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    Clinical Trial Results:
    A Phase III randomized open-label multi-center study of ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation 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

    Summary
    EudraCT number
    		 2016-002584-33
    Trial protocol
    		 DE   IT   ES   AT   FR   NO   SE   DK   GB   CZ   PT   HU   BG   PL   NL   GR  
    Global end of trial date
    23 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Nov 2021
    First version publication date
    08 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424C2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02913261
    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 8627788300, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 8627788300, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000901-PIP03-16
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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.
    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
    10 Mar 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Japan: 30
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Saudi Arabia: 3
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Turkey: 12
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Israel: 16
    Worldwide total number of subjects
    309
    EEA total number of subjects
    188
    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)
    9
    Adults (18-64 years)
    243
    From 65 to 84 years
    57
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 310 patients with SR-aGvHD were enrolled, out of which 309 patients were included in the analysis (as one patient did not sign the study informed consent prior to receiving BAT (protocol deviation) and was excluded from all analyses). Completed = Completed the treatment period Not completed = Discontinued from treatment period

    Pre-assignment
    Screening details
    		 The screening period ranged from Day -28 to Day -1. Screening activities and assessment of inclusion and exclusion criteria began once the patient was diagnosed with aGvHD. Any occurrence of SR-aGvHD was monitored closely.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ruxolitinib (RUX)
    Arm description
    		 These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ruxolitinib was administered orally twice per day at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regard to food.

    Arm title
    		 Best Available Therapy (BAT)
    Arm description
    		 These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    9 different BATS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid, Tablet, Capsule, Cutaneous liquid
    Routes of administration
    Intravenous use, Subcutaneous use, Oral use
    Dosage and administration details
    Multiform forms of BATs: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), everolimus, sirolimus, etanercept, infliximab

    Number of subjects in period 1
    		Ruxolitinib (RUX) Best Available Therapy (BAT)
    Started
    154
    155
    Not treated
    2 [1]
    5 [2]
    Crossover treatment at end of rand.
    0 [3]
    49
    Entered long-term follow-up
    102
    51
    Completed
    35
    20
    Not completed
    119
    135
         Adverse event, serious fatal
    25
    22
         Physician decision
    8
    9
         Graft loss
    2
    -
         Adverse event, non-fatal
    27
    5
         Technical problems
    -
    1
         Failure to meet protocol continuation criteria
    13
    10
         Disease relapse
    8
    13
         Subject/guardian decision
    4
    6
         Lack of efficacy
    32
    69
    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: These were patients who were never treated with study drug
    [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: These were only the patients who crossed over from BAT to study drug - ruxolitinib. Patients from ruxolitinib did not cross over to BAT.
    [3] - 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: Not all patients were in the long term follow up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ruxolitinib (RUX)
    Reporting group description
    		 These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

    Reporting group values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT) Total
    Number of subjects
    		 154 155 309
    Age Categorical
    Units: Participants
        Adolescents, 12 - <18 years
    		 5 4 9
        18 - 65 years
    		 128 126 254
        >65 years
    		 21 25 46
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.1 ± 16.30 50.9 ± 14.97 -
    Sex: Female, Male
    Units:
        Female
    		 62 64 126
        Male
    		 92 91 183
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 111 102 213
        Black or African American
    		 0 1 1
        Asian
    		 19 29 48
        Other
    		 8 4 12
        Unknown
    		 16 19 35
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 67.5 ± 14.04 66.2 ± 14.78 -

    End points

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    End points reporting groups
    Reporting group title
    Ruxolitinib (RUX)
    Reporting group description
    		 These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

    Subject analysis set title
    Cross-Over
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These were patients randomized to BAT who were eligible to cross over to Ruxolitinib between Day 28 and Week 24.

    Primary: Overall response rate (ORR) at Day 28

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    End point title
    		 Overall response rate (ORR) at Day 28
    End point description
    Overall response rate at Day 28 after randomization was defined as the percentage participants in each arm demonstrating a complete response (CR) or partial response (PR), based on investigator assessment & according to standard criteria, without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the time of randomization. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs & symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Primary
    End point timeframe
    Day 28
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
        number (confidence interval 95%)
    62.3 (54.2 to 70.0)
    39.4 (31.6 to 47.5)
    Statistical analysis title
    		 ORR at Day 28
    Comparison groups
    Ruxolitinib (RUX) v Best Available Therapy (BAT)
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 4.22

    Secondary: Durable overall response rate (DORR) (Key Secondary endpoint) at Day 56

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    End point title
    		 Durable overall response rate (DORR) (Key Secondary endpoint) at Day 56
    End point description
    Percentage of all participants in each arm who achieved a complete response (CR) or partial response (PR) at Day 28 (primary endpoint) AND maintained a CR or PR at Day 56 based on investigator assessment and according to standard criteria. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Secondary
    End point timeframe
    Day 56
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
        number (confidence interval 95%)
    39.6 (31.8 to 47.8)
    21.9 (15.7 to 29.3)
    Statistical analysis title
    		 DORR at Day 56
    Comparison groups
    Ruxolitinib (RUX) v Best Available Therapy (BAT)
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0005
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 3.94

    Secondary: Overall response rate (ORR) at Day 14

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    End point title
    		 Overall response rate (ORR) at Day 14
    End point description
    ORR at Da4 14 is the percentage of participants who achieved overall response (CR+PR) at Day 14 based on investigator assessment and according to standard criteria. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
        number (confidence interval 95%)
    63.0 (54.8 to 70.6)
    47.1 (39.0 to 55.3)
    Statistical analysis title
    		 ORR at Day 14
    Comparison groups
    Ruxolitinib (RUX) v Best Available Therapy (BAT)
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0029
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 3.17

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    Duration of response was defined for patients who had a CR or PR at Day 28. This was the interval between the date of first documented response of CR or PR (i.e., the start date of response), till the date of progression or addition of systemic therapies for aGvHD on or after Day 28. Death without prior observation of aGvHD progression and onset of chronic GvHD were considered. Duration of response was censored at the last response assessment prior to or at the analysis cut-off date, if no events/competing risk occurred before or at the cut-off date.
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    98
    62
    Units: Days
        median (full range (min-max))
    167.0 (22.0 to 677.0)
    106.0 (10.0 to 526.0)
    No statistical analyses for this end point

    Secondary: Cumulative steroid dosing until Day 56

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    End point title
    		 Cumulative steroid dosing until Day 56
    End point description
    Weekly cumulative steroid dose for each participant up to Day 56 or discontinuation of randomized treatment. Participants should have undergone tapering of steroids if it had been required. Tapering the immunosuppression therapy was performed in 2 steps: Taper of corticosteroids: initiated not earlier than Day 7, and performed as per institutional guidelines.
    End point type
    Secondary
    End point timeframe
    up to Day 56
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: mg
    median (full range (min-max))
        By Week 1 (n = 151, 154)
    962.5 (140.0 to 2337.5)
    923.6 (140.0 to 6093.8)
        By Week 2 (n = 150, 150)
    1740.0 (280.0 to 3500.0)
    1725.0 (280.0 to 7173.3)
        By Week 3 (n = 143, 141)
    2375.0 (350.0 to 5250.0)
    2340.0 (370.0 to 8000.0)
        By Week 4 (n = 132, 136)
    2866.9 (420.0 to 7000.0)
    2816.3 (420.0 to 9050.0)
        By Week 5 (n = 124, 106)
    3268.1 (455.0 to 8750.0)
    3290.6 (420.0 to 9825.0)
        By Week 6 (n = 115, 84)
    3606.3 (490.0 to 10500.0)
    3543.8 (420.0 to 10435.0)
        By Week 7 (n = 107, 75)
    3850.0 (495.0 to 11250.0)
    3706.3 (420.0 to 10955.0)
        By Week 8 (n = 87, 67)
    4000.0 (857.5 to 9475.0)
    4006.3 (420.0 to 11875.0)
    No statistical analyses for this end point

    Secondary: Patient Reported Outcomes (PROs): Change from Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Total score

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    End point title
    		 Patient Reported Outcomes (PROs): Change from Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Total score
    End point description
    The Functional assessment of Cancer Therapy – Bone Marrow Transplant (FACT-BMT) is a 50-item self-report questionnaire that measures the effect of a therapy on domains including physical, functional, social/family and emotional well-being, together with additional concerns relevant for bone marrow transplantation patients. Patients are requested to indicate their response on a scale of 0 to 4 on each statement. Depending on the statement, 0 or 4 may mean the best or worst feeling. Descriptive statistics (mean, standard deviation, median, Q1, Q3, minimum, and maximum) were calculated based on the scored scales at each scheduled assessment time point. Additionally, change from baseline in the scores at the time of each assessment were also calculated. Missing items data in a scale were handled based on each instrument manual. No imputation were applied if the total or subscale scores are missing at a visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: scores on a scale
    median (full range (min-max))
        Baseline (n = 106, 94)
    89.00 (41.0 to 138.0)
    81.00 (29.0 to 129.0)
        Week (W) 24 (n = 36, 13)
    108.50 (67.0 to 139.0)
    86.00 (21.0 to 124.0)
        Change from Baseline to W24 (n = 29, 12)
    9.00 (-40.0 to 44.0)
    4.50 (-29.0 to 41.0)
    No statistical analyses for this end point

    Secondary: Patient Reported Outcomes (PROs): Change from Baseline in EuroQol-5D-5L UK Score

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    End point title
    		 Patient Reported Outcomes (PROs): Change from Baseline in EuroQol-5D-5L UK Score
    End point description
    The EQ-5D descriptive classification consists of five dimensions of health: mobility, self-care, usual activities, anxiety/depression and pain/discomfort. Patients are requested to select the statement which best describes their condition on that day for each dimension. For overall health that day, the EuroQoL-5D-5L scale is numbered from 0 to 100, with 100 being the best health you can imagine and 0 being the worst health you can imagine. Descriptive statistics (mean, standard deviation, median, Q1, Q3, minimum, and maximum) were calculated based on the scored scales at each scheduled assessment time point. In order to measure Quality-of-Life (QoL) among aGvHD patients, and potential changes over time, change from baseline in EuroQol-5D-5L scores at the time of each assessment were also calculated. Missing items data in a scale will be handled based on each instrument manual. No imputation will be applied if the total or subscale scores are missing at a visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: scores on a scale
    median (full range (min-max))
        Baseline (n= 122, 118)
    0.60 (-0.6 to 1.0)
    0.54 (-0.6 to 1.0)
        W24 (n = 36, 14)
    0.78 (0.4 to 1.0)
    0.68 (-0.1 to 1.0)
        Change from Baseline (n = 32, 12)
    0.12 (-0.3 to 1.1)
    0.12 (-0.2 to 0.3)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Area Under the Curve (AUC) (AUCinf, AUClast, AUCtau) of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Area Under the Curve (AUC) (AUCinf, AUClast, AUCtau) of Ruxolitinib [1]
    End point description
    AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) AUCinf: The AUC from time zero to infinity (mass x time x volume-1) AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    Notes
    [1] - 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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1 AUCinf (n = 11)
    529.6 ± 55.2
        Week 1 Day 1 AUClast (n = 26)
    522.9 ± 89.6
        Week 1 Day 1 AUCtau (n = 20)
    578.9 ± 97.5
        Week 1 Day 7 AUCinf (n = 9)
    440.9 ± 91.5
        Week 1 Day 7 AUClast (n = 22)
    597.3 ± 73.2
        Week 1 Day 7 AUCtau (n = 18)
    651.9 ± 86.4
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Plasma concentration at peak (Cmax) of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Plasma concentration at peak (Cmax) of Ruxolitinib [2]
    End point description
    Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass X volume-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    26
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1
    118 ± 70.4
        Week 1 Day 7 (n = 22)
    129.3 ± 76.0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: CL/F of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: CL/F of Ruxolitinib [3]
    End point description
    CL/F is the total body clearance of ruxolitinib from the plasma after a single dose and at steady state. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was assayed for Ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: L/hr
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1 CL/F (n = 11)
    18.88 ± 55.2
        Week 1 Day 7 CL/F (n = 9)
    23.31 ± 89.4
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: VzF of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: VzF of Ruxolitinib [4]
    End point description
    VzF is the apparent volume of distribution during terminal phase after a single dose and at steady state. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: Liters (L)
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1 (n = 11)
    52.57 ± 46.4
        Week 1 Day 7 (n = 9)
    66.76 ± 71.6
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Lambda_z of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Lambda_z of Ruxolitinib [5]
    End point description
    Lambda_z is the smallest (slowest) disposition (hybrid) rate constant (hr-1) may also be used for terminal elimination rate constant (hr-1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: 1/hr
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1 (n = 11)
    0.3592 ± 34.2
        Week 1 Day 7 (n = 9)
    0.3492 ± 31.0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: T1/2 of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: T1/2 of Ruxolitinib [6]
    End point description
    T1/2 is the elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve (hr). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: hour (hr)
    geometric mean (geometric coefficient of variation)
        Week 1 Day 1 (n = 11)
    1.93 ± 34.2
        Week 1 Day 7 (n = 9)
    1.985 ± 31.0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Tmax of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Tmax of Ruxolitinib [7]
    End point description
    Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose and repeated dose administration (hr). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: hour (hr)
    median (full range (min-max))
        Week 1 Day 1 (n = 26)
    1.767 (0.5167 to 8.917)
        Week 1 Day 7 (n = 22)
    1.542 (0.5 to 4.083)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Racc of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Racc of Ruxolitinib [8]
    End point description
    Racc is the accumulation ratio (AUC at steady state/AUC Day 1). Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients was be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 1.5, 2, 4, 6, 9 hrs post-dose
    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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: ratio
        geometric mean (geometric coefficient of variation)
    1.145 ± 27.2
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Ctrough of Ruxolitinib

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    End point title
    		 Pharmacokinetic (PK) parameter: Ctrough of Ruxolitinib [9]
    End point description
    Minimum concentration (Ctrough) of ruxolitinib and at steady state in corticosteroid refractory acute GVHD patients. Plasma samples for PK was taken at Day 1 (start of treatment), at Day 7 (week 1) to characterize the PK after first dose, and at steady state by non-compartmental analysis. The plasma samples from all patients will be assayed for ruxolitinib concentrations using validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS)
    End point type
    Secondary
    End point timeframe
    pre-dose
    Notes
    [9] - 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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    152
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    17.22 ± 187.1
    No statistical analyses for this end point

    Secondary: Cumulative Incidence rate of Failure-Free survival (FFS)

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    End point title
    		 Cumulative Incidence rate of Failure-Free survival (FFS)
    End point description
    FFS was defined as the time from the date of randomization to date of hematologic disease relapse/progression, non-relapse mortality, or addition of new systemic aGvHD treatment. Incidence rate for FFS with 95% CIs are presented for each treatment group, accounting for onset of chronic GvHD as the competing risk.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12, 18, & 24 Months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
    number (confidence interval 95%)
        1 Month
    17.92 (12.26 to 24.46)
    49.13 (40.94 to 56.80)
        2 Months
    35.39 (27.79 to 43.07)
    61.32 (53.00 to 68.61)
        6 Months
    53.67 (45.28 to 61.34)
    80.17 (72.52 to 85.89)
        12 Months
    58.64 (50.18 to 66.16)
    80.91 (73.32 to 86.54)
        18 Months
    59.35 (50.88 to 66.84)
    80.91 (73.32 to 86.54)
        24 Months
    61.48 (53.01 to 68.88)
    81.66 (74.12 to 87.19)
    No statistical analyses for this end point

    Secondary: Cumulative Incidence rate of Non Relapse Mortality (NRM)

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    End point title
    		 Cumulative Incidence rate of Non Relapse Mortality (NRM)
    End point description
    NRM was defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression was considered a competing risk for NRM with the date of hematologic disease relapse/progression being the earlier of documented hematologic disease relapse/progression or institution of therapy to treat potential hematologic disease relapse/progression. If a patient was not known to have died or to have relapsed/progressed, then NRM was censored at the latest date the patient was known to be alive (on or before the cut-off date). Data is provided based on incidence of hematologic disease relapse/progression.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12, 18 & 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
    number (confidence interval 95%)
        1 Month
    9.96 (5.83 to 15.39)
    14.52 (9.45 to 20.64)
        2 Months
    20.71 (14.61 to 27.54)
    23.54 (17.04 to 30.65)
        6 Months
    37.59 (29.81 to 45.33)
    42.42 (34.18 to 50.41)
        12 Months
    43.91 (35.75 to 51.77)
    46.11 (37.68 to 54.12)
        18 Months
    46.03 (37.77 to 53.89)
    49.21 (40.63 to 57.22)
        24 Months
    49.53 (40.91 to 57.55)
    49.99 (41.38 to 57.99)
    No statistical analyses for this end point

    Secondary: Cumulative Incidence rate of Malignancy Relapse/Progression (MR)

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    End point title
    		 Cumulative Incidence rate of Malignancy Relapse/Progression (MR)
    End point description
    MR was defined as the time from date of randomization to hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy relapse/progression were considered competing risks. If a patient was not known to have event or competing risks, then MR was censored at the latest date the patient was known to be alive (on or before the cut-off date). Calculated for patients with underlying hematologic malignant disease.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12 , 18 & 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    147
    147
    Units: Percentage of participants
    number (confidence interval 95%)
        1 Month
    0.69 (0.06 to 3.51)
    2.80 (0.92 to 6.54)
        2 Months
    4.21 (1.73 to 8.46)
    4.29 (1.75 to 8.60)
        6 Months
    8.46 (4.60 to 13.79)
    13.49 (8.32 to 19.91)
        12 Months
    10.68 (6.24 to 16.47)
    15.06 (9.56 to 21.71)
        18 Months
    12.91 (7.96 to 19.09)
    16.72 (10.89 to 23.64)
        24 Months
    14.75 (9.32 to 21.37)
    18.81 (12.46 to 26.17)
    No statistical analyses for this end point

    Secondary: Cumulative Incidence rate of chronic Graft versus Host Disease (cGvHD)

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    End point title
    		 Cumulative Incidence rate of chronic Graft versus Host Disease (cGvHD)
    End point description
    Incidence of cGvHD was the time from date of randomization to onset of cGvHD is the diagnosis of any cGvHD including mild, moderate, severe. Deaths without prior onset of cGvHD and hematologic disease relapse/progression were competing risks. If a patient was not known to have event or competing risks, then the incidence of cGvHD was censored at the latest date the patient was known to be alive (on or before the cut-off date). Calculated for patients with underlying hematologic malignant disease and the participants with incidence has been provided.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12, 18 & 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
    number (confidence interval 95%)
        1 Month
    0 (-999 to 999)
    1.33 (0.26 to 4.34)
        2 Months
    1.34 (0.26 to 4.39)
    2.03 (0.55 to 5.41)
        6 Months
    15.60 (10.26 to 21.96)
    12.19 (7.40 to 18.25)
        12 Months
    29.66 (22.41 to 37.25)
    20.24 (13.98 to 27.34)
        18 Months
    32.48 (24.96 to 40.20)
    23.36 (16.62 to 30.76)
        24 Months
    36.00 (28.20 to 43.84)
    24.95 (18.00 to 32.50)
    No statistical analyses for this end point

    Secondary: Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK- Durable Overall Response Rate (DORR)

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    End point title
    		 Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK- Durable Overall Response Rate (DORR) [10]
    End point description
    Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. DORR is the percentage of all participants in each arm who achieved a complete response (CR) or partial response (PR) at Day 28 (primary endpoint) AND maintained a CR or PR at Day 56. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Secondary
    End point timeframe
    Day 56
    Notes
    [10] - 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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    67
    Units: Percentage of participants
        number (not applicable)
    91.0
    No statistical analyses for this end point

    Secondary: Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK-Overall Response Rate

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    End point title
    		 Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK-Overall Response Rate [11]
    End point description
    Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) as assessed by local investigators. CR was defined as a score of 0 for the Acute Graft vs. Host Disease (aGvHD) grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Secondary
    End point timeframe
    Day 28
    Notes
    [11] - 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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    118
    Units: Percentage of participants
        number (not applicable)
    82.2
    No statistical analyses for this end point

    Secondary: Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK-Overall Survival

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    End point title
    		 Exposure-efficacy relationship of ruxolitinib in corticosteroid refractory aGvHD: PK-Overall Survival [12]
    End point description
    Exposure-efficacy relationship of ruxolitinib in terms of concentration-effect and dose-effect. Overall survival (OS) was defined as the time from the date of randomization to If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive (on or before the cut-off date).the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    up to 24 months
    Notes
    [12] - 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 statistics was planned for this endpoint
    End point values
    		 Ruxolitinib (RUX)
    Number of subjects analysed
    150
    Units: Percentage of participants
        number (not applicable)
    80.0
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from the date of randomization to date of death due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive (on or before the cut-off date). Results are based on Kaplan Meier (KM) estimates.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12, 18 & 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: months
    number (confidence interval 95%)
        KM median estimates: 0 - <1 Month
    90.04 (84.02 to 93.87)
    85.48 (78.79 to 90.19)
        KM median estimates: 1 - <2 Months
    77.95 (70.42 to 83.79)
    75.69 (67.92 to 81.83)
        KM median estimates: 2 - <6 Months
    58.38 (50.03 to 65.82)
    49.42 (40.89 to 57.37)
        KM median estimates: 6 - <12 Months
    49.27 (40.96 to 57.05)
    42.71 (34.39 to 50.75)
        KM median estimates: 12 - <18 Months
    42.94 (34.82 to 50.79)
    37.97 (29.86 to 46.03)
        KM median estimates: 18 - <24 Months
    38.65 (30.50 to 46.72)
    35.55 (27.57 to 43.59)
    No statistical analyses for this end point

    Secondary: Event-free survival

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    End point title
    		 Event-free survival
    End point description
    Event-free survival was defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. If a patient was not known to have any event, then EFS was censored at the latest date the patient was known to be alive (on or before the cut-off date). Results are based on Kaplan Meier (KM) estimates.
    End point type
    Secondary
    End point timeframe
    1, 2, 6, 12, 18 & 24 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Days
    median (confidence interval 95%)
        KM median estimates: 0 - <1 Month
    89.38 (83.24 to 93.35)
    82.83 (75.81 to 87.97)
        KM median estimates: 1 - <2 Months
    74.60 (66.82 to 80.82)
    71.72 (63.71 to 78.26)
        KM median estimates: 2- <6 Months
    53.68 (45.34 to 61.30)
    44.14 (35.82 to 52.13)
        KM median estimates: 6- <12 Months
    44.53 (36.36 to 52.36)
    39.98 (30.90 to 46.96)
        KM median estimates: 12- <18 Months
    40.29 (32.30 to 48.12)
    35.09 (27.23 to 43.04)
        KM median estimates: 18- <24 Months
    34.98 (27.01 to 43.04)
    32.38 (24.61 to 40.37)
    No statistical analyses for this end point

    Secondary: Best overall response rate (BOR)

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    End point title
    		 Best overall response rate (BOR)
    End point description
    Percentage of participants who achieved overall response (OR) (CR+PR) at any time point up to and including Day 28 and before the start of additional systemic therapy for aGvHD. CR was defined as a score of 0 for the Acute Graft vs. Host Disease (aGvHD) grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT)
    Number of subjects analysed
    154
    155
    Units: Percentage of participants
        number (confidence interval 95%)
    81.8 (74.8 to 87.6)
    60.6 (52.5 to 68.4)
    Statistical analysis title
    		 BOR
    Comparison groups
    Ruxolitinib (RUX) v Best Available Therapy (BAT)
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 5.25

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 708 days (treatment duration ranged from 6.0 to 678.0) for the RUX arm and 218 days (treatment duration ranged from 1.0 to 188.0 days) for the BAT arm. Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 49 months. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
    End point type
    Post-hoc
    End point timeframe
    approx. 708 days, approx. 49 months
    End point values
    		 Ruxolitinib (RUX) Best Available Therapy (BAT) Cross-Over
    Number of subjects analysed
    152
    150
    49
    Units: Participants
        Total Deaths
    89
    89
    29
        Deaths on-treatment
    43
    36
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 708 days for the RUX arm and 218 days for the BAT arm.
    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
    24.0
    Reporting groups
    Reporting group title
    Ruxolitinib (RUX) (Experimental)
    Reporting group description
    		 These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.

    Reporting group title
    Cross-Over
    Reporting group description
    		 These were patients randomized to BAT who were eligible to cross over to Ruxolitinib between Day 28 and Week 24.

    Reporting group title
    Best Available Therapy (BAT)
    Reporting group description
    		 These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

    Serious adverse events
    		 Ruxolitinib (RUX) (Experimental) Cross-Over Best Available Therapy (BAT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 152 (66.45%)
    38 / 49 (77.55%)
    80 / 150 (53.33%)
         number of deaths (all causes)
    89
    29
    89
         number of deaths resulting from adverse events
    10
    4
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute erythroid leukaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Anogenital warts
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Leukaemia recurrent
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microangiopathy
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Disease recurrence
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    Pyrexia
         subjects affected / exposed
    10 / 152 (6.58%)
    0 / 49 (0.00%)
    6 / 150 (4.00%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 0
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Acute graft versus host disease in intestine
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    2 / 150 (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 / 1
    Allergy to immunoglobulin therapy
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Serum sickness
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Perineal ulceration
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchial fistula
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Cough
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Dyspnoea
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 152 (0.00%)
    2 / 49 (4.08%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Pulmonary oedema
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    2 / 150 (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 / 1
    Respiratory disorder
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Respiratory distress
         subjects affected / exposed
    2 / 152 (1.32%)
    2 / 49 (4.08%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 152 (3.95%)
    6 / 49 (12.24%)
    6 / 150 (4.00%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    2 / 4
    0 / 4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Mental disorder
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Bacterial test positive
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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 bilirubin increased
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 49 (0.00%)
    0 / 150 (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
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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 condition abnormal
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Liver function test abnormal
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Neutrophil count decreased
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    White blood cell count decreased
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (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
    Graft loss
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Hip fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Infusion related reaction
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Rib fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Transplantation complication
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Cardiac arrest
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Nervous system disorders
    Basal ganglia haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Chorea
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Coma
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (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
    Depressed level of consciousness
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Mononeuropathy
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Stupor
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (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
    Tremor
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Febrile neutropenia
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 49 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Leukopenia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    3 / 152 (1.97%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 152 (1.97%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 152 (1.32%)
    2 / 49 (4.08%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Colitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Diarrhoea
         subjects affected / exposed
    8 / 152 (5.26%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 152 (1.32%)
    2 / 49 (4.08%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Ileal stenosis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Ileus
         subjects affected / exposed
    1 / 152 (0.66%)
    2 / 49 (4.08%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Intestinal ischaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Small intestinal obstruction
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Hepatic failure
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    2 / 150 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 152 (1.97%)
    2 / 49 (4.08%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Renal tubular necrosis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Muscular weakness
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Myopathy
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Bacteraemia
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Bacterial sepsis
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Cerebral aspergillosis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Clostridial sepsis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         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 viral
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus enteritis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 152 (1.97%)
    1 / 49 (2.04%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    3 / 152 (1.97%)
    2 / 49 (4.08%)
    6 / 150 (4.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Encephalitis viral
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Enteritis infectious
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Enterobacter sepsis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Enterococcal infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Escherichia infection
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (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
    Escherichia sepsis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Herpes zoster
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Human herpesvirus 6 infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Influenza
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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 enterococcal
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Mucormycosis
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (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
    Peritonitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    7 / 152 (4.61%)
    2 / 49 (4.08%)
    8 / 150 (5.33%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    1 / 4
    Pneumonia bacterial
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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 cytomegaloviral
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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 streptococcal
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    0 / 150 (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
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Sepsis
         subjects affected / exposed
    12 / 152 (7.89%)
    7 / 49 (14.29%)
    10 / 150 (6.67%)
         occurrences causally related to treatment / all
    6 / 14
    2 / 7
    1 / 10
         deaths causally related to treatment / all
    3 / 8
    1 / 2
    1 / 4
    Septic shock
         subjects affected / exposed
    10 / 152 (6.58%)
    3 / 49 (6.12%)
    8 / 150 (5.33%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    2 / 7
    0 / 0
    1 / 4
    Staphylococcal infection
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection viral
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Viral diarrhoea
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    0 / 150 (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
    Viral infection
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 49 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 49 (2.04%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 49 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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 (RUX) (Experimental) Cross-Over Best Available Therapy (BAT)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 152 (94.74%)
    43 / 49 (87.76%)
    136 / 150 (90.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 152 (13.82%)
    6 / 49 (12.24%)
    18 / 150 (12.00%)
         occurrences all number
    22
    7
    20
    Hypotension
         subjects affected / exposed
    15 / 152 (9.87%)
    1 / 49 (2.04%)
    10 / 150 (6.67%)
         occurrences all number
    17
    1
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 152 (7.24%)
    3 / 49 (6.12%)
    6 / 150 (4.00%)
         occurrences all number
    13
    3
    6
    Generalised oedema
         subjects affected / exposed
    5 / 152 (3.29%)
    0 / 49 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    5
    0
    8
    Oedema peripheral
         subjects affected / exposed
    37 / 152 (24.34%)
    5 / 49 (10.20%)
    32 / 150 (21.33%)
         occurrences all number
    45
    6
    39
    Pyrexia
         subjects affected / exposed
    29 / 152 (19.08%)
    9 / 49 (18.37%)
    21 / 150 (14.00%)
         occurrences all number
    38
    12
    29
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    14 / 152 (9.21%)
    3 / 49 (6.12%)
    7 / 150 (4.67%)
         occurrences all number
    15
    3
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 152 (10.53%)
    2 / 49 (4.08%)
    12 / 150 (8.00%)
         occurrences all number
    16
    2
    15
    Dyspnoea
         subjects affected / exposed
    8 / 152 (5.26%)
    3 / 49 (6.12%)
    6 / 150 (4.00%)
         occurrences all number
    9
    3
    6
    Epistaxis
         subjects affected / exposed
    8 / 152 (5.26%)
    2 / 49 (4.08%)
    6 / 150 (4.00%)
         occurrences all number
    9
    2
    6
    Pleural effusion
         subjects affected / exposed
    4 / 152 (2.63%)
    0 / 49 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    4
    0
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 152 (5.92%)
    1 / 49 (2.04%)
    4 / 150 (2.67%)
         occurrences all number
    9
    1
    4
    Insomnia
         subjects affected / exposed
    9 / 152 (5.92%)
    2 / 49 (4.08%)
    8 / 150 (5.33%)
         occurrences all number
    10
    2
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 152 (10.53%)
    2 / 49 (4.08%)
    11 / 150 (7.33%)
         occurrences all number
    20
    3
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 152 (5.92%)
    1 / 49 (2.04%)
    9 / 150 (6.00%)
         occurrences all number
    15
    4
    11
    Blood bilirubin increased
         subjects affected / exposed
    7 / 152 (4.61%)
    3 / 49 (6.12%)
    15 / 150 (10.00%)
         occurrences all number
    9
    3
    19
    Blood creatinine increased
         subjects affected / exposed
    8 / 152 (5.26%)
    3 / 49 (6.12%)
    10 / 150 (6.67%)
         occurrences all number
    11
    6
    11
    C-reactive protein increased
         subjects affected / exposed
    4 / 152 (2.63%)
    3 / 49 (6.12%)
    5 / 150 (3.33%)
         occurrences all number
    4
    3
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    14 / 152 (9.21%)
    2 / 49 (4.08%)
    12 / 150 (8.00%)
         occurrences all number
    17
    2
    13
    Neutrophil count decreased
         subjects affected / exposed
    19 / 152 (12.50%)
    4 / 49 (8.16%)
    16 / 150 (10.67%)
         occurrences all number
    36
    7
    30
    Platelet count decreased
         subjects affected / exposed
    31 / 152 (20.39%)
    6 / 49 (12.24%)
    24 / 150 (16.00%)
         occurrences all number
    38
    7
    39
    Weight decreased
         subjects affected / exposed
    7 / 152 (4.61%)
    3 / 49 (6.12%)
    5 / 150 (3.33%)
         occurrences all number
    7
    3
    6
    White blood cell count decreased
         subjects affected / exposed
    21 / 152 (13.82%)
    2 / 49 (4.08%)
    16 / 150 (10.67%)
         occurrences all number
    38
    2
    35
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 152 (7.89%)
    2 / 49 (4.08%)
    3 / 150 (2.00%)
         occurrences all number
    13
    2
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 152 (1.97%)
    2 / 49 (4.08%)
    9 / 150 (6.00%)
         occurrences all number
    3
    2
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 152 (8.55%)
    2 / 49 (4.08%)
    5 / 150 (3.33%)
         occurrences all number
    25
    2
    5
    Tremor
         subjects affected / exposed
    6 / 152 (3.95%)
    3 / 49 (6.12%)
    5 / 150 (3.33%)
         occurrences all number
    16
    3
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 152 (40.13%)
    16 / 49 (32.65%)
    47 / 150 (31.33%)
         occurrences all number
    107
    38
    93
    Leukopenia
         subjects affected / exposed
    14 / 152 (9.21%)
    3 / 49 (6.12%)
    2 / 150 (1.33%)
         occurrences all number
    21
    3
    2
    Neutropenia
         subjects affected / exposed
    36 / 152 (23.68%)
    10 / 49 (20.41%)
    19 / 150 (12.67%)
         occurrences all number
    64
    20
    39
    Thrombocytopenia
         subjects affected / exposed
    56 / 152 (36.84%)
    14 / 49 (28.57%)
    30 / 150 (20.00%)
         occurrences all number
    85
    27
    57
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 152 (1.32%)
    3 / 49 (6.12%)
    1 / 150 (0.67%)
         occurrences all number
    2
    3
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 152 (13.16%)
    4 / 49 (8.16%)
    11 / 150 (7.33%)
         occurrences all number
    23
    4
    14
    Constipation
         subjects affected / exposed
    9 / 152 (5.92%)
    2 / 49 (4.08%)
    6 / 150 (4.00%)
         occurrences all number
    9
    2
    6
    Diarrhoea
         subjects affected / exposed
    18 / 152 (11.84%)
    4 / 49 (8.16%)
    20 / 150 (13.33%)
         occurrences all number
    28
    5
    28
    Nausea
         subjects affected / exposed
    30 / 152 (19.74%)
    3 / 49 (6.12%)
    16 / 150 (10.67%)
         occurrences all number
    43
    4
    19
    Stomatitis
         subjects affected / exposed
    6 / 152 (3.95%)
    3 / 49 (6.12%)
    5 / 150 (3.33%)
         occurrences all number
    7
    3
    5
    Vomiting
         subjects affected / exposed
    25 / 152 (16.45%)
    5 / 49 (10.20%)
    16 / 150 (10.67%)
         occurrences all number
    39
    5
    22
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    7 / 152 (4.61%)
    0 / 49 (0.00%)
    8 / 150 (5.33%)
         occurrences all number
    8
    0
    8
    Purpura
         subjects affected / exposed
    0 / 152 (0.00%)
    3 / 49 (6.12%)
    0 / 150 (0.00%)
         occurrences all number
    0
    3
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    8 / 152 (5.26%)
    0 / 49 (0.00%)
    6 / 150 (4.00%)
         occurrences all number
    9
    0
    6
    Acute kidney injury
         subjects affected / exposed
    18 / 152 (11.84%)
    2 / 49 (4.08%)
    7 / 150 (4.67%)
         occurrences all number
    20
    2
    7
    Haematuria
         subjects affected / exposed
    12 / 152 (7.89%)
    1 / 49 (2.04%)
    6 / 150 (4.00%)
         occurrences all number
    14
    1
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 152 (8.55%)
    3 / 49 (6.12%)
    6 / 150 (4.00%)
         occurrences all number
    15
    5
    8
    Back pain
         subjects affected / exposed
    8 / 152 (5.26%)
    4 / 49 (8.16%)
    7 / 150 (4.67%)
         occurrences all number
    8
    4
    8
    Myopathy
         subjects affected / exposed
    7 / 152 (4.61%)
    3 / 49 (6.12%)
    9 / 150 (6.00%)
         occurrences all number
    7
    3
    9
    Pain in extremity
         subjects affected / exposed
    9 / 152 (5.92%)
    0 / 49 (0.00%)
    10 / 150 (6.67%)
         occurrences all number
    12
    0
    11
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    11 / 152 (7.24%)
    1 / 49 (2.04%)
    9 / 150 (6.00%)
         occurrences all number
    15
    1
    9
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    38 / 152 (25.00%)
    8 / 49 (16.33%)
    30 / 150 (20.00%)
         occurrences all number
    55
    9
    39
    Device related infection
         subjects affected / exposed
    13 / 152 (8.55%)
    1 / 49 (2.04%)
    5 / 150 (3.33%)
         occurrences all number
    14
    1
    5
    Epstein-Barr virus infection reactivation
         subjects affected / exposed
    8 / 152 (5.26%)
    1 / 49 (2.04%)
    6 / 150 (4.00%)
         occurrences all number
    8
    1
    6
    Pneumonia
         subjects affected / exposed
    10 / 152 (6.58%)
    3 / 49 (6.12%)
    6 / 150 (4.00%)
         occurrences all number
    10
    3
    6
    Sepsis
         subjects affected / exposed
    5 / 152 (3.29%)
    3 / 49 (6.12%)
    9 / 150 (6.00%)
         occurrences all number
    7
    5
    9
    Urinary tract infection
         subjects affected / exposed
    15 / 152 (9.87%)
    1 / 49 (2.04%)
    9 / 150 (6.00%)
         occurrences all number
    21
    1
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 152 (4.61%)
    1 / 49 (2.04%)
    8 / 150 (5.33%)
         occurrences all number
    7
    1
    9
    Hyperglycaemia
         subjects affected / exposed
    10 / 152 (6.58%)
    1 / 49 (2.04%)
    15 / 150 (10.00%)
         occurrences all number
    10
    1
    18
    Hyperkalaemia
         subjects affected / exposed
    9 / 152 (5.92%)
    2 / 49 (4.08%)
    9 / 150 (6.00%)
         occurrences all number
    11
    2
    10
    Hypertriglyceridaemia
         subjects affected / exposed
    9 / 152 (5.92%)
    4 / 49 (8.16%)
    4 / 150 (2.67%)
         occurrences all number
    9
    4
    5
    Hypoalbuminaemia
         subjects affected / exposed
    18 / 152 (11.84%)
    2 / 49 (4.08%)
    20 / 150 (13.33%)
         occurrences all number
    30
    2
    22
    Hypocalcaemia
         subjects affected / exposed
    15 / 152 (9.87%)
    4 / 49 (8.16%)
    16 / 150 (10.67%)
         occurrences all number
    19
    5
    31
    Hypokalaemia
         subjects affected / exposed
    34 / 152 (22.37%)
    10 / 49 (20.41%)
    28 / 150 (18.67%)
         occurrences all number
    51
    12
    67
    Hypomagnesaemia
         subjects affected / exposed
    23 / 152 (15.13%)
    6 / 49 (12.24%)
    23 / 150 (15.33%)
         occurrences all number
    34
    7
    42
    Hyponatraemia
         subjects affected / exposed
    5 / 152 (3.29%)
    3 / 49 (6.12%)
    6 / 150 (4.00%)
         occurrences all number
    6
    3
    10
    Hypophosphataemia
         subjects affected / exposed
    15 / 152 (9.87%)
    4 / 49 (8.16%)
    15 / 150 (10.00%)
         occurrences all number
    21
    6
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2017
    The main purpose of the amendment was to clarify exclusion criterion #5 and other eligibility criteria to follow standard medical practice. The revision of exclusion criterion #5 was to follow standard medical practice in determining the presence of active viral infection. This determination was based on the treating physician’s clinical assessment according to local institutional guidelines at the time of randomization including but not limited to vital signs, physical examination, laboratory and relevant radiologic studies and viral load testing results when available.
    21 Jun 2018
    The main purpose of the amendment was to allow for more flexibility in the tapering of corticosteroids, calcineurin inhibitors (CNI) and ruxolitinib; and if needed, for this taper to be completed safely beyond Week 24. This change included clarification that institutional guidelines for the tapering of corticosteroids and CNI could be followed. Additionally, the physician could tailor the tapering strategy to each patient’s condition, including stopping ruxolitinib more slowly in case of an acute Graft vs. Host Disease (aGvHD) flare or other safety concerns which may prevent the taper from being completed by Week 24. • Patients who met the protocol criteria for treatment discontinuation were not eligible to continue receiving ruxolitinib within the study. However, as part of Novartis “Posttrial access” commitment, patients who met all of the following criteria : • responded to ruxolitinib at Day 28 (or Crossover Day 28), • met study discontinuation criteria, other than safety reasons, • are assessed by the Investigator to still be deriving clinical benefit from ruxolitinib, were given the possibility to continue ruxolitinib outside the study, where permitted by and in accordance to local laws and regulations, if requested; they would then not enter the Long-Term Follow-Up period.

    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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