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    Clinical Trial Results:
    A Randomized Phase II, Open-Label study of the Efficacy and Safety of Orally Administered SAR302503 in patients with polycythemia vera (PV) or essential thrombocythemia (ET) who are resistant or intolerant to hydroxyurea

    Summary
    EudraCT number
    		 2011-001847-58
    Trial protocol
    		 FR   GB   ES   IT  
    Global end of trial date
    19 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    15 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARD12042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01420783
    WHO universal trial number (UTN)
    		 U1111-1121-4203
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-us@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-us@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of daily oral doses of 100, 200 and 400 mg fedratinib in subjects with polycythemia vera (PV) or essential thrombocythemia (ET) who are resistant or intolerant to hydroxyurea (per European Leukemia Net Consensus criteria): - Inducing the absence of phlebotomy and a hematocrit below 45% for a minimum of 3 months in subjects with PV, and Reduction of platelet count to =<400 x 10^9/L for a minimum of 3 months in subjects with ET. Polycythemia vera (PV) Dose Expansion Phase and ET Dose Ranging Phase (only 600 mg dose group): To evaluate the efficacy of daily oral SAR302503 in subjects with PV and ET who are resistant or intolerant to hydroxyurea (per European LeukemiaNet criteria) for: -Inducing absence of phlebotomy eligibility beginning at Day 1 of Cycle 4 and continuing through Day 1 of Cycle 6 in subjects with PV, and Reduction of platelet count to =<400 x 10^9/L beginning at Day 1 of Cycle 4 and continuing through Day 1 of Cycle 6 in subjects with ET.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 4
    Country: Number of subjects enrolled
    Canada: 6
    Worldwide total number of subjects
    81
    EEA total number of subjects
    44
    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)
    47
    From 65 to 84 years
    32
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 30 sites in 9 countries. A total of 81 subjects were screened between 17 October 2011 to 26 August 2013.

    Pre-assignment
    Screening details
    		 Of 81 screened subjects, 80 subjects were randomized and treated. The enrollment of additional ET subjects at 600 mg dose level was stopped prior to the termination of the SAR302503 program.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fedratinib 100 mg
    Arm description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fedratinib
    Investigational medicinal product code
    SAR302503
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Fedratinib 100 mg once daily.

    Arm title
    		 Fedratinib 200 mg
    Arm description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fedratinib
    Investigational medicinal product code
    SAR302503
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Fedratinib 200 mg once daily.

    Arm title
    		 Fedratinib >= 400 mg
    Arm description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fedratinib
    Investigational medicinal product code
    SAR302503
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Fedratinib 400 mg once daily. The study drug dose was titrated up or down in a 100 mg step to optimize efficacy and to minimize drug toxicity for individual subjects. The maximum allowable dose was 600 mg/day.

    Number of subjects in period 1 [1]
    		Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Started
    22
    24
    34
    Completed
    0
    0
    0
    Not completed
    22
    24
    34
         Consent withdrawn by subject
    -
    -
    12
         Disease progression
    -
    1
    1
         Adverse event
    3
    4
    10
         Unspecified
    19
    19
    11
    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: One subject was randomized but not treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fedratinib 100 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib 200 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib >= 400 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg Total
    Number of subjects
    		 22 24 34 80
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.7 ( 13.8 ) 52.6 ( 16 ) 61.7 ( 12.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 16 17 45
        Male
    		 10 8 17 35

    End points

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    End points reporting groups
    Reporting group title
    Fedratinib 100 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib 200 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib >= 400 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Primary: Percentage of Polycythemia Vera (PV) Subjects With Absence of Phlebotomy and Hematocrit Below 45% for a Minimum of 3 Months

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    End point title
    		 Percentage of Polycythemia Vera (PV) Subjects With Absence of Phlebotomy and Hematocrit Below 45% for a Minimum of 3 Months [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline up to Cycle 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to termination of the study (when the SAR302503 clinical program was terminated due to safety reason), no analysis was performed.
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [2] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [3] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [4] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Primary: Percentage of PV Subjects With Absence of Phlebotomy Eligibility

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    End point title
    		 Percentage of PV Subjects With Absence of Phlebotomy Eligibility [5]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 of Cycle 4 up to Day 1 of Cycle 6
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to termination of the study (when the SAR302503 clinical program was terminated due to safety reason), no analysis was performed.
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [6] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [7] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [8] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Primary: Percentage of Essential Thrombocythemia (ET) Subjects With Platelet Count <=400 × 10^9/L for a Minimum of 3 Months

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    End point title
    		 Percentage of Essential Thrombocythemia (ET) Subjects With Platelet Count <=400 × 10^9/L for a Minimum of 3 Months [9]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 of Cycle 4 up to Day 1 of Cycle 6
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to termination of the study (when the SAR302503 clinical program was terminated due to safety reason), no analysis was performed.
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [10] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [11] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [12] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of PV Subjects With Absence of Phlebotomy From Cycle 4 to Cycle 8

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    End point title
    		 Percentage of PV Subjects With Absence of Phlebotomy From Cycle 4 to Cycle 8
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 4 up to End of Cycle 8
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [13] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [14] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [15] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of ET Subjects With Platelet Count of <=400 × 10^9/L From Cycle 4 to Cycle 8

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    End point title
    		 Percentage of ET Subjects With Platelet Count of <=400 × 10^9/L From Cycle 4 to Cycle 8
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 4 up to End of Cycle 8
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [16] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [17] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [18] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinicohematologic Response From Cycle 6 to Cycle 8

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    End point title
    		 Percentage of Subjects With Clinicohematologic Response From Cycle 6 to Cycle 8
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 6 up to End of Cycle 8 (Up to Day 224)
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [19] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [20] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [21] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spleen Volume at End of Cycle 4, 8 and End of Treatment

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    End point title
    		 Percent Change From Baseline in Spleen Volume at End of Cycle 4, 8 and End of Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Cycle 4, 8 and End of Treatment
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    Units: percent change
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [22] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [23] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [24] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a >=35% Reduction From Baseline in Spleen Volume

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    End point title
    		 Percentage of Subjects with a >=35% Reduction From Baseline in Spleen Volume
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Cycle 4, 8 and End of Treatment
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [25] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [26] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [27] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Had Changes in Histological, Cytogenetic, and Molecular Responses in Bone Marrow

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    End point title
    		 Number of Subjects Who Had Changes in Histological, Cytogenetic, and Molecular Responses in Bone Marrow
    End point description
    End point type
    Secondary
    End point timeframe
    Up to end of treatment
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [28]
    0 [29]
    0 [30]
    Units: subjects
    Notes
    [28] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [29] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [30] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Response Measured by The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)

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    End point title
    		 Percentage of Subjects With Response Measured by The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Cycle 1, 4, and 8
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [31]
    0 [32]
    0 [33]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [31] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [32] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [33] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Cumulative Distribution Function of Response on the MPN-SAF

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    End point title
    		 Cumulative Distribution Function of Response on the MPN-SAF
    End point description
    End point type
    Secondary
    End point timeframe
    End of Cycles1, 4, 8 and End of Treatment
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [34]
    0 [35]
    0 [36]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [34] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [35] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [36] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Resolution of Symptoms on MPN-SAF

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    End point title
    		 Percentage of Subjects With Resolution of Symptoms on MPN-SAF
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Cycle 1, 4, and 8 (up to Day 224)
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [37]
    0 [38]
    0 [39]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [37] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [38] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [39] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Quality of Life and Utility Values Using the EuroQoL (EQ)-5D Questionnaire

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    End point title
    		 Quality of Life and Utility Values Using the EuroQoL (EQ)-5D Questionnaire
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Cycle 8
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    0 [40]
    0 [41]
    0 [42]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [40] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [41] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    [42] - The study was terminated when the SAR302503 clinical program was terminated due to safety reason.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experienced TEAEs, Grade 3-4 TEAEs, SAEs and Discontinued

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    End point title
    		 Number of Subjects Who Experienced TEAEs, Grade 3-4 TEAEs, SAEs and Discontinued
    End point description
    Treatment-emergent adverse event (TEAE) defined as any adverse event that is new, gets worse, or becomes serious during the treatment period. Clinical and laboratory AEs were assessed and reported using terminology of the National Cancer Institute (NCI) – CTCAE version 4.03. Grade 3 TEAE are severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 TEAE are Life-threatening consequences, urgent intervention indicated. Analysis was done on safety population defined as all randomized and treated subjects.
    End point type
    Secondary
    End point timeframe
    Up to Week 32
    End point values
    		 Fedratinib 100 mg Fedratinib 200 mg Fedratinib >= 400 mg
    Number of subjects analysed
    22
    24
    34
    Units: subjects
        Subjects with any TEAE
    21
    24
    34
        Subjects with any Grade 3-4 TEAE
    10
    10
    18
        Subjects with any treatment-emergent SAE
    7
    7
    8
        Subjects with any TEAE leading to discontinuation
    3
    4
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (up to 27 cycles) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (from first dose of the study drug up to end of treatment). Analysis was done on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Fedratinib 100 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib >= 400 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Reporting group title
    Fedratinib 200 mg
    Reporting group description
    		 Fedratinib for a minimum of 8 cycles (each cycle of 28 days) in the absence of disease progression or unacceptable toxicity. Subjects who completed 8 cycles of therapy and who tolerated study treatment and benefited clinically were allowed to continue treatment.

    Serious adverse events
    		 Fedratinib 100 mg Fedratinib >= 400 mg Fedratinib 200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 22 (31.82%)
    8 / 34 (23.53%)
    7 / 24 (29.17%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Investigations
    Lipase Increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Headache
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (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
    Migraine
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wernicke's Encephalopathy
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic Infarction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (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
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (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
    Ileus
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Inguinal Hernia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (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
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Soft Tissue Mass
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         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
    Diverticulitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    0 / 24 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fedratinib 100 mg Fedratinib >= 400 mg Fedratinib 200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 22 (90.91%)
    34 / 34 (100.00%)
    23 / 24 (95.83%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 34 (14.71%)
    6 / 24 (25.00%)
         occurrences all number
    2
    5
    8
    Fatigue
         subjects affected / exposed
    6 / 22 (27.27%)
    7 / 34 (20.59%)
    4 / 24 (16.67%)
         occurrences all number
    6
    8
    6
    Influenza Like Illness
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    Malaise
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Oedema Peripheral
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 34 (14.71%)
    2 / 24 (8.33%)
         occurrences all number
    3
    6
    2
    Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    3 / 24 (12.50%)
         occurrences all number
    0
    1
    4
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
    5 / 34 (14.71%)
    3 / 24 (12.50%)
         occurrences all number
    1
    7
    4
    Reproductive system and breast disorders
    Erectile Dysfunction
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 34 (11.76%)
    5 / 24 (20.83%)
         occurrences all number
    0
    5
    5
    Dyspnoea
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 34 (11.76%)
    0 / 24 (0.00%)
         occurrences all number
    2
    5
    0
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 34 (8.82%)
    1 / 24 (4.17%)
         occurrences all number
    0
    3
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 34 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 34 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    1
    3
    0
    Confusional State
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    0
    Depression
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    Insomnia
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 34 (2.94%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    1
    Investigations
    Amylase Increased
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 34 (11.76%)
    0 / 24 (0.00%)
         occurrences all number
    1
    5
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 34 (14.71%)
    0 / 24 (0.00%)
         occurrences all number
    3
    5
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 34 (8.82%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    5 / 34 (14.71%)
    0 / 24 (0.00%)
         occurrences all number
    0
    7
    0
    Lipase Increased
         subjects affected / exposed
    1 / 22 (4.55%)
    6 / 34 (17.65%)
    1 / 24 (4.17%)
         occurrences all number
    1
    9
    2
    Weight Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 34 (8.82%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    2
    Weight Increased
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    2
    1
    4
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 34 (8.82%)
    0 / 24 (0.00%)
         occurrences all number
    2
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 22 (18.18%)
    4 / 34 (11.76%)
    2 / 24 (8.33%)
         occurrences all number
    6
    4
    5
    Headache
         subjects affected / exposed
    8 / 22 (36.36%)
    4 / 34 (11.76%)
    7 / 24 (29.17%)
         occurrences all number
    10
    4
    10
    Memory Impairment
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 34 (8.82%)
    1 / 24 (4.17%)
         occurrences all number
    3
    4
    1
    Sciatica
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    5 / 34 (14.71%)
    0 / 24 (0.00%)
         occurrences all number
    3
    6
    0
    Neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Eye Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Periorbital Oedema
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Vision Blurred
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 34 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    3
    0
    1
    Abdominal Pain
         subjects affected / exposed
    2 / 22 (9.09%)
    6 / 34 (17.65%)
    2 / 24 (8.33%)
         occurrences all number
    2
    14
    4
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 34 (11.76%)
    0 / 24 (0.00%)
         occurrences all number
    1
    4
    0
    Diarrhoea
         subjects affected / exposed
    9 / 22 (40.91%)
    21 / 34 (61.76%)
    10 / 24 (41.67%)
         occurrences all number
    11
    31
    22
    Constipation
         subjects affected / exposed
    1 / 22 (4.55%)
    8 / 34 (23.53%)
    4 / 24 (16.67%)
         occurrences all number
    1
    8
    5
    Dyspepsia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    1
    Dry Mouth
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 34 (8.82%)
    1 / 24 (4.17%)
         occurrences all number
    2
    3
    1
    Flatulence
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 34 (8.82%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    1
    Nausea
         subjects affected / exposed
    9 / 22 (40.91%)
    22 / 34 (64.71%)
    12 / 24 (50.00%)
         occurrences all number
    10
    32
    18
    Oesophageal Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 22 (9.09%)
    16 / 34 (47.06%)
    8 / 24 (33.33%)
         occurrences all number
    4
    31
    13
    Skin and subcutaneous tissue disorders
    Actinic Keratosis
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Ecchymosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    0
    5
    Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 34 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    0
    4
    Night Sweats
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    2
    Pain Of Skin
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Pruritus
         subjects affected / exposed
    4 / 22 (18.18%)
    4 / 34 (11.76%)
    2 / 24 (8.33%)
         occurrences all number
    4
    4
    3
    Pruritus Generalised
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    3
    1
    2
    Skin Lesion
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 34 (5.88%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 34 (14.71%)
    2 / 24 (8.33%)
         occurrences all number
    2
    5
    2
    Bone Pain
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 34 (8.82%)
    1 / 24 (4.17%)
         occurrences all number
    2
    3
    1
    Back Pain
         subjects affected / exposed
    4 / 22 (18.18%)
    5 / 34 (14.71%)
    0 / 24 (0.00%)
         occurrences all number
    4
    6
    0
    Haemarthrosis
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Muscle Spasms
         subjects affected / exposed
    4 / 22 (18.18%)
    7 / 34 (20.59%)
    2 / 24 (8.33%)
         occurrences all number
    5
    13
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    3
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    1
    Pain In Extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 34 (17.65%)
    2 / 24 (8.33%)
         occurrences all number
    0
    8
    4
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    Influenza
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 34 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    0
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 34 (8.82%)
    2 / 24 (8.33%)
         occurrences all number
    4
    3
    2
    Urinary Tract Infection
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 34 (11.76%)
    1 / 24 (4.17%)
         occurrences all number
    2
    4
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    2
    Hyperlipasaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 34 (8.82%)
    0 / 24 (0.00%)
         occurrences all number
    1
    4
    0
    Hyperamylasaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 34 (8.82%)
    0 / 24 (0.00%)
         occurrences all number
    0
    8
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    3 / 24 (12.50%)
         occurrences all number
    0
    2
    5
    Hypocalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 34 (5.88%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 34 (2.94%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2011
    Addition of electrocardiograms (ECG) to safety monitoring.
    09 Dec 2011
    1.Exclusion Criteria E 20 was changed to harmonize the exclusion of CYP3A4 concomitant medications across protocols studying SAR302503, the discretion for subjects’s use such of medications with the sponsor’s approval as allowed in E 20 was removed. 2. Added language that drugs which are strong inhibitors of CYP2C19 should be used with caution. 3. sites were increased form 8 to approximately 45 globally.
    17 Feb 2012
    1. Updated exclusion criteria of subjects who may be at risk for liver function test (LFT) abnormalities : added more frequent monitoring of LFTs (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin [total and direct]) during the first 3 cycles of treatment in case severe liver enzyme elevations occur at any time during study treatment. 2. To give explicit instructions for dose modifications in case LFT abnormalities are detected. 3. Clarification in the concomitant medication section regarding the recommendation to not use oral contraceptives and hormonal replacement therapies that include estrogen (ie, ethinyl estradiol) and progesterone (ie, levonorgestrel) during study treatment.
    07 Nov 2012
    1. Clarification on ‘Dose modification for toxicity’ of the interval allowed for dose interruption in case of transfusion dependency. 2. ‘Adverse events of special interest’ list was updated. 3. Statistical section was updated. 4. Initially a singular center was selected to evaluate changes in endogenous erythroid colony formation and replenishment of iron in iron-deficient subjects in subjects with PV, however the test was not set up contractually and therefore was deleted from the protocol and will be revisited at future studies.
    12 Jul 2013
    The primary reason for issuance of Protocol Amendment was to halt further enrollment subjects with essential thrombocythemia (ET). Other changes included following points: 1. Statistical considerations had revised to account for the closure of enrollment to ET subjects. 2. Clarification was added to specify that granulocyte tumor samples may be analyzed for additional MPN related gene mutations in addition to JAK2V617F. 3. Administrative corrections/revisions throughout the document was made.
    27 Nov 2013
    Based on an internal assessment of the potential benefits and risks of the treatment, Sanofi has decided to terminate all SAR302503 clinical trials including those in myelofibrosis, polycythemia vera, essential thrombocythemia, and solid tumors, and would not ask the FDA to remove the clinical hold that was imposed. Thus going forward, all subjects permanently discontinued from further SAR302503 treatment. Sanofi, therefore, urges investigators to seek alternative therapies for the subjects on their studies. All subjects will continue to be followed for safety.

    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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