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    Clinical Trial Results:
    A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD after Unrelated Donor Hematopoietic Cell Transplantation using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies A Multi-Center Trial

    Summary
    EudraCT number
    		 2011-000088-28
    Trial protocol
    		 DK   DE  
    Global end of trial date
    30 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2022
    First version publication date
    22 Jan 2022
    Other versions
    Summary report(s)
    		 Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplant

    Trial information

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    Trial identification
    Sponsor protocol code
    FHCRC2448
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fred Hutchinson Cancer Research Center
    Sponsor organisation address
    1100 Fairview Ave. N., Seattle, United States,
    Public contact
    Kim Drever, Fred Hutchinson Cancer Research Center, +1 (206) 667-6825, kdrever@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 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine which of two Graft versus host disease prophylaxis regimens results in a reduction of acute grades II-IV GVHD
    Protection of trial subjects
    Patient were followed closely in very specialized department of bone marrow transplant.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2011
    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: 22
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 149
    Worldwide total number of subjects
    174
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    106
    From 65 to 84 years
    68
    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 0
    Arm description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011
    Arm type
    		 Experimental

    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.

    Investigational medicinal product name
    Cyclosporine
    Investigational medicinal product code
    Other name
    CSP
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    CSP is given based on adjusted body weight, at 5.0 mg/kg PO q12 hours from day –3. If there is nausea and vomiting at anytime during CSP treatment the drug should be given intravenously at the appropriate dose that was used to obtain a therapeutic level. In the absence of acute or chronic GVHD, CSP is tapered at day 96 over 55 days (to be completed on Day +150).

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamycin, Rapamune
    Pharmaceutical forms
    Capsule, hard, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Sirolimus should be given at least 4 hours after an oral dose of cyclosporine as concurrent administration leads to elevation of sirolimus levels.

    Arm title
    		 Arm 1
    Arm description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.
    Arm type
    		 Experimental

    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.

    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
    MMF will be given based on adjusted body weight, at 15 mg/kg PO at 4-6 hours after SCT infusion is complete, then to be given at 15 mg/kg PO Q8 hours and then reduce to Q12 hours on day +30. Continue MMF Q12 hours until day +150 then taper until day +180 GVHD or disease relapse/progression occurs.

    Investigational medicinal product name
    Cyclosporine
    Investigational medicinal product code
    Other name
    CSP
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    CSP is given based on adjusted body weight, at 5.0 mg/kg PO q12 hours from day –3. If there is nausea and vomiting at anytime during CSP treatment the drug should be given intravenously at the appropriate dose that was used to obtain a therapeutic level. In the absence of acute or chronic GVHD, CSP is tapered at day 96 over 55 days (to be completed on Day +150).

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamycin, Rapamune
    Pharmaceutical forms
    Capsule, hard, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Sirolimus should be given at least 4 hours after an oral dose of cyclosporine as concurrent administration leads to elevation of sirolimus levels.

    Arm title
    		 Arm 2
    Arm description
    		 Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.
    Arm type
    		 Experimental

    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.

    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
    MMF will be given based on adjusted body weight, at 15 mg/kg PO at 4-6 hours after SCT infusion is complete, then to be given at 15 mg/kg PO Q8 hours and then reduce to Q12 hours on day +30. Continue MMF Q12 hours until day +40, MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

    Investigational medicinal product name
    Cyclosporine
    Investigational medicinal product code
    Other name
    CSP
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    CSP is given based on adjusted body weight, at 5.0 mg/kg PO q12 hours from day –3. If there is nausea and vomiting at anytime during CSP treatment the drug should be given intravenously at the appropriate dose that was used to obtain a therapeutic level. In the absence of acute or chronic GVHD, CSP is tapered at day 96 over 55 days (to be completed on Day +150).

    Number of subjects in period 1
    		Arm 0 Arm 1 Arm 2
    Started
    6
    77
    91
    Completed
    6
    77
    90
    Not completed
    0
    0
    1
         Aborted transplant during conditioning and subsequ
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 0
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011

    Reporting group title
    Arm 1
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.

    Reporting group title
    Arm 2
    Reporting group description
    		 Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

    Reporting group values
    		 Arm 0 Arm 1 Arm 2 Total
    Number of subjects
    		 6 77 91 174
    Age categorical
    Units: Subjects
        Less than 18
    		 0 0 0 0
        Between 18 and 65
    		 4 52 50 106
        Greater than 65
    		 2 25 41 68
    Age continuous
    Units: years
        median (full range (min-max))
    		 59.515 (36.47 to 67.83) 61.94 (18.2 to 77.09) 63.75 (41.02 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 2 27 28 57
        Male
    		 4 50 63 117

    End points

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    End points reporting groups
    Reporting group title
    Arm 0
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011

    Reporting group title
    Arm 1
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.

    Reporting group title
    Arm 2
    Reporting group description
    		 Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

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

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    End point title
    		 Number of Patients With Grades II-IV Acute GVHD
    End point description
    Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL 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
    100 days post-transplant
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [1]
    Units: Subjects
    3
    39
    22
    Notes
    [1] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    Statistical analysis title
    		 Cumulative incidence of grade 2–4 acute GVHD
    Statistical analysis description
    Cumulative incidence of grade 2–4 acute graft versus host disease at day 100
    Comparison groups
    Arm 2 v Arm 1
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Regression, Cox
    Confidence interval

    Secondary: Number of Patients With Chronic Extensive GVHD

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    End point title
    		 Number of Patients With Chronic Extensive GVHD
    End point description
    Number of patients who developed chronic extensive GVHD post-transplant. The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [2]
    Units: Subjects
    3
    38
    43
    Notes
    [2] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    No statistical analyses for this end point

    Secondary: Number of Patients With Grades III-IV Acute GVHD

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    End point title
    		 Number of Patients With Grades III-IV Acute GVHD
    End point description
    Number of patients with grades III-IV acute GVHD aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL 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
    Secondary
    End point timeframe
    100 days post-transplant
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [3]
    Units: Subjects
    0
    8
    2
    Notes
    [3] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    No statistical analyses for this end point

    Secondary: Number of Non-Relapse Mortalities

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    End point title
    		 Number of Non-Relapse Mortalities
    End point description
    Number of subjects expired without disease progression/relapse.
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [4]
    Units: Subjects
    0
    12
    4
    Notes
    [4] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    No statistical analyses for this end point

    Secondary: Number of of Participants Surviving Overall

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    End point title
    		 Number of of Participants Surviving Overall
    End point description
    One year post-transplant
    End point type
    Secondary
    End point timeframe
    Number of subjects surviving overall post-transplant.
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [5]
    Units: Subjects
    6
    53
    75
    Notes
    [5] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    No statistical analyses for this end point

    Secondary: Number of Participants With Relapse/Progression

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    End point title
    		 Number of Participants With Relapse/Progression
    End point description
    Relapse/Progression criteria: CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever >38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%. AML, ALL, MDS >5% blasts by morphologic or flow cytometric evaluation of the BMA or appearance of extramedullary disease CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or numb
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Arm 0 Arm 1 Arm 2
    Number of subjects analysed
    6
    77
    90 [6]
    Units: Subjects
    1
    16
    16
    Notes
    [6] - One subject counted towards accrual but not evaluated with respect to outcome measures.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: Conditioning through Day 100 SAEs: Conditioning through Day 200 All-Cause Mortality: Conditioning through 1 Year.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Adapted CTC
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Arm 0
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011

    Reporting group title
    Arm 1
    Reporting group description
    		 Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.

    Reporting group title
    Arm 2
    Reporting group description
    		 Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

    Serious adverse events
    		 Arm 0 Arm 1 Arm 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    0 / 90 (0.00%)
         number of deaths (all causes)
    0
    23
    13
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm 0 Arm 1 Arm 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    27 / 77 (35.06%)
    26 / 90 (28.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Treatment related secondary malignancy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 77 (2.60%)
    0 / 90 (0.00%)
         occurrences all number
    0
    3
    0
    Thromboembolic event
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 77 (2.60%)
    1 / 90 (1.11%)
         occurrences all number
    0
    3
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 77 (3.90%)
    0 / 90 (0.00%)
         occurrences all number
    1
    3
    0
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    2 / 90 (2.22%)
         occurrences all number
    0
    1
    2
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 77 (7.79%)
    3 / 90 (3.33%)
         occurrences all number
    0
    6
    0
    Laryngeal inflammation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 77 (0.00%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    0
    Lung infection
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 77 (3.90%)
    0 / 90 (0.00%)
         occurrences all number
    0
    3
    0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Pulmonary edema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 77 (2.60%)
    1 / 90 (1.11%)
         occurrences all number
    0
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 77 (2.60%)
    0 / 90 (0.00%)
         occurrences all number
    0
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 77 (9.09%)
    1 / 90 (1.11%)
         occurrences all number
    1
    7
    1
    Creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 77 (5.19%)
    4 / 90 (4.44%)
         occurrences all number
    0
    4
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    1
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 77 (1.30%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 77 (7.79%)
    3 / 90 (3.33%)
         occurrences all number
    0
    7
    3
    Hemolysis
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 77 (3.90%)
    0 / 90 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Colonic hemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhea
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 77 (2.60%)
    1 / 90 (1.11%)
         occurrences all number
    0
    2
    1
    Fecal incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Gastric ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Mucositis oral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    2 / 90 (2.22%)
         occurrences all number
    0
    1
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    3 / 90 (3.33%)
         occurrences all number
    0
    0
    3
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Hemorrhagic cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Encephalitis infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Pleural infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Weight loss
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 77 (1.30%)
    0 / 90 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypertriglyceridemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 77 (0.00%)
    4 / 90 (4.44%)
         occurrences all number
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Sep 2011
    The study was modified from 3-arm randomized phase II to 2-arm randomized phase III.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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