft-versus-host disease (GvHD) prophylaxis regimen using tacrolimus/sirolimus (Tac/Sir).
    Arm type
    		 Experimental

    Investigational medicinal product name
    SIROLIMUS
    Investigational medicinal product code
    Other name
    Rapamune, Rapamycin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the experimental arm started Tac/Sir in combination on day −3 before graft infusion. Sirolimus was given orally once daily, starting with a bolus dose of 6 mg in adults and 0.1 mg/kg in children, followed by continuous individual adjustment with monitored plasma target levels of 3-12 ng/mL.

    Investigational medicinal product name
    TACROLIMUS
    Investigational medicinal product code
    Other name
    Prograf, FK-506
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the experimental arm started Tac/Sir in combination on day −3 before graft infusion. Tacrolimus was given orally twice a day, starting at 0.15 mg/kg/day, with a target plasma concentration of 5-15 ng/mL.

    Number of subjects in period 1 [1]
    		CsA/Mtx Tac/Sir
    Started
    106
    103
    Completed
    106
    103
    Notes
    [1] - 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: Six patients were excluded from the trial after randomization but before administration of their assigned GvHD prophylaxis. These 6 patients were considered as protocol violations, and they were excluded from further analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CsA/Mtx
    Reporting group description
    		 graft-versus-host disease (GvHD) prophylaxis regimen using cyclosporine/methotrexate (CsA/Mtx)

    Reporting group title
    Tac/Sir
    Reporting group description
    		 Graft-versus-host disease (GvHD) prophylaxis regimen using tacrolimus/sirolimus (Tac/Sir).

    Reporting group values
    		 CsA/Mtx Tac/Sir Total
    Number of subjects
    		 106 103 209
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 52 (0.6 to 71) 50 (2.8 to 68) -
    Gender categorical
    Units: Subjects
        Female
    		 46 36 82
        Male
    		 60 67 127
    Diagnosis
    Indication for transplant
    Units: Subjects
        CLL
    		 7 15 22
        Lymphoma
    		 14 13 27
        MDS
    		 20 14 34
        Other malignancies
    		 6 8 14
        Non-malignant
    		 10 3 13
        AML
    		 30 27 57
        ALL
    		 19 23 42
    Donor
    Units: Subjects
        Sibling
    		 29 33 62
        MUD (8/8)
    		 58 39 97
        URD (7/8, HLA-C mismatch)
    		 15 29 44
        URD (7/8, HLA-DR allele mismatch)
    		 4 2 6
    type of HSCT graft
    Units: Subjects
        BM
    		 21 18 39
        PBSCs
    		 85 85 170

    End points

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    End points reporting groups
    Reporting group title
    CsA/Mtx
    Reporting group description
    		 graft-versus-host disease (GvHD) prophylaxis regimen using cyclosporine/methotrexate (CsA/Mtx)

    Reporting group title
    Tac/Sir
    Reporting group description
    		 Graft-versus-host disease (GvHD) prophylaxis regimen using tacrolimus/sirolimus (Tac/Sir).

    Primary: Acute GVHD of grades II-IV

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    End point title
    		 Acute GVHD of grades II-IV
    End point description
    End point type
    Primary
    End point timeframe
    within 200 days post allogeneic HSCT
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    41 (32 to 50)
    51 (41 to 61)
    Statistical analysis title
    		 Cumulative incidence of acute GVHD of grades II-IV
    Statistical analysis description
    Cumulative incidence of acute GVHD of grades II-IV in the two treatment arms within 200 days post allogeneic HSCT
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.19
    Method
    		 Estimator of cumulative incidence curves
    Confidence interval
    Notes
    [1] - Intention-to-treat analysis

    Secondary: Time to neutrophil engraftment

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    End point title
    		 Time to neutrophil engraftment
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of the study
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: day
        median (full range (min-max))
    18 (10 to 305)
    17 (11 to 32)
    Statistical analysis title
    		 Difference in time to neutrophil engraftment
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.24
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Intention-to-treat analysis

    Secondary: Time to platelets engraftment

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    End point title
    		 Time to platelets engraftment
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of the study
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: day
        median (full range (min-max))
    14 (0 to 190)
    12 (0 to 68)
    Statistical analysis title
    		 Difference in time to platelet engraftment
    Comparison groups
    Tac/Sir v CsA/Mtx
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.008
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Intent-to-treat analysis

    Secondary: Incidence of aGVHD (gr. III-IV)

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    End point title
    		 Incidence of aGVHD (gr. III-IV)
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of study
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    13 (7 to 19)
    7 (2 to 12)
    Statistical analysis title
    		 Difference in incidence of aGvHD (gr. III-IV)
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.09
    Method
    		 Estimator of cumulative incidence curves
    Confidence interval
    Notes
    [4] - Intent-to-treat analysis

    Secondary: Incidence of cGVHD (gr. III-IV)

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    End point title
    		 Incidence of cGVHD (gr. III-IV)
    End point description
    End point type
    Secondary
    End point timeframe
    From start to end of study
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    41 (31 to 51)
    37 (26 to 48)
    Statistical analysis title
    		 Difference in incidence of cGvHD (gr. III-IV)
    Comparison groups
    Tac/Sir v CsA/Mtx
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.51
    Method
    		 Estimator of cumulative incidence curves
    Confidence interval
    Notes
    [5] - Intent-to-treat analysis

    Secondary: Incidence of transplant-related mortality

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    End point title
    		 Incidence of transplant-related mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Three years after HSCT
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    18 (11 to 25)
    12 (6 to 18)
    Statistical analysis title
    		 Difference in transplant-related mortality
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.4
    Method
    		 Estimator of cumulative incidence curves
    Confidence interval
    Notes
    [6] - Intent-to-treat analysis

    Secondary: Relapse-free survival

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    End point title
    		 Relapse-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Five years after HSCT
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    65 (55 to 75)
    63 (53 to 73)
    Statistical analysis title
    		 Difference in Relapse-free survival
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.73
    Method
    		 Kaplan-Meier method
    Confidence interval
    Notes
    [7] - Intent-to-treat analysis

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Five years after transplantation
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: percent
        number (confidence interval 95%)
    72 (63 to 81)
    71 (62 to 80)
    Statistical analysis title
    		 Difference in Overall survival
    Comparison groups
    CsA/Mtx v Tac/Sir
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.71
    Method
    		 Kaplan-Meier method
    Confidence interval
    Notes
    [8] - Intent-to-treat analysis

    Secondary: Incidence of oral mucositis

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    End point title
    		 Incidence of oral mucositis
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed three times a week until day +24 or until hospital discharge.
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: Number of patients
    61
    66
    No statistical analyses for this end point

    Secondary: Incidence of infections

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    End point title
    		 Incidence of infections
    End point description
    End point type
    Secondary
    End point timeframe
    Once a week for three months after HSCT
    End point values
    		 CsA/Mtx Tac/Sir
    Number of subjects analysed
    106
    103
    Units: Number of post-transplant infections
        CMV
    48
    49
        BSI
    19
    27
        PTLD
    9
    6
        IFI
    9
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    2007-2015
    Adverse event reporting additional description
    Adverse events were reported to study sponsor (Nordic Safety Unit at Wyeth Nordic) by fax, transmittal forms (1747B, 7443)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Free text
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    All study subjects
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events in this study.
    Serious adverse events
    		 All study subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 209 (1.91%)
         number of deaths (all causes)
    63
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thrombotic microangiopathy
         subjects affected / exposed
    2 / 209 (0.96%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Venoocclusive liver disease
         subjects affected / exposed
    2 / 209 (0.96%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All study subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 209 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27662016
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