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    Clinical Trial Results:
    Randomized, open-label, multi-center Phase IIIb study evaluating the efficacy and safety of ruxolitinib versus best available therapy in patients with polycythemia vera who are hydroxyurea resistant or intolerant (RESPONSE-2)

    Summary
    EudraCT number
    		 2013-003583-31
    Trial protocol
    		 DE   ES   IT   HU   BE   FR  
    Global end of trial date
    07 Apr 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Sep 2021
    First version publication date
    22 Apr 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424B2401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02038036
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    07 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the efficacy of ruxolitinib to best available therapy (BAT) as assessed by hematocrit (Hct) control at Week 28. Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Turkey: 6
    Worldwide total number of subjects
    149
    EEA total number of subjects
    119
    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)
    69
    From 65 to 84 years
    77
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized in 48 centers across 12 countries: Australia (1), Belgium (2), Canada (1), France (7), Germany (9), Hungary (3), India (2), Israel (3), Italy (7), South Korea (2), Spain (9) and Turkey (2)

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio either to Ruxolitinib or Best available Therapy (BAT). Randomization was stratified by patients who were resistant to or intolerant of Hydroxyurea (HU).

    Period 1
    Period 1 title
    Core Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    open-label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ruxolitinib
    Arm description
    		 Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose was adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    INC424
    Other name
    Jakafi®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose was adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid

    Arm title
    		 Best Available Therapy (BAT)
    Arm description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydroxyurea, IFN/PEG-IFN, popobroman, anagrelide, IMIDs, or observation.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation as prescribed by the Investigator

    Number of subjects in period 1
    		Ruxolitinib Best Available Therapy (BAT)
    Started
    74
    75
    Full analysis set
    74
    75
    Crossover set
    0 [1]
    58 [2]
    Completed
    59
    61
    Not completed
    15
    14
         Adverse event, serious fatal
    1
    1
         Physician decision
    2
    1
         Consent withdrawn by subject
    3
    1
         Disease progression
    2
    2
         Adverse event, non-fatal
    7
    7
         Lost to follow-up
    -
    1
         Subject/guardian decision
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Cross-over set included only participants that crossed-over to Ruxolitinib
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Cross-over set included only participants that crossed-over to Ruxolitinib
    Period 2
    Period 2 title
    Crossover Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label

    Arms
    Arm title
    		 Best Available Therapy (BAT)
    Arm description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydroxyurea, IFN/PEG-IFN, popobroman, anagrelide, IMIDs, or observation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation as prescribed by the investigator

    Number of subjects in period 2 [3]
    		Best Available Therapy (BAT)
    Started
    58
    Completed
    38
    Not completed
    20
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    3
         Physician decision
    2
         Disease progression
    3
         Adverse event, non-fatal
    9
         Lost to follow-up
    1
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Cross-over set included only participants that crossed-over to Ruxolitinib

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ruxolitinib
    Reporting group description
    		 Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose was adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib

    Reporting group values
    		 Ruxolitinib Best Available Therapy (BAT) Total
    Number of subjects
    		 74 75 149
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 40 29 69
        From 65-84 years
    		 34 43 77
        85 years and over
    		 0 3 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 11.31 ) 66.0 ( 11.12 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 35 28 63
        Male
    		 39 47 86
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 67 66 133
        Asian
    		 4 5 9
        Other
    		 3 4 7

    End points

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    End points reporting groups
    Reporting group title
    Ruxolitinib
    Reporting group description
    		 Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose was adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib
    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib

    Subject analysis set title
    All crossover patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to the BAT arm, who crossed over and received at least one dose of ruxolitinib

    Primary: Number of participants achieving hematocrit (Hct) control at Week 28

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    End point title
    		 Number of participants achieving hematocrit (Hct) control at Week 28 [1]
    End point description
    Proportion of patients achieving Hct control at Week 28 was defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8. Phlebotomy eligibility was defined by: - Confirmed Hct > 45% that is at least 3 percentage points higher than the Hct obtained at Baseline Or - Confirmed Hct > 48% The confirmation occurred 2 to 14 days subsequent to the initial observation.
    End point type
    Primary
    End point timeframe
    Week 28
    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: No statistical analysis was planned for this outcome measure.
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    46
    14
    No statistical analyses for this end point

    Secondary: Number of participants achieving a complete hematological remission at Week 28

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    End point title
    		 Number of participants achieving a complete hematological remission at Week 28
    End point description
    Proportion of patients achieving a complete hematological remission at Week 28 was defined by: - Hct control at Week 28 defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and - WBC < 10 x109/L at Week 28, and - Platelets ≤ 400 x 109/L at Week 28
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    17
    4
    No statistical analyses for this end point

    Secondary: Number of participants achieving a hematocrit (Hct) control at Week 52 and Week 80

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    End point title
    		 Number of participants achieving a hematocrit (Hct) control at Week 52 and Week 80
    End point description
    Proportion of patients achieving a Hct control at Week 52 was defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52, and no more than one phlebotomy eligibility occurring post randomization and prior to Week 8 - Endpoint for Week 80 was defined, similarly.
    End point type
    Secondary
    End point timeframe
    Week 52 and 80
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Week 52
    44
    5
        Week 80
    35
    2
    No statistical analyses for this end point

    Secondary: Number of participants achieving a complete hematological remission at Week 52 and Week 80

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    End point title
    		 Number of participants achieving a complete hematological remission at Week 52 and Week 80
    End point description
    Proportion of patients achieving a complete hematological remission at Week 52, was defined by: - Hct control at Week 52, as defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52 with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and - White Blood Count (WBC) < 10 x10^9/L at Week 52, and - Platelets ≤ 400 x 10^9/L at Week 52 - Endpoint for Week 80 was defined, similarly.
    End point type
    Secondary
    End point timeframe
    Week 52 and 80
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Week 52
    17
    3
        Week 80
    18
    2
    No statistical analyses for this end point

    Secondary: Number of participants with phlebotomies over time

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    End point title
    		 Number of participants with phlebotomies over time
    End point description
    Phlebotomy eligibility was defined by Confirmed Hct > 45% that is at least 3 percentage points higher than the Hct obtained at Baseline Or Confirmed Hct > 48%. The confirmation occurred 2 to 14 days subsequent to the initial observation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 260
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Phlebotomy frequency: >0 – <=2
    12
    29
        Phlebotomy frequency: >2 - <=4
    7
    17
        Phlebotomy frequency: >4 - <=6
    4
    2
        Phlebotomy frequency: >6 - <=8
    0
    1
    No statistical analyses for this end point

    Secondary: Change from baseline in Hematocrit (Hct) at each visit

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    End point title
    		 Change from baseline in Hematocrit (Hct) at each visit
    End point description
    Hematocrit is the volume percentage of red blood cells (RBC) in the blood.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 66, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and 260
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: volume percentage of RBC in blood
    arithmetic mean (standard deviation)
        Week 4
    -0.65 ( 2.943 )
    1.25 ( 2.994 )
        Week 8
    -1.22 ( 3.634 )
    1.63 ( 3.344 )
        Week 12
    -2.33 ( 4.581 )
    1.70 ( 3.485 )
        Week 16
    -3.25 ( 4.179 )
    1.83 ( 3.439 )
        Week 20
    -3.05 ( 4.307 )
    1.45 ( 3.984 )
        Week 24
    -2.85 ( 4.094 )
    1.52 ( 2.934 )
        Week 28
    -2.60 ( 4.101 )
    2.09 ( 3.852 )
        Week 40
    -2.77 ( 4.538 )
    2.05 ( 4.587 )
        Week 52
    -2.49 ( 4.445 )
    1.68 ( 4.854 )
        Week 66
    -3.06 ( 4.573 )
    2.73 ( 2.922 )
        Week 80
    -3.20 ( 3.886 )
    0.62 ( 4.436 )
        Week 92
    -2.91 ( 4.203 )
    999 ( 999 )
        Week 104
    -3.19 ( 4.314 )
    999 ( 999 )
        Week 117
    -2.86 ( 4.540 )
    999 ( 999 )
        Week 130
    -3.13 ( 4.263 )
    999 ( 999 )
        Week 143
    -3.50 ( 3.463 )
    999 ( 999 )
        Week 156
    -3.54 ( 4.005 )
    999 ( 999 )
        Week 169
    -3.57 ( 4.477 )
    999 ( 999 )
        Week 182
    -2.94 ( 4.428 )
    999 ( 999 )
        Week 195
    -3.36 ( 4.515 )
    999 ( 999 )
        Week 208
    -3.23 ( 4.150 )
    999 ( 999 )
        Week 221
    -3.55 ( 4.413 )
    999 ( 999 )
        Week 234
    -3.31 ( 4.621 )
    999 ( 999 )
        Week 247
    -3.45 ( 4.053 )
    999 ( 999 )
        Week 260
    -2.93 ( 3.799 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematocrit (Hct) at each scheduled visit after crossover in participants randomized to BAT who cross over to ruxolitinib

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    End point title
    		 Change from Baseline in hematocrit (Hct) at each scheduled visit after crossover in participants randomized to BAT who cross over to ruxolitinib
    End point description
    Hematocrit is the percentage of red blood cells (RBC) in the blood.
    End point type
    Secondary
    End point timeframe
    Baseline (last assessment before cross over), Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 64, 76, 89, 102, 115, 128, 141, 154, 167, 180, 193, 206, 219 and 232 after cross-over
    End point values
    		 All crossover patients
    Number of subjects analysed
    58
    Units: Volume percentage of RBC in blood
    arithmetic mean (standard deviation)
        Week +4
    -2.44 ( 3.394 )
        Week +8
    -4.24 ( 5.322 )
        Week +12
    -5.73 ( 6.597 )
        Week +16
    -6.27 ( 7.101 )
        Week +20
    -5.76 ( 6.563 )
        Week +24
    -5.29 ( 6.518 )
        Week +28
    -6.04 ( 5.825 )
        Week +40
    -6.06 ( 6.301 )
        Week +52
    -5.91 ( 6.399 )
        Week +64
    -7.06 ( 6.051 )
        Week +76
    -6.16 ( 6.247 )
        Week +89
    -6.79 ( 6.046 )
        Week +102
    -6.21 ( 6.599 )
        Week +115
    -7.04 ( 6.103 )
        Week +128
    -7.41 ( 6.812 )
        Week +141
    -7.00 ( 6.310 )
        Week +154
    -7.06 ( 7.000 )
        Week +167
    -7.44 ( 7.426 )
        Week +180
    -7.51 ( 7.298 )
        Week +193
    -7.16 ( 5.331 )
        Week +206
    -7.09 ( 5.742 )
        Week +219
    -6.95 ( 5.936 )
        Week +232
    -7.51 ( 5.880 )
    No statistical analyses for this end point

    Secondary: Spleen length by visit

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    End point title
    		 Spleen length by visit
    End point description
    Spleen length was assessed by manual palpation at every study visit.
    End point type
    Secondary
    End point timeframe
    Week 4, 8, 12, 16, 20, 24, 28, 40, 52, 66, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247 and 260
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: cm
    arithmetic mean (standard deviation)
        Week 4
    0.00 ( 0.000 )
    0.04 ( 0.351 )
        Week 8
    0.00 ( 0.000 )
    0.01 ( 0.119 )
        Week 12
    0.00 ( 0.000 )
    0.01 ( 0.120 )
        Week 16
    0.00 ( 0.000 )
    0.23 ( 1.010 )
        Week 20
    0.00 ( 0.000 )
    0.13 ( 0.716 )
        Week 24
    0.00 ( 0.000 )
    0.09 ( 0.555 )
        Week 28
    0.00 ( 0.000 )
    0.20 ( 0.909 )
        Week 40
    0.01 ( 0.120 )
    0.52 ( 1.473 )
        Week 52
    0.06 ( 0.482 )
    0.07 ( 0.258 )
        Week 66
    0.00 ( 0.000 )
    0.00 ( 0.000 )
        Week 80
    0.03 ( 0.246 )
    0.00 ( 0.000 )
        Week 92
    0.00 ( 0.000 )
    999 ( 999 )
        Week 104
    0.05 ( 0.378 )
    999 ( 999 )
        Week 117
    0.12 ( 0.985 )
    999 ( 999 )
        Week 130
    0.18 ( 1.162 )
    999 ( 999 )
        Week 143
    0.08 ( 0.458 )
    999 ( 999 )
        Week 156
    0.05 ( 0.372 )
    999 ( 999 )
        Week 169
    0.05 ( 0.378 )
    999 ( 999 )
        Week 182
    0.05 ( 0.381 )
    999 ( 999 )
        Week 195
    0.00 ( 0.000 )
    999 ( 999 )
        Week 208
    0.00 ( 0.000 )
    999 ( 999 )
        Week 221
    0.02 ( 0.129 )
    999 ( 999 )
        Week 234
    0.00 ( 0.000 )
    999 ( 999 )
        Week 247
    0.02 ( 0.136 )
    999 ( 999 )
        Week 260
    0.10 ( 0.617 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Eastern Cooperative Oncology Group (ECOG) performance status to Week 28

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    End point title
    		 Change from baseline in Eastern Cooperative Oncology Group (ECOG) performance status to Week 28
    End point description
    The ECOG scale of performance status described the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 28
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Grade 0 at baseline|0: Fully active
    49
    17
        Grade 1 at baseline|0: Fully active
    9
    1
        Grade 0 at baseline|1: Restricted
    2
    1
        Grade 1 at baseline|1: Restricted
    10
    5
        Grade 0 at baseline|2: Ambulatory
    0
    0
        Grade 1 at baseline|2: Ambulatory
    1
    0
        Grade 0 at baseline|3: limited self-care
    0
    0
        Grade 1 at baseline|3: limited self-care
    0
    0
        Grade 0 at baseline|4: Completely disabled
    0
    0
        Grade 1 at baseline|4: Completely disabled
    0
    0
        Grade 0 at baseline|Missing
    2
    38
        Grade 1 at baseline|Missing
    1
    13
    No statistical analyses for this end point

    Secondary: Number of participants achieving a partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 28

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    End point title
    		 Number of participants achieving a partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 28
    End point description
    Proportion of patients achieving a partial remission at Week 28, based on the ELN and IWG-MRT criteria, as defined by: - Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) score reduction of greater than or equal to 10 points from baseline to Week 28, and - Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 28, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and - WBC < 10 x10^9/L at Week 28, and - Platelets ≤ 400 x 10^9/L at Week 28, and - No palpable spleen at Week 28, and - No hemorrhagic or thrombotic events, and - No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria).
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    7
    0
    No statistical analyses for this end point

    Secondary: Number of participants who achieved partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 52 and Week 80

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    End point title
    		 Number of participants who achieved partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 52 and Week 80
    End point description
    Proportion of patients who achieved partial remission at Week 52 based on the ELN and IWG-MRT criteria, as defined by: - MPN-SAF TSS score reduction of greater than or equal to 10 points from baseline to Week 52 and - Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 52 with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and - WBC < 10 x109/L at Week 52 and - Platelets ≤ 400 x 109/L at Week 52 and - No palpable spleen at Week 52 and - No hemorrhagic or thrombotic events, and - No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria). - Endpoint for Week 80 was defined, similarly.
    End point type
    Secondary
    End point timeframe
    Week 52 and 80
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Week 52
    5
    0
        Week 80
    4
    0
    No statistical analyses for this end point

    Secondary: Number of participants achieving a Hematocrit (Hct) control at Week 104, Week 156, Week 208 and Week 260.

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    End point title
    		 Number of participants achieving a Hematocrit (Hct) control at Week 104, Week 156, Week 208 and Week 260. [2]
    End point description
    Proportion of patients achieving a Hct control at Week 104 as defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104 and with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8 Endpoint for Week 156, Week 208 and Week 260 were defined, similarly.
    End point type
    Secondary
    End point timeframe
    From Week 8 to Week 104, 156, 208 and 260
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    74
    Units: Participants
        Week 104|HU Resistant
    9
        Week 156|HU Resistant
    9
        Week 208|HU Resistant
    7
        Week 260|HU Resistant
    4
        Week 104|HU Intolerant
    25
        Week 156|HU Intolerant
    21
        Week 208|HU Intolerant
    18
        Week 260|HU Intolerant
    12
    No statistical analyses for this end point

    Secondary: Number of participants achieving a complete hematological remission at Week 104, Week 156, Week 208 and Week 260

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    End point title
    		 Number of participants achieving a complete hematological remission at Week 104, Week 156, Week 208 and Week 260 [3]
    End point description
    Proportion of patients achieving a complete hematological remission at Week 104 as defined by Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104, with no more than one phlebotomy eligibility occurring post randomization and prior to Week 8, and - WBC < 10 x10^9/L at Week 104, and - Platelets ≤ 400 x 10^9/L at Week 104 Endpoint for Week 156, Week 208 and Week 260 were defined, similarly.
    End point type
    Secondary
    End point timeframe
    From Week 8 to Week 104, 156, 208 and 260
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    74
    Units: Participants
        Week 104
    15
        Week 156
    19
        Week 208
    11
        Week 260
    9
    No statistical analyses for this end point

    Secondary: Number of participants who achieved partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 104, Week 156, Week 208 and Week 260.

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    End point title
    		 Number of participants who achieved partial remission based on the European Leukemia Net (ELN) and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at Week 104, Week 156, Week 208 and Week 260. [4]
    End point description
    Proportion of patients who achieved partial remission at Week 104, based on the ELN and IWG-MRT criteria, as defined by: - MPN-SAF TSS score reduction of greater than or equal to 10 points from baseline to Week 104, and - Hct control defined by the absence of phlebotomy eligibility starting at Week 8 and continuing through Week 104, with no more than one phlebotomy eligibility occurring post-randomization and prior to Week 8, and - WBC < 10 x10^9/L at Week 104, and - Platelets ≤ 400 x 10^9/L at Week 104, and - No palpable spleen at Week 104, and - No hemorrhagic or thrombotic events, and - No transformation into post-PV myelofibrosis, myelodysplastic syndrome (IWG-MRT criteria) or acute leukemia (WHO criteria) Endpoint for Week 156, Week 208 and Week 260 are defined, similarly.
    End point type
    Secondary
    End point timeframe
    From Week 8 to Week 104, 156, 208 and 260
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    74
    Units: Participants
        Week 104
    4
        Week 156
    9
        Week 208
    4
        Week 260
    0
    No statistical analyses for this end point

    Secondary: Number of participants with Transformation free survival events

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    End point title
    		 Number of participants with Transformation free survival events
    End point description
    Transformation-free survival is defined as one of the following: 1. Myelofibrosis (MF) as evidenced by bone marrow biopsy, or 2. Acute leukemia as evidenced by bone marrow blast counts of at least 20%, or peripheral blast counts of at least 20% lasting at least 2 weeks. 3. Death due to any cause during treatment period
    End point type
    Secondary
    End point timeframe
    Week 260 (ruxolitinib arm) and Week 80 (BAT arm)
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    4
    3
    No statistical analyses for this end point

    Secondary: Number of participants with Overall survival (OS) events

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    End point title
    		 Number of participants with Overall survival (OS) events
    End point description
    Overall survival (OS) event is defined as death due to any cause. OS events were counted in the BAT arm, irrespective of whether participants crossed over to receive ruxolitinib when the event occurred.
    End point type
    Secondary
    End point timeframe
    up to Week 260
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    3
    6
    No statistical analyses for this end point

    Secondary: Change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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    End point title
    		 Change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
    End point description
    The MPN-SAF TSS is a disease specific questionnaire comprised of 10 items that measures fatigue related to MPN disease and the severity of nine of the most prevalent associated symptoms. Each item is scored on a scale ranging from 0 (no fatigue/absent) to 10 (As bad as you can imagine/worst imaginable).The MPN-SAF TSS is computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus has a possible score range of 0 to 100 where a decrease indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16, 28, 40, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 4
    -8.43 ( 12.341 )
    0.40 ( 12.586 )
        Week 8
    -9.86 ( 12.210 )
    1.37 ( 12.046 )
        Week 16
    -9.14 ( 13.980 )
    1.41 ( 10.760 )
        Week 28
    -10.29 ( 14.204 )
    2.34 ( 13.047 )
        Week 40
    -9.35 ( 14.027 )
    0.10 ( 9.586 )
        Week 52
    -8.63 ( 13.403 )
    0.63 ( 9.334 )
        Week 80
    -9.04 ( 13.520 )
    999 ( 999 )
        Week 92
    -7.69 ( 11.971 )
    999 ( 999 )
        Week 104
    -6.82 ( 13.297 )
    999 ( 999 )
        Week 117
    -6.76 ( 13.702 )
    999 ( 999 )
        Week 130
    -8.26 ( 16.234 )
    999 ( 999 )
        Week 143
    -8.56 ( 15.653 )
    999 ( 999 )
        Week 156
    -8.48 ( 15.081 )
    999 ( 999 )
        Week 169
    -7.65 ( 14.392 )
    999 ( 999 )
        Week 182
    -9.34 ( 14.675 )
    999 ( 999 )
        Week 195
    -7.57 ( 14.922 )
    999 ( 999 )
        Week 208
    -9.26 ( 16.347 )
    999 ( 999 )
        Week 221
    -7.20 ( 16.054 )
    999 ( 999 )
        Week 234
    -7.50 ( 15.922 )
    999 ( 999 )
        Week 247
    -7.82 ( 16.905 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in total scores of MPN-SAF by visit in patients from BAT group who cross over to ruxolitinib after crossover

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    End point title
    		 Change from Baseline in total scores of MPN-SAF by visit in patients from BAT group who cross over to ruxolitinib after crossover [5]
    End point description
    The MPN-SAF TSS is a disease specific questionnaire comprised of 10 items that measures fatigue related to MPN disease and the severity of nine of the most prevalent associated symptoms. Each item is scored on a scale ranging from 0 (no fatigue/absent) to 10 (As bad as you can imagine/worst imaginable).The MPN-SAF TSS is computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus has a possible score range of 0 to 100 where a decrease indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 40, 52, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247 after cross-over
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Best Available Therapy (BAT)
    Number of subjects analysed
    58
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week +4
    -8.00 ( 10.532 )
        Week +8
    -9.76 ( 11.543 )
        Week +16
    -9.40 ( 12.040 )
        Week +24
    -9.15 ( 12.738 )
        Week +28
    -8.46 ( 12.212 )
        Week +40
    -8.58 ( 13.302 )
        Week +52
    -7.15 ( 14.392 )
        Week 92
    -10.49 ( 13.902 )
        Week 104
    -8.08 ( 16.288 )
        Week 117
    -9.01 ( 14.708 )
        Week 130
    -10.18 ( 15.740 )
        Week 143
    -8.36 ( 17.030 )
        Week 156
    -9.54 ( 14.573 )
        Week 169
    -11.15 ( 14.305 )
        Week 182
    -10.13 ( 16.113 )
        Week 195
    -10.88 ( 14.357 )
        Week 208
    -9.43 ( 15.360 )
        Week 221
    -10.02 ( 15.986 )
        Week 234
    -8.01 ( 14.404 )
        Week 247
    -9.84 ( 14.979 )
    No statistical analyses for this end point

    Secondary: Change from baseline in score as per European Quality of Life 5-Dimension 5-level (EQ-5D-5L) questionnaire

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    End point title
    		 Change from baseline in score as per European Quality of Life 5-Dimension 5-level (EQ-5D-5L) questionnaire
    End point description
    EQ-5D-5L is a standardized instrument for measuring health outcomes in a wide range of health conditions and treatments. It consists of visual analogue scale (EQ VAS) which records the respondent’s self-rated health on a vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ and ‘worst imaginable health state’. The EQ VAS scores were anchored on 100 = the best health you can imagine and 0 = worst health you can imagine.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16, 28, 52, 80, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 4
    4.24 ( 11.661 )
    0.04 ( 18.323 )
        Week 8
    7.62 ( 14.846 )
    -2.73 ( 16.097 )
        Week 16
    6.35 ( 17.946 )
    -3.12 ( 14.435 )
        Week 28
    7.56 ( 14.309 )
    0.16 ( 15.201 )
        Week 52
    7.36 ( 13.996 )
    2.50 ( 10.697 )
        Week 80
    4.50 ( 18.273 )
    999 ( 999 )
        Week 92
    6.77 ( 18.948 )
    999 ( 999 )
        Week 104
    6.25 ( 18.143 )
    999 ( 999 )
        Week 117
    6.42 ( 15.130 )
    999 ( 999 )
        Week 130
    7.70 ( 16.488 )
    999 ( 999 )
        Week 143
    5.68 ( 17.332 )
    999 ( 999 )
        Week 156
    4.74 ( 19.032 )
    999 ( 999 )
        Week 169
    6.08 ( 18.717 )
    999 ( 999 )
        Week 182
    7.68 ( 17.992 )
    999 ( 999 )
        Week 195
    6.41 ( 18.239 )
    999 ( 999 )
        Week 208
    7.94 ( 18.614 )
    999 ( 999 )
        Week 221
    3.64 ( 19.866 )
    999 ( 999 )
        Week 234
    5.48 ( 18.625 )
    999 ( 999 )
        Week 247
    6.28 ( 17.854 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D-5L VAS, by visit in patients from BAT group who cross over to ruxolitinib after crossover

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    End point title
    		 Change from Baseline in EQ-5D-5L VAS, by visit in patients from BAT group who cross over to ruxolitinib after crossover [6]
    End point description
    EQ-5D-5L is a standardized instrument for measuring health outcomes in a wide range of health conditions and treatments. It consists of visual analogue scale (EQ VAS) which records the respondent’s self-rated health on a vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health state’ and ‘worst imaginable health state’. The EQ VAS scores were anchored on 100 = the best health you can imagine and 0 = worst health you can imagine.
    End point type
    Secondary
    End point timeframe
    Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 52, 92, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234 and 247 after cross-over
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Best Available Therapy (BAT)
    Number of subjects analysed
    58
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week +4
    4.54 ( 14.756 )
        Week +8
    4.62 ( 15.807 )
        Week +16
    6.58 ( 14.667 )
        Week +24
    6.38 ( 17.564 )
        Week +28
    5.26 ( 15.923 )
        Week +52
    4.71 ( 21.006 )
        Week 92
    8.09 ( 16.119 )
        Week 104
    6.48 ( 18.085 )
        Week 117
    4.92 ( 16.983 )
        Week 130
    4.87 ( 20.047 )
        Week 143
    3.19 ( 17.798 )
        Week 156
    2.65 ( 20.221 )
        Week 169
    4.59 ( 13.731 )
        Week 182
    2.71 ( 19.673 )
        Week 195
    5.65 ( 18.286 )
        Week 208
    5.35 ( 18.099 )
        Week 221
    7.71 ( 16.701 )
        Week 234
    5.30 ( 18.342 )
        Week 247
    4.14 ( 16.427 )
    No statistical analyses for this end point

    Secondary: Change from baseline in work productivity and activity impairment (WPAI) questionnaire

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    End point title
    		 Change from baseline in work productivity and activity impairment (WPAI) questionnaire
    End point description
    The Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) is a six item questionnaire which intended to measure work and activity impairment associated with polycythemia vera. WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to the polycythemia vera; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the polycythemia vera on productivity while working; Q6=Impact of the polycythemia vera on productivity while doing regular daily activities other than work). Higher WPAI scores indicated greater activity impairment. Scores were multiplied by 100 to express in percentages. Percent work time missed due to problem (past 7 days) =Q2/(Q2+Q4) Percent impairment while working due to problem (past 7 days): Q5/10 Percent overall work impairment due to problem (past 7 says): Q2/(Q2+Q4)+[(1 Q2/(Q2+Q4))x(Q5/10)] Percent activity impairment due to problem (past 7 says): Q6/10
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16, 28, 52 and 80
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Percent
    arithmetic mean (standard deviation)
        Percent work time missed Week 4
    -5.50 ( 18.425 )
    -0.40 ( 13.928 )
        Percent work time missed Week 8
    -4.88 ( 13.381 )
    -4.35 ( 20.820 )
        Percent work time missed Week 16
    4.50 ( 35.948 )
    4.79 ( 25.917 )
        Percent work time missed Week 28
    -5.85 ( 17.119 )
    -2.19 ( 9.852 )
        Percent work time missed Week 52
    -2.82 ( 30.770 )
    -8.33 ( 11.785 )
        Percent work time missed Week 80
    1.87 ( 34.151 )
    999 ( 999 )
        Percent impairment while working Week 4
    -6.67 ( 23.310 )
    0.00 ( 14.951 )
        Percent impairment while working Week 8
    -13.16 ( 19.164 )
    -0.59 ( 13.449 )
        Percent impairment while working Week 16
    -14.00 ( 21.374 )
    4.12 ( 16.977 )
        Percent impairment while working Week 28
    -14.29 ( 23.994 )
    -10.00 ( 14.142 )
        Percent impairment while working Week 52
    -10.00 ( 23.170 )
    -20.00 ( 42.426 )
        Percent impairment while working Week 80
    -14.76 ( 26.385 )
    999 ( 999 )
        Percent overall work impairment Week 4
    -9.63 ( 22.495 )
    -2.34 ( 14.807 )
        Percent overall work impairment Week 8
    -11.32 ( 18.505 )
    -4.38 ( 17.568 )
        Percent overall work impairment Week 16
    -10.26 ( 33.296 )
    5.34 ( 22.063 )
        Percent overall work impairment Week 28
    -15.98 ( 23.077 )
    -8.85 ( 11.722 )
        Percent overall work impairment Week 52
    -12.61 ( 27.576 )
    -22.50 ( 45.962 )
        Percent overall work impairment Week 80
    -14.36 ( 30.691 )
    999 ( 999 )
        Percent activity impairment Week 4
    -11.97 ( 22.122 )
    2.42 ( 24.310 )
        Percent activity impairment Week 8
    -11.58 ( 24.985 )
    1.97 ( 16.413 )
        Percent activity impairment Week 16
    -14.36 ( 25.222 )
    0.65 ( 18.980 )
        Percent activity impairment Week 28
    -11.67 ( 25.826 )
    2.73 ( 23.941 )
        Percent activity impairment Week 52
    -11.23 ( 25.360 )
    0.00 ( 15.374 )
        Percent activity impairment Week 80
    -11.09 ( 24.166 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in work productivity and activity impairment questionnaire (WPAI), by visit in patients from BAT group who cross over to ruxolitinib after crossover

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    End point title
    		 Change from Baseline in work productivity and activity impairment questionnaire (WPAI), by visit in patients from BAT group who cross over to ruxolitinib after crossover [7]
    End point description
    The Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) is a six item questionnaire which intended to measure work and activity impairment associated with polycythemia vera. WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to the polycythemia vera; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the polycythemia vera on productivity while working; Q6=Impact of the polycythemia vera on productivity while doing regular daily activities other than work). Higher WPAI scores indicated greater activity impairment. Scores were multiplied by 100 to express in percentages. Percent work time missed due to problem (past 7 days) =Q2/(Q2+Q4) Percent impairment while working due to problem (past 7 days): Q5/10 Percent overall work impairment due to problem (past 7 says): Q2/(Q2+Q4)+[(1 Q2/(Q2+Q4))x(Q5/10)] Percent activity impairment due to problem (past 7 says): Q6/10
    End point type
    Secondary
    End point timeframe
    Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28 and 52 after cross-over
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Best Available Therapy (BAT)
    Number of subjects analysed
    58
    Units: Percent
    arithmetic mean (standard deviation)
        Percent work time missed Week +4
    -7.45 ( 28.102 )
        Percent work time missed +8
    -3.90 ( 33.237 )
        Percent work time missed +16
    -2.66 ( 40.422 )
        Percent work time missed +24
    -1.67 ( 5.000 )
        Percent work time missed +28
    7.06 ( 21.757 )
        Percent work time missed +52
    1.12 ( 3.175 )
        Percent impairment while working Week +4
    -5.33 ( 9.904 )
        Percent impairment while working Week +8
    -4.29 ( 11.579 )
        Percent impairment while working Week +16
    -10.83 ( 20.207 )
        Percent impairment while working Week +24
    -6.92 ( 13.156 )
        Percent impairment while working Week +28
    -3.33 ( 23.868 )
        Percent impairment while working Week +52
    -6.00 ( 13.499 )
        Percent overall work impairment Week +4
    -10.98 ( 20.249 )
        Percent overall work impairment Week +8
    -6.91 ( 24.416 )
        Percent overall work impairment Week +16
    -4.73 ( 30.167 )
        Percent overall work impairment Week +24
    -6.06 ( 14.099 )
        Percent overall work impairment Week +28
    -1.81 ( 20.220 )
        Percent overall work impairment Week +52
    -4.03 ( 12.712 )
        Percent activity impairment Week +4
    -10.43 ( 19.886 )
        Percent activity impairment Week +8
    -8.63 ( 20.978 )
        Percent activity impairment Week +16
    -8.82 ( 21.877 )
        Percent activity impairment Week +24
    -6.47 ( 25.363 )
        Percent activity impairment Week +28
    -6.94 ( 26.395 )
        Percent activity impairment Week +52
    -7.00 ( 22.781 )
    No statistical analyses for this end point

    Secondary: Patient global impression of change (PGIC)

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    End point title
    		 Patient global impression of change (PGIC)
    End point description
    The Patient Global Impression of Change (PGIC) is comprised of a single question intended to measure a patient’s perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where one (1) equals very much improved and seven (7) equals very much worse.
    End point type
    Secondary
    End point timeframe
    Week 4, 8, 16, 28, 40, 52 and 80
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Week 4|Very much improved
    10
    0
        Week 8|Very much improved
    11
    1
        Week 16|Very much improved
    18
    2
        Week 28|Very much improved
    19
    0
        Week 40|Very much improved
    23
    0
        Week 52|Very much improved
    27
    2
        Week 66|Very much improved
    23
    1
        Week 80|Very much improved
    22
    0
        Week 4|Much improved
    22
    8
        Week 8|Much improved
    27
    14
        Week 16|Much improved
    25
    13
        Week 28|Much improved
    25
    4
        Week 40|Much improved
    30
    7
        Week 52|Much improved
    28
    5
        Week 66|Much improved
    31
    1
        Week 80|Much improved
    24
    0
        Week 4|Minimally improved
    21
    7
        Week 8|Minimally improved
    15
    9
        Week 16|Minimally improved
    13
    12
        Week 28|Minimally improved
    12
    5
        Week 40|Minimally improved
    5
    2
        Week 52|Minimally improved
    8
    1
        Week 66|Minimally improved
    6
    3
        Week 80|Minimally improved
    9
    0
        Week 4|No change
    14
    50
        Week 8|No change
    15
    35
        Week 16|No change
    8
    33
        Week 28|No change
    9
    15
        Week 40|No change
    6
    10
        Week 52|No change
    5
    5
        Week 66|No change
    6
    0
        Week 80|No change
    10
    0
        Week 4|Minimally worse
    1
    6
        Week 8|Minimally worse
    0
    10
        Week 16|Minimally worse
    2
    4
        Week 28|Minimally worse
    1
    3
        Week 40|Minimally worse
    2
    0
        Week 52|Minimally worse
    2
    1
        Week 66|Minimally worse
    1
    0
        Week 80|Minimally worse
    2
    0
        Week 4|Much worse
    0
    0
        Week 8|Much worse
    1
    0
        Week 16|Much worse
    0
    5
        Week 28|Much worse
    0
    0
        Week 40|Much worse
    0
    0
        Week 52|Much worse
    0
    0
        Week 66|Much worse
    0
    0
        Week 80|Much worse
    0
    0
        Week 4|Very much worse
    0
    1
        Week 8|Very much worse
    0
    1
        Week 16|Very much worse
    0
    0
        Week 28|Very much worse
    0
    0
        Week 40|Very much worse
    0
    0
        Week 52|Very much worse
    0
    0
        Week 66|Very much worse
    0
    0
        Week 80|Very much worse
    1
    0
    No statistical analyses for this end point

    Secondary: Summary of patient global impression of change (PGIC), by visit in patients from BAT group who cross over to ruxolitinib after crossover

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    End point title
    		 Summary of patient global impression of change (PGIC), by visit in patients from BAT group who cross over to ruxolitinib after crossover [8]
    End point description
    The Patient Global Impression of Change (PGIC) is comprised of a single question intended to measure a patient’s perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where one (1) equals very much improved and seven (7) equals very much worse.
    End point type
    Secondary
    End point timeframe
    Baseline (last assessment before cross over), Week 4, 8, 16, 24, 28, 40, and 52 after cross-over
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this outcome measure.
    End point values
    		 Best Available Therapy (BAT)
    Number of subjects analysed
    58
    Units: Participants
        Week +4|Very much improved
    10
        Week +8|Very much improved
    11
        Week +16|Very much improved
    12
        Week +24|Very much improved
    19
        Week +28|Very much improved
    18
        Week +40|Very much improved
    18
        Week +52|Very much improved
    17
        Week +4|Much improved
    13
        Week +8|Much improved
    25
        Week +16|Much improved
    28
        Week +24|Much improved
    17
        Week +28|Much improved
    19
        Week +40|Much improved
    15
        Week +52|Much improved
    16
        Week +4|Minimally improved
    13
        Week +8|Minimally improved
    9
        Week +16|Minimally improved
    6
        Week +24|Minimally improved
    5
        Week +28|Minimally improved
    6
        Week +40|Minimally improved
    5
        Week +52|Minimally improved
    6
        Week +4|No change
    16
        Week +8|No change
    7
        Week +16|No change
    6
        Week +24|No change
    8
        Week +28|No change
    6
        Week +40|No change
    6
        Week +52|No change
    3
        Week +4|Minimally worse
    0
        Week +8|Minimally worse
    1
        Week +16|Minimally worse
    0
        Week +24|Minimally worse
    1
        Week +28|Minimally worse
    1
        Week +40|Minimally worse
    0
        Week +52|Minimally worse
    0
        Week +4|Much worse
    0
        Week +8|Much worse
    0
        Week +16|Much worse
    0
        Week +24|Much worse
    0
        Week +28|Much worse
    0
        Week +40|Much worse
    0
        Week +52|Much worse
    0
    No statistical analyses for this end point

    Secondary: Number of participants developing thrombosis

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    End point title
    		 Number of participants developing thrombosis
    End point description
    Proportion of participants developing any arterial or venous thromboembolic event
    End point type
    Secondary
    End point timeframe
    From randomization to Week 80 for BAT and Week 260 for Ruxolitinib
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Post-hoc: Total number of deaths

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    End point title
    		 Total number of deaths
    End point description
    On-treatment deaths were reported from the day of first dose of study medication to the End of study (End of Treatment +30 days) visit which was Week 260 or prior (+30 days for Rux + crossover) and Week 80 or prior (+30 days for BAT only). Post-treatment deaths were reported following completion study treatment (Week 80 for patients receiving BAT, or Week 260 for patients receiving ruxolitinib) or from the time of premature discontinuation. Patients were followed for survival every three months up to end of study.
    End point type
    Post-hoc
    End point timeframe
    Up to Week 260
    End point values
    		 Ruxolitinib Best Available Therapy (BAT)
    Number of subjects analysed
    74
    75
    Units: Participants
        Death up to 30 days after EOT
    1
    1
        Death after cross over (BAT arm only)
    0
    3
        Death more than 30 days after EOT
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the day of first dose of study medication to the End of study (End of Treatment +30 days) visit which was Week 260 or prior (+30 days for Rux + crossover) and Week 80 or prior (+30 days for BAT only).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Ruxolitinib
    Reporting group description
    		 Ruxolitinib at a starting dose of 10 mg twice a day (bid). Dose was adjusted based on efficacy and safety parameters up to a maximum dose of 25 mg bid

    Reporting group title
    All crossover patients
    Reporting group description
    		 All crossover patients

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 Best Available Therapy as selected by the investigator from: Hydroxyurea, Pegylated-Interferon (IFN/PEG-IFN), pipobroman, anagrelide, IMIDs, or observation. Participants randomized to BAT who did not respond by Week 28 were eligible to crossover and start treatment with ruxolitinib

    Serious adverse events
    		 Ruxolitinib All crossover patients Best Available Therapy (BAT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 74 (45.95%)
    23 / 58 (39.66%)
    9 / 75 (12.00%)
         number of deaths (all causes)
    1
    3
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    7 / 10
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blast cell crisis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Bone marrow tumour cell infiltration
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Bowen's disease
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoma in situ
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Juvenile melanoma benign
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Metastases to spine
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Prostate cancer
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Renal cancer
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Skin cancer
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    6 / 8
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine neoplasm
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Vaginal cancer
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Blue toe syndrome
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Extremity necrosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Venous haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    General physical health deterioration
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Dyspnoea exertional
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Hypoxia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Blood uric acid increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Weight decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Muscle rupture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Radius fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Spinal fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Tendon rupture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Ulna fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Angina pectoris
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Atrial fibrillation
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Mitral valve incompetence
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Cognitive disorder
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Dizziness
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Epilepsy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Facial neuralgia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Syncope
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperleukocytosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Neutropenia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Retinal artery occlusion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Vision blurred
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Visual acuity reduced
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Abdominal pain
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Inguinal hernia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Nausea
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Urethral stenosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Haemarthrosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Osteoarthritis
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 58 (5.17%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Influenza
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Meningitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Pneumonia
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 58 (3.45%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Pyonephrosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Sepsis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Septic shock
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Urinary tract infection
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Dehydration
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    0 / 75 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Hyperuricaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    0 / 75 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         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
    		 Ruxolitinib All crossover patients Best Available Therapy (BAT)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 74 (98.65%)
    56 / 58 (96.55%)
    56 / 75 (74.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 58 (5.17%)
    0 / 75 (0.00%)
         occurrences all number
    2
    4
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    10 / 74 (13.51%)
    4 / 58 (6.90%)
    1 / 75 (1.33%)
         occurrences all number
    12
    6
    1
    Hypertension
         subjects affected / exposed
    15 / 74 (20.27%)
    11 / 58 (18.97%)
    3 / 75 (4.00%)
         occurrences all number
    18
    15
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 74 (10.81%)
    6 / 58 (10.34%)
    6 / 75 (8.00%)
         occurrences all number
    11
    12
    7
    Fatigue
         subjects affected / exposed
    13 / 74 (17.57%)
    6 / 58 (10.34%)
    6 / 75 (8.00%)
         occurrences all number
    15
    7
    7
    Oedema peripheral
         subjects affected / exposed
    10 / 74 (13.51%)
    6 / 58 (10.34%)
    2 / 75 (2.67%)
         occurrences all number
    13
    6
    2
    Pyrexia
         subjects affected / exposed
    13 / 74 (17.57%)
    7 / 58 (12.07%)
    1 / 75 (1.33%)
         occurrences all number
    23
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 74 (9.46%)
    6 / 58 (10.34%)
    2 / 75 (2.67%)
         occurrences all number
    11
    7
    2
    Dyspnoea
         subjects affected / exposed
    11 / 74 (14.86%)
    4 / 58 (6.90%)
    2 / 75 (2.67%)
         occurrences all number
    11
    4
    2
    Epistaxis
         subjects affected / exposed
    4 / 74 (5.41%)
    7 / 58 (12.07%)
    2 / 75 (2.67%)
         occurrences all number
    7
    7
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 58 (3.45%)
    1 / 75 (1.33%)
         occurrences all number
    5
    2
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 74 (12.16%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences all number
    11
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences all number
    5
    2
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 58 (6.90%)
    1 / 75 (1.33%)
         occurrences all number
    2
    4
    1
    Haematocrit increased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 58 (1.72%)
    5 / 75 (6.67%)
         occurrences all number
    0
    1
    5
    Weight decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 58 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    1
    0
    4
    Weight increased
         subjects affected / exposed
    19 / 74 (25.68%)
    9 / 58 (15.52%)
    1 / 75 (1.33%)
         occurrences all number
    22
    10
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 74 (10.81%)
    7 / 58 (12.07%)
    5 / 75 (6.67%)
         occurrences all number
    10
    11
    5
    Headache
         subjects affected / exposed
    13 / 74 (17.57%)
    8 / 58 (13.79%)
    9 / 75 (12.00%)
         occurrences all number
    19
    9
    10
    Memory impairment
         subjects affected / exposed
    0 / 74 (0.00%)
    4 / 58 (6.90%)
    0 / 75 (0.00%)
         occurrences all number
    0
    4
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 58 (5.17%)
    0 / 75 (0.00%)
         occurrences all number
    0
    3
    0
    Paraesthesia
         subjects affected / exposed
    7 / 74 (9.46%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences all number
    7
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 74 (36.49%)
    19 / 58 (32.76%)
    1 / 75 (1.33%)
         occurrences all number
    48
    29
    1
    Thrombocytopenia
         subjects affected / exposed
    5 / 74 (6.76%)
    3 / 58 (5.17%)
    6 / 75 (8.00%)
         occurrences all number
    7
    3
    12
    Leukocytosis
         subjects affected / exposed
    5 / 74 (6.76%)
    3 / 58 (5.17%)
    4 / 75 (5.33%)
         occurrences all number
    6
    6
    5
    Thrombocytosis
         subjects affected / exposed
    8 / 74 (10.81%)
    5 / 58 (8.62%)
    3 / 75 (4.00%)
         occurrences all number
    10
    9
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences all number
    7
    1
    1
    Tinnitus
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 58 (5.17%)
    2 / 75 (2.67%)
         occurrences all number
    3
    3
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 58 (6.90%)
    2 / 75 (2.67%)
         occurrences all number
    1
    5
    3
    Abdominal distension
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    8
    0
    1
    Abdominal pain
         subjects affected / exposed
    10 / 74 (13.51%)
    8 / 58 (13.79%)
    1 / 75 (1.33%)
         occurrences all number
    12
    9
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 58 (3.45%)
    3 / 75 (4.00%)
         occurrences all number
    5
    2
    3
    Constipation
         subjects affected / exposed
    13 / 74 (17.57%)
    8 / 58 (13.79%)
    4 / 75 (5.33%)
         occurrences all number
    14
    11
    4
    Diarrhoea
         subjects affected / exposed
    7 / 74 (9.46%)
    4 / 58 (6.90%)
    7 / 75 (9.33%)
         occurrences all number
    7
    4
    9
    Flatulence
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 58 (5.17%)
    1 / 75 (1.33%)
         occurrences all number
    1
    4
    1
    Dyspepsia
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 58 (6.90%)
    2 / 75 (2.67%)
         occurrences all number
    5
    4
    3
    Nausea
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 58 (5.17%)
    5 / 75 (6.67%)
         occurrences all number
    4
    3
    5
    Vomiting
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 58 (6.90%)
    1 / 75 (1.33%)
         occurrences all number
    3
    5
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 58 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    2
    0
    7
    Pruritus
         subjects affected / exposed
    12 / 74 (16.22%)
    7 / 58 (12.07%)
    17 / 75 (22.67%)
         occurrences all number
    16
    7
    18
    Night sweats
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 58 (1.72%)
    5 / 75 (6.67%)
         occurrences all number
    8
    1
    6
    Skin ulcer
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences all number
    4
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 74 (27.03%)
    6 / 58 (10.34%)
    3 / 75 (4.00%)
         occurrences all number
    23
    7
    3
    Back pain
         subjects affected / exposed
    12 / 74 (16.22%)
    7 / 58 (12.07%)
    0 / 75 (0.00%)
         occurrences all number
    12
    8
    0
    Bone pain
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    4
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 58 (1.72%)
    0 / 75 (0.00%)
         occurrences all number
    4
    1
    0
    Muscle spasms
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 58 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    6
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 58 (1.72%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    1
    Myalgia
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 58 (3.45%)
    2 / 75 (2.67%)
         occurrences all number
    7
    3
    2
    Osteoporosis
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    4
    0
    0
    Osteoarthritis
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 58 (3.45%)
    1 / 75 (1.33%)
         occurrences all number
    6
    2
    1
    Pain in extremity
         subjects affected / exposed
    11 / 74 (14.86%)
    4 / 58 (6.90%)
    2 / 75 (2.67%)
         occurrences all number
    15
    6
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 74 (16.22%)
    2 / 58 (3.45%)
    2 / 75 (2.67%)
         occurrences all number
    12
    2
    2
    Cystitis
         subjects affected / exposed
    10 / 74 (13.51%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences all number
    13
    2
    0
    Herpes zoster
         subjects affected / exposed
    11 / 74 (14.86%)
    8 / 58 (13.79%)
    0 / 75 (0.00%)
         occurrences all number
    13
    8
    0
    Influenza
         subjects affected / exposed
    10 / 74 (13.51%)
    2 / 58 (3.45%)
    4 / 75 (5.33%)
         occurrences all number
    12
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    8 / 74 (10.81%)
    10 / 58 (17.24%)
    2 / 75 (2.67%)
         occurrences all number
    12
    16
    2
    Sinusitis
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 58 (5.17%)
    0 / 75 (0.00%)
         occurrences all number
    1
    3
    0
    Urinary tract infection
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 58 (3.45%)
    0 / 75 (0.00%)
         occurrences all number
    13
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 58 (8.62%)
    7 / 75 (9.33%)
         occurrences all number
    6
    9
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 58 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    5
    0
    4
    Dyslipidaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    4 / 58 (6.90%)
    0 / 75 (0.00%)
         occurrences all number
    0
    4
    0
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 58 (8.62%)
    0 / 75 (0.00%)
         occurrences all number
    5
    5
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 58 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    4
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 58 (5.17%)
    1 / 75 (1.33%)
         occurrences all number
    3
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2014
    -At most one phlebotomy was allowed between randomization and Week 4, which was changed from randomization to Week 8. -Study treatment period was extended up to 5 years from the last patient randomized and Survival follow-up after treatment discontinuation to be conducted in all patients until last patient last visit. -Addition of secondary endpoints. -Change to local labs for the hematology assessments. -Sample size increased from 104 to 130 patients.
    24 Mar 2016
    -Removal of data cut, 52 weeks after last patient first visit (LPFV). -End of Study definition changed: The study was extended to a total of 5 years and 30 days from the date when the last patient was randomized.

    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.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    For support, Contact us.
    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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