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    Clinical Trial Results:
    A Randomized Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD after Unrelated Donor G-CSF mobilized Peripheral Blood Mononuclear Cell (G-PBMC) Transplantation using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies. A Multi-Center Trial.

    Summary
    EudraCT number
    		 2005-003305-90
    Trial protocol
    		 DK   DE  
    Global end of trial date
    08 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2019
    First version publication date
    28 Dec 2019
    Other versions
    Summary report(s)
    		 1938 Final Paper

    Trial information

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    Trial identification
    Sponsor protocol code
    1938.00
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00105001
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fred Hutchinson Cancer Research Center
    Sponsor organisation address
    1100 Fairview Ave. N., Seattle, United States, 98109
    Public contact
    Brittany Carroll-Watts, Fred Hutchinson Cancer Research Center, 1 206-667-6815, bmcarrol@fredhutch.org
    Scientific contact
    Brenda Sandmaier, MD, Fred Hutchinson Cancer Research Center, 1 206-667-4961, bsandmai@fredhutch.org
    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
    01 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine which of 3 GVHD prophylaxis regimens results in a reduction of acute grades II-IV GVHD to <40%.
    Protection of trial subjects
    Please see the Data and Safety Monitoring Plan of the protocol, pgs. 57 - 59.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 100 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    United States: 176
    Worldwide total number of subjects
    210
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    156
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients and donors are screened using the protocol's inclusion/exclusion criteria and, if accepted, randomized to an arm by data management.

    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
    		 Arm I (MMF and Tacrolimus)
    Arm description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf, FK 506
    Pharmaceutical forms
    Concentrate for solution for infusion, Capsule, hard
    Routes of administration
    Oral use, Intravenous bolus use
    Dosage and administration details
    Patients receive 0.06 mg/kg tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Cellcept, MMF
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive 15 mg/kg MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    2-F-ara-AMP, Beneflur, SH T 586
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive 30 mg/m^2 fludarabine administered over 30 minutes on Days -4, -3, and -2.

    Arm title
    		 Arm II (MMF and tacrolimus alternate schedule)
    Arm description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf, FK 506
    Pharmaceutical forms
    Capsule, hard, Concentrate for solution for infusion
    Routes of administration
    Intravascular use , Oral use
    Dosage and administration details
    Patients receive 0.06 mg/kg tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Cellcept, MMF
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive 15 mg/kg MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    2-F-ara-AMP, Beneflur, SH T 586
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive 30 mg/m^2 fludarabine administered over 30 minutes on Days -4, -3, and -2.

    Arm title
    		 Arm III (MMF, tacrolimus, and sirolimus)
    Arm description
    		 Patients receive tacrolimus and Mycophenolate Mofetil [MMF] as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO Sirolimus: Given PO
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf, FK 506
    Pharmaceutical forms
    Capsule, hard, Concentrate for solution for infusion
    Routes of administration
    Intravascular use , Oral use
    Dosage and administration details
    Patients receive 0.06 mg/kg tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Cellcept, MMF
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive 15 mg/kg MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    AY 22989, RAPA, SILA 9268A, WY-090217
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive 2 mg sirolimus PO once daily on days -3 to 80.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    2-F-ara-AMP, Beneflur, SH T 586
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive 30 mg/m^2 fludarabine administered over 30 minutes on Days -4, -3, and -2.

    Number of subjects in period 1
    		Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Started
    70
    71
    69
    Completed
    69
    71
    68
    Not completed
    1
    0
    1
         Did not proceed to transplant
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm I (MMF and Tacrolimus)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm II (MMF and tacrolimus alternate schedule)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm III (MMF, tacrolimus, and sirolimus)
    Reporting group description
    		 Patients receive tacrolimus and Mycophenolate Mofetil [MMF] as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO Sirolimus: Given PO

    Reporting group values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus) Total
    Number of subjects
    		 70 71 69 210
    Age categorical
    Units: Subjects
        <= 18 years
    		 0 1 1 2
        18 - 65 years
    		 57 50 49 156
        >=65 years
    		 13 20 19 52
    Age continuous
    Units: years
        median (full range (min-max))
    		 60 (26 to 74) 60 (13 to 72) 60 (15 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 29 30 23 82
        Male
    		 41 41 46 128

    End points

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    End points reporting groups
    Reporting group title
    Arm I (MMF and Tacrolimus)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm II (MMF and tacrolimus alternate schedule)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm III (MMF, tacrolimus, and sirolimus)
    Reporting group description
    		 Patients receive tacrolimus and Mycophenolate Mofetil [MMF] as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO Sirolimus: Given PO

    Primary: Number of Participants With Grades II-IV Acute GVHD

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    End point title
    		 Number of Participants With Grades II-IV Acute GVHD
    End point description
    Percentage patients w/ grade II-IV aGHVD, estimated by cumulative incidence methods. aGVHD Stages Skin: 1. a maculopapular eruption involving < 25% BSA 2. a maculopapular eruption involving 25 - 50% BSA 3. generalized erythroderma 4. generalized erythroderma w/ bullous formation and often w/ desquamation Liver: 1. bilirubin 2.0 - 3.0 mg/100 mL 2. bilirubin 3 - 5.9 mg/100 mL 3. bilirubin 6 - 14.9 mg/100 mL 4. bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death
    End point type
    Primary
    End point timeframe
    From the start of conditioning to 150 days post-transplant
    End point values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects analysed
    69 [1]
    71
    68 [2]
    Units: Participants
    44
    34
    32
    Notes
    [1] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    [2] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm III (MMF, tacrolimus, and sirolimus) v Arm II (MMF and tacrolimus alternate schedule)
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09 [3]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [3] - Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm II (MMF and tacrolimus alternate schedule)
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.1
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1

    Secondary: Number of Non-Relapse Mortalities

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    End point title
    		 Number of Non-Relapse Mortalities
    End point description
    Percentage of NRM as estimated by cumulative incidence methods with competing risks. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198
    End point type
    Secondary
    End point timeframe
    From the start of conditioning to 200 days post-transplant
    End point values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects analysed
    69 [4]
    71
    68 [5]
    Units: Participants
    3
    6
    2
    Notes
    [4] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    [5] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm II (MMF and tacrolimus alternate schedule) v Arm I (MMF and Tacrolimus) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55 [6]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [6] - Overall test of homogeneity among arms, reflecting events over the entire period of follow-up

    Secondary: Number Participants Utilizing High-Dose Corticosteroid

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    End point title
    		 Number Participants Utilizing High-Dose Corticosteroid
    End point description
    Percentage of patients utilizing high-dose corticosteroid (as a surrogate marker for reduction of acute GVHD), estimated by cumulative incidence methods. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198
    End point type
    Secondary
    End point timeframe
    From the start of conditioning to 150 days post-transplant
    End point values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects analysed
    69 [7]
    71
    68 [8]
    Units: Participants
    38
    35
    22
    Notes
    [7] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    [8] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm II (MMF and tacrolimus alternate schedule) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009 [9]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [9] - Overall test of homogeneity among arms, reflecting events over the entire period of follow-up
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm II (MMF and tacrolimus alternate schedule)
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.8

    Secondary: Number of of Participants Surviving Overall

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    End point title
    		 Number of of Participants Surviving Overall
    End point description
    Percentage of patients surviving, estimated by cumulative incidence methods Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198
    End point type
    Secondary
    End point timeframe
    From the start of conditioning to 2 Years post-transplant.
    End point values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects analysed
    69 [10]
    71
    68 [11]
    Units: Participants
    36
    32
    30
    Notes
    [10] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    [11] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm II (MMF and tacrolimus alternate schedule) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93 [12]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [12] - Overall test of homogeneity among arms, reflecting events over the entire period of follow-up

    Secondary: Number of Participants Surviving Without Progression

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    End point title
    		 Number of Participants Surviving Without Progression
    End point description
    Percentage of patients with progression-free survival, estimated by cumulative incidence methods Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198
    End point type
    Secondary
    End point timeframe
    From the start of conditioning to 2 Years post-transplant
    End point values
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects analysed
    69 [13]
    71
    68 [14]
    Units: Participants
    28
    27
    26
    Notes
    [13] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    [14] - One subject counted towards accrual but did not proceed to transplant and thus was not evaluable.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm I (MMF and Tacrolimus) v Arm II (MMF and tacrolimus alternate schedule) v Arm III (MMF, tacrolimus, and sirolimus)
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96 [15]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [15] - Overall test of homogeneity among arms, reflecting events over the entire period of follow-up

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: From the start of conditioning to 100 Days post-transplant SAEs: From the start of conditioning to 200 Days post-transplant All-Cause Mortality: Conditioning through 1 Year
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Adapted CTC
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    Arm I (MMF and Tacrolimus)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm II (MMF and tacrolimus alternate schedule)
    Reporting group description
    		 Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive Mycophenolate Mofetil [MMF] PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO

    Reporting group title
    Arm III (MMF, tacrolimus, and sirolimus)
    Reporting group description
    		 Patients receive tacrolimus and Mycophenolate Mofetil [MMF] as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. Fludarabine Phosphate: Given IV Total-Body Irradiation: Undergo total-body irradiation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplantation Tacrolimus: Given IV or PO Mycophenolate Mofetil: Given PO Sirolimus: Given PO

    Serious adverse events
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 69 (13.04%)
    8 / 71 (11.27%)
    7 / 68 (10.29%)
         number of deaths (all causes)
    21
    24
    28
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Severe hemoptysis 
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    CNS cerebrovascular ischemia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 69 (2.90%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Toxic leukoencephalopathy, infections w/ pneumonia and pyelonephritis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    GVHD
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GVHD w/ Infection
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    Gastrointestinal disorders
    Intestinal pneumatosis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal insufficiency
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Mucormycosis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory infection
         subjects affected / exposed
    1 / 69 (1.45%)
    3 / 71 (4.23%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm I (MMF and Tacrolimus) Arm II (MMF and tacrolimus alternate schedule) Arm III (MMF, tacrolimus, and sirolimus)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 69 (36.23%)
    22 / 71 (30.99%)
    25 / 68 (36.76%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Treatment related secondary malignancy
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences all number
    2
    3
    1
    Thromboembolic event
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    1
    Fever
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 71 (4.23%)
    0 / 68 (0.00%)
         occurrences all number
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    5 / 69 (7.25%)
    8 / 71 (11.27%)
    4 / 68 (5.88%)
         occurrences all number
    5
    9
    4
    Pleural effusion
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    2 / 68 (2.94%)
         occurrences all number
    0
    1
    2
    Pneumonitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Respiratory failure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders - Other, specify (Pulmonary, NOS)
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Psychosis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 71 (2.82%)
    1 / 68 (1.47%)
         occurrences all number
    2
    2
    1
    Creatinine increased
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    4 / 68 (5.88%)
         occurrences all number
    1
    1
    4
    Neutrophil count decreased
         subjects affected / exposed
    1 / 69 (1.45%)
    3 / 71 (4.23%)
    0 / 68 (0.00%)
         occurrences all number
    1
    3
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 71 (2.82%)
    0 / 68 (0.00%)
         occurrences all number
    0
    2
    0
    White blood cell decreased
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac arrest
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Heart failure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Pericardial tamponade
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Ventricular arrhythmia
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    2 / 68 (2.94%)
         occurrences all number
    0
    1
    2
    Seizure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    1
    0
    3
    Syncope
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 71 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    2
    0
    3
    Tremor
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    1
    1
    0
    Hemolysis
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    1
    1
    0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Colitis
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    1
    1
    0
    Diarrhea
         subjects affected / exposed
    5 / 69 (7.25%)
    1 / 71 (1.41%)
    4 / 68 (5.88%)
         occurrences all number
    5
    1
    4
    Enterocolitis
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    2
    0
    0
    Mucositis oral
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    3 / 68 (4.41%)
         occurrences all number
    1
    1
    3
    Vomiting
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 71 (1.41%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Generalized muscle weakness
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 71 (2.82%)
    0 / 68 (0.00%)
         occurrences all number
    1
    2
    0
    Musculoskeletal and connective tissue disorder - Other, specify (Cervical disk herniation)
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorder - Other, specify (Pain, NOS)
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    0
    0
    0
    Infections and infestations
    Duodenal infection
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    0
    1
    0
    Lung infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    1
    0
    1
    Hyperglycemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Hypertriglyceridemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 71 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    0
    1
    Hypokalemia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
    0 / 68 (0.00%)
         occurrences all number
    0
    1
    0
    Hyponatremia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    0

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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
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