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    Clinical Trial Results:
    A phase III randomized open-label multi-center study of ruxolitinib vs. best available therapy in patients with corticosteroid-refractory chronic graft versus 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
    		 2016-004432-38
    Trial protocol
    		 GB   SE   DE   AT   ES   BE   DK   NL   IT   FR   PT   HU   PL   BG   NO   GR   RO  
    Global end of trial date
    15 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2023
    First version publication date
    01 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424D2301 (INCB 18424-365)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03112603
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000901-PIP04-17
    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
    15 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of ruxolitinib vs. Investigator’s choice Best Available Therapy (BAT) in patients with moderate or severe SR-cGvHD assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 visit.
    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
    29 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 50
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Jordan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Saudi Arabia: 10
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Turkey: 15
    Country: Number of subjects enrolled
    United States: 34
    Worldwide total number of subjects
    329
    EEA total number of subjects
    159
    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)
    12
    Adults (18-64 years)
    267
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 29 countries globally. During the main treatment period, participants were randomly assigned to a ruxolitinib arm or a Best Available Therapy (BAT) arm for 6 cycles of treatment. On Cycle 7 Day 1 and thereafter, participants in the BAT arm could cross over to ruxolitinib treatment.

    Pre-assignment
    Screening details
    		 A total of 404 participants were screened, of whom 72 were screen failures and 3 were not randomized for various reasons. Out of the 329 participants randomized, 6 did not receive BAT due to logistical reasons. A total of 329 participants were included in the Full Analysis Set (FAS); 165 were in the ruxolitinib arm and 164 were in the BAT arm.

    Period 1
    Period 1 title
    End of Randomization/Crossover Periods (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Ruxolitinib
    Arm description
    		 Ruxolitinib was administered orally twice per day at a dose of 10 milligrams (mg).
    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 and was taken without regard to food.

    Arm title
    		 Best Available Therapy
    Arm description
    		 Subjects received best available therapies (BATs), including, but not limited to, extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, and ibrutinib based on the investigator's decision.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    extracorporeal photopheresis (ECP)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Blood fraction modifier
    Routes of administration
    Intravenous use
    Dosage and administration details
    0 mg weekly/every 2 weeks, taken intravenously. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    low-dose methotrexate (MTX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg weekly, 1 week on/1 week off, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    mycophenolate mofetil (MMF)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2000 mg per day, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg per day, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Blood fraction modifier
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg every 2 weeks, taken intravenously. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg every 2 weeks, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    420 mg per day, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    STI571
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg per day, taken orally. As these treatments varied from administered tablets to cellular therapy and photopheresis, the open-label design of this study was inevitable to accommodate the variety of treatments that were considered by investigators for these patients. Additionally, there was a necessity for modifications and dose adjustments in these therapies depending on the subject’s response made utilizing a placebo operationally impossible and would have presented an undue burden to the patient.

    Arm title
    		 Ruxolitinib Cross-Over Period (Other)
    Arm description
    		 Participants from the BAT arm at the end of Cycle 6 crossed over to ruxolitinib treatment.
    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 milligrams (mg).

    Number of subjects in period 1
    		Ruxolitinib Best Available Therapy Ruxolitinib Cross-Over Period (Other)
    Started
    165
    164
    70
    Completed
    29
    24
    16
    Not completed
    136
    140
    54
         Adverse event, serious fatal
    10
    7
    2
         Physician decision
    43
    18
    29
         Disease Relapse
    12
    7
    2
         Participant/Guardian Decision
    7
    14
    7
         Adverse event, non-fatal
    32
    12
    6
         Failure to Meet Protocol Continuation Criteria
    4
    5
    -
         Lost to follow-up
    3
    -
    -
         Lack of efficacy
    25
    77
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    End of Randomization/Crossover Periods
    Reporting group description
    		 -

    Reporting group values
    		 End of Randomization/Crossover Periods Total
    Number of subjects
    		 329 329
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 12 12
        Adults (18-64 years)
    		 267 267
        From 65-84 years
    		 50 50
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 46.5 ± 15.92 -
    Sex: Female, Male
    Units: Participants
        Female
    		 128 128
        Male
    		 201 201
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 248 248
        Black or African American
    		 2 2
        Asian
    		 54 54
        American Indian or Alaska Native
    		 2 2
        Other
    		 13 13
        Unknown
    		 10 10
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic/Latino
    		 26 26
        Not Hispanic/Latino
    		 233 233
        Not Reported
    		 51 51
        Unknown
    		 19 19
    ECOG Performance Status
    The Eastern Cooperative Oncology Group (ECOG) Performance Score has 6 grades (0-5). 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. 5 = Death.
    Units: Subjects
        ECOG Score - 0
    		 81 81
        ECOG Score - 1
    		 174 174
        ECOG Score - 2
    		 44 44
        ECOG Score - 3
    		 2 2
        ECOG Score - Missing
    		 28 28

    End points

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    End points reporting groups
    Reporting group title
    Ruxolitinib
    Reporting group description
    		 Ruxolitinib was administered orally twice per day at a dose of 10 milligrams (mg).

    Reporting group title
    Best Available Therapy
    Reporting group description
    		 Subjects received best available therapies (BATs), including, but not limited to, extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, and ibrutinib based on the investigator's decision.

    Reporting group title
    Ruxolitinib Cross-Over Period (Other)
    Reporting group description
    		 Participants from the BAT arm at the end of Cycle 6 crossed over to ruxolitinib treatment.

    Primary: Efficacy of ruxolitinib versus investigator's choice best available therapy (BAT) in participants with moderate or severe Steroid Refractory Chronic Graft versus Host Disease (SR-cGvHD) assessed by overall response rate (ORR) at the Cycle 7 Day 1 visit

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    End point title
    		 Efficacy of ruxolitinib versus investigator's choice best available therapy (BAT) in participants with moderate or severe Steroid Refractory Chronic Graft versus Host Disease (SR-cGvHD) assessed by overall response rate (ORR) at the Cycle 7 Day 1 visit [1]
    End point description
    ORR was defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on chronic GvHD (cGvHD) disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
    End point type
    Primary
    End point timeframe
    Cycle 7 Day 1 (24 weeks [each cycle was comprised of 4 weeks])
    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 statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: percentage of participants
        number (confidence interval 95%)
    49.7 (41.8 to 57.6)
    25.6 (19.1 to 33.0)
    Statistical analysis title
    		 RUX vs. BAT (ORR)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.86
         upper limit
    		 4.8

    Secondary: Rate of failure-free survival (FFS)

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    End point title
    		 Rate of failure-free survival (FFS) [2]
    End point description
    Composite time to event endpoint incorporating the following FFS events: (i) relapse or recurrence of underlying disease or death due to underlying disease, (ii) nonrelapse mortality, or (iii) addition or initiation of another systemic therapy for cGvHD.
    End point type
    Secondary
    End point timeframe
    Baseline to when the last participant reached Cycle 7 Day 1 (24 weeks [each cycle was comprised of 4 weeks])
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: months
        median (confidence interval 95%)
    999 (18.6 to 999)
    5.7 (5.6 to 6.5)
    Statistical analysis title
    		 RUX vs. BAT (FFS)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.268
         upper limit
    		 0.51
    Notes
    [3] - The p-value was derived from a 1-sided stratified log-rank test.

    Secondary: Rate of participants with clinically relevant improvement of the modified Lee cGvHD symptom scale score

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    End point title
    		 Rate of participants with clinically relevant improvement of the modified Lee cGvHD symptom scale score [4]
    End point description
    To assess improvement of symptoms based on the total symptom score (TSS); a responder was defined as having achieved a clinically relevant reduction from Baseline of the TSS. The scale consists of 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy, and psychological). Participants reported their level of symptom “bother” over the previous month on a 5-point likert scale: not at all, slightly, moderately, quite a bit, or extremely. Subscale scores and the summary score range from 0 to 100, with a higher score indicating worse symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycle 7 Day 1 (24 weeks [each cycle was comprised of 4 weeks])
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: percentage of participants
        number (confidence interval 95%)
    24.2 (17.9 to 31.5)
    11.0 (6.6 to 16.8)
    No statistical analyses for this end point

    Secondary: Rate of FFS at study completion

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    End point title
    		 Rate of FFS at study completion [5]
    End point description
    Composite time to event endpoint incorporating the following FFS events: (i) relapse or recurrence of underlying disease or death due to underlying disease, (ii) nonrelapse mortality, or (iii) addition or initiation of another systemic therapy for cGvHD.
    End point type
    Secondary
    End point timeframe
    up to 1348 days
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: months
        median (confidence interval 95%)
    38.4 (22.1 to 999)
    5.7 (5.6 to 6.5)
    Statistical analysis title
    		 RUX vs. BAT (FFS at study end)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.361
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.268
         upper limit
    		 0.485

    Secondary: Best overall response (BOR) at Cycle 7 Day 1

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    End point title
    		 Best overall response (BOR) at Cycle 7 Day 1 [6]
    End point description
    BOR was defined as the percentage of participants who achieved an overall response (CR+PR) based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD). Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
    End point type
    Secondary
    End point timeframe
    up to Cycle 7 Day 1 (up to approximately 24 weeks [each cycle was comprised of 4 weeks])
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: percentage of participants
        number (confidence interval 95%)
    76.4 (69.1 to 82.6)
    60.4 (52.4 to 67.9)
    Statistical analysis title
    		 RUX vs. BAT (BOR)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0011 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.34
         upper limit
    		 3.52
    Notes
    [7] - The one-sided p-value was calculated using a stratified Cochran-Mantel-Haenszel test.

    Secondary: BOR during cross-over treatment with ruxolitinib

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    End point title
    		 BOR during cross-over treatment with ruxolitinib [8]
    End point description
    BOR was defined as the percentage of participants who achieved an overall response (CR+PR) based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD). Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
    End point type
    Secondary
    End point timeframe
    up to Day 995 of Cross-over Period
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Cross-Over Period (Other)
    Number of subjects analysed
    70
    Units: percentage of participants
        number (confidence interval 95%)
    81.4 (70.3 to 89.7)
    No statistical analyses for this end point

    Secondary: ORR at the end of Cycle 3

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    End point title
    		 ORR at the end of Cycle 3 [9]
    End point description
    ORR was defined as the percentage of participants in each arm demonstrating a CR or PR based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1 (12 weeks [each cycle was comprised of 4 weeks])
    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 statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: percentage of participants
        number (confidence interval 95%)
    54.5 (46.6 to 62.3)
    31.1 (24.1 to 38.8)
    Statistical analysis title
    		 RUX vs. BAT (ORR at end of Cycle 3)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.75
         upper limit
    		 4.39
    Notes
    [10] - The one-sided p-value was calculated using a stratified Cochran-Mantel-Haenszel (CMH) test.

    Secondary: Duration of response through study completion

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    End point title
    		 Duration of response through study completion [11]
    End point description
    DOR was defined as the time from first response until cGvHD progression, death, or the date of change/addition of systemic therapies for cGvHD and as assessed for responders only. Response was based on cGvHD disease assessments (National Institutes of Health consensus criteria).
    End point type
    Secondary
    End point timeframe
    up to 1153 days
    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 statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    126
    103
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    6.4 (4.9 to 11.4)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS) [12]
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    up to approximately 318 weeks
    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 statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (41.0 to 999)
    Statistical analysis title
    		 RUX vs. BAT (OS)
    Comparison groups
    Ruxolitinib v Best Available Therapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2396 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.851
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.544
         upper limit
    		 1.331
    Notes
    [13] - The p-value was derived from a 1-sided stratified log-rank test.

    Secondary: Cumulative incidence of non-relapse mortality (NRM)

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    End point title
    		 Cumulative incidence of non-relapse mortality (NRM) [14]
    End point description
    Defined as the cumulative incidence rate from competing risk analysis for NRM from the date of randomization to the date of death not preceded by underlying disease relapse/recurrence.
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 12, 18, 24, 30, and 36
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: percentage of participants
    number (confidence interval 95%)
        Month 3
    5.45 (2.68 to 9.67)
    4.44 (1.96 to 8.48)
        Month 6
    9.13 (5.34 to 14.15)
    6.43 (3.28 to 11.03)
        Month 12
    15.30 (10.26 to 21.26)
    15.12 (9.94 to 21.30)
        Month 18
    15.93 (10.78 to 21.98)
    16.48 (11.06 to 22.84)
        Month 24
    17.83 (12.37 to 24.10)
    19.22 (13.36 to 25.90)
        Month 30
    17.83 (12.37 to 24.10)
    19.22 (13.94 to 26.67)
        Month 36
    17.83 (12.37 to 24.10)
    22.0 (15.73 to 28.96)
    No statistical analyses for this end point

    Secondary: Percentage of participants with a ≥ 50% reduction in daily corticosteroid dose up to Cycle 7 Day 1

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    End point title
    		 Percentage of participants with a ≥ 50% reduction in daily corticosteroid dose up to Cycle 7 Day 1 [15]
    End point description
    All corticosteroid dosages prescribed to the participant and all dose changes during the study were to be recorded for assessment of participants with a ≥ 50% reduction in daily corticosteroid dose. Data reported are from the start of the study to Cycle 7 Day 1 (data cutoff of 08 May 2020).
    End point type
    Secondary
    End point timeframe
    Cycle 7 Day 1 (up to 24 weeks [each cycle was comprised of 4 weeks])
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    158
    Units: percentage of participants
    number (not applicable)
        Day 15 to ≤ Day 28
    12.7
    13.2
        Day 29 to ≤ Day 42
    35.0
    33.1
        Day 43 to ≤ Day 56
    48.4
    41.1
        Day 57 to ≤ Day 70
    58.7
    47.9
        Day 71 to ≤ Day 84
    62.3
    51.4
        Day 85 to ≤ Day 98
    69.5
    54.0
        Day 99 to ≤ Day 112
    71.2
    60.4
        Day 113 to ≤ Day 126
    73.2
    66.2
        Day 127 to ≤ Day 140
    72.8
    68.3
        Day 141 to ≤ Day 154
    70.0
    68.3
        Day 155 to ≤ Day 168
    74.6
    71.6
        Day 169 to ≤ Day 182
    81.9
    88.8
    No statistical analyses for this end point

    Secondary: Percentage of participants successfully tapered off of all corticosteroids up to Cycle 7 Day 1

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    End point title
    		 Percentage of participants successfully tapered off of all corticosteroids up to Cycle 7 Day 1 [16]
    End point description
    All corticosteroid dosages prescribed to the participant and all dose changes during the study were to be recorded for assessment of participants who successfully tapered off of all corticosteroids. Participants who completely tapered off corticosteroids refer to those who permanently discontinued steroids as per the dose administration panel and who did not restart steroids in the same interval. Participants who were tapered off and continued follow-up were also counted as being tapered off with 0 dose in subsequent intervals until they discontinued from the main treatment period or restarted steroid treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 7 Day 1 (up to 24 weeks [each cycle was comprised of 4 weeks])
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    158
    Units: percentage of participants
    number (not applicable)
        Day 1 to ≤ Day 28
    2.5
    2.6
        Day 29 to ≤ Day 56
    9.6
    5.4
        Day 57 to ≤ Day 84
    14.0
    8.5
        Day 85 to ≤ Day 112
    16.3
    10.3
        Day 113 to ≤ Day 140
    19.7
    12.4
        Day 141 to ≤ Day 168
    24.2
    16.8
        Day 169 to ≤ Day 179
    24.1
    15.9
    No statistical analyses for this end point

    Secondary: Cumulative incidence of malignancy relapse/recurrence (MR)

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    End point title
    		 Cumulative incidence of malignancy relapse/recurrence (MR) [17]
    End point description
    Defined as the cumulative incidence rate from competing risk analysis of MR from the date of randomization to hematologic malignancy relapse/recurrence.
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 12, 18, 24, 30, and 36
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    156
    160
    Units: percentage of participants
    number (confidence interval 95%)
        0 to < 3 months
    1.92 (0.52 to 5.12)
    1.31 (0.26 to 4.27)
        3 to < 6 months
    3.22 (1.20 to 6.93)
    2.65 (0.87 to 6.21)
        6 to < 12 months
    5.18 (2.42 to 9.49)
    6.08 (2.98 to 10.73)
        12 to < 18 months
    7.82 (4.25 to 12.77)
    6.08 (2.98 to 10.73)
        18 to < 24 months
    8.48 (4.74 to 13.57)
    6.08 (2.98 to 10.73)
        24 to <30 months
    8.48 (4.74 to 13.57)
    6.78 (3.46 to 11.62)
        30 to <36 months
    8.48 (4.74 to 13.57)
    7.50 (3.96 to 12.52)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT-BMT)

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    End point title
    		 Change from Baseline in Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT-BMT) [18]
    End point description
    Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The 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 participants. The questions were based on a 5-point Likert scale, where 0 corresponds to "not at all" and 4 corresponds to "very much." The higher the final score, the better the quality of life. The FACT-BMT total score ranges from 0 to 148.
    End point type
    Secondary
    End point timeframe
    Baseline; up to Cycle 39 Day 1 (up to 156 weeks [each cycle was comprised of 4 weeks])
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1
    2.32 ± 12.191
    -0.22 ± 14.949
        Cycle 3 Day 1
    0.62 ± 14.452
    -1.82 ± 15.849
        Cycle 4 Day 1
    1.98 ± 15.888
    -1.05 ± 16.147
        Cycle 5 Day 1
    1.25 ± 14.577
    -0.23 ± 18.903
        Cycle 6 Day 1
    2.91 ± 14.562
    2.41 ± 14.766
        Cycle 7 Day 1
    4.14 ± 14.669
    0.85 ± 16.811
        Cycle 9 Day 1
    5.32 ± 16.815
    1.20 ± 17.635
        Cycle 12 Day 1
    7.26 ± 19.296
    3.74 ± 18.059
        Cycle 15 Day 1
    5.07 ± 18.220
    7.58 ± 17.063
        Cycle 18 Day 1
    4.10 ± 19.440
    8.19 ± 17.993
        Cycle 21 Day 1
    5.24 ± 19.485
    3.68 ± 17.378
        Cycle 24 Day 1
    5.90 ± 19.662
    7.84 ± 18.561
        Cycle 27 Day 1
    6.23 ± 18.880
    5.10 ± 18.885
        Cycle 30 Day 1
    7.53 ± 20.314
    5.75 ± 21.037
        Cycle 33 Day 1
    5.17 ± 20.330
    5.67 ± 22.573
        Cycle 36 Day 1
    8.72 ± 18.710
    4.77 ± 24.186
        Cycle 39 Day 1
    8.65 ± 21.669
    6.64 ± 22.384
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D-5L

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    End point title
    		 Change from Baseline in EQ-5D-5L [19]
    End point description
    The EQ-5D-5L is a descriptive classification consisting of five dimensions of health: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. The five-level version (no problems, slight problems, moderate problems, severe problems, and extreme problems) uses a 5-point Likert scale, with 1 being no problems and 5 being extreme problems.
    End point type
    Secondary
    End point timeframe
    Baseline; up to Cycle 39 Day 1 (156 weeks [each cycle was comprised of 4 weeks])
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    164
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1
    0.03 ± 0.214
    -0.01 ± 0.163
        Cycle 3 Day 1
    0.03 ± 0.221
    -0.04 ± 0.259
        Cycle 4 Day 1
    0.04 ± 0.196
    -0.01 ± 0.192
        Cycle 5 Day 1
    0.02 ± 0.210
    -0.03 ± 0.243
        Cycle 6 Day 1
    0.05 ± 0.230
    0.01 ± 0.186
        Cycle 7 Day 1
    0.07 ± 0.234
    -0.00 ± 0.225
        Cycle 9 Day 1
    0.07 ± 0.228
    -0.02 ± 0.166
        Cycle 12 Day 1
    0.07 ± 0.187
    0.02 ± 0.158
        Cycle 15 Day 1
    0.07 ± 0.250
    0.03 ± 0.140
        Cycle 18 Day 1
    0.07 ± 0.299
    0.02 ± 0.110
        Cycle 21 Day 1
    0.08 ± 0.268
    -0.00 ± 0.222
        Cycle 24 Day 1
    0.07 ± 0.272
    0.01 ± 0.164
        Cycle 27 Day 1
    0.06 ± 0.299
    0.03 ± 0.182
        Cycle 30 Day 1
    0.05 ± 0.261
    0.01 ± 0.159
        Cycle 33 Day 1
    0.00 ± 0.282
    0.05 ± 0.186
        Cycle 36 Day 1
    0.06 ± 0.231
    0.04 ± 0.216
        Cycle 39 Day 1
    0.06 ± 0.255
    0.01 ± 0.214
    No statistical analyses for this end point

    Secondary: Cmax of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 Cmax of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [20]
    End point description
    Cmax was defined as the maximum observed plasma concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1
    167 ± 39.3
        Day 15
    215 ± 48.8
    No statistical analyses for this end point

    Secondary: AUClast of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 AUClast of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [21]
    End point description
    AUClast was defined as the area under the concentration-time curve up to the last measurable concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: ng*hour/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    636 ± 40.8
        Day 15
    945 ± 56.1
    No statistical analyses for this end point

    Secondary: Number of participants with any treatment-emergent adverse event (TEAE)

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    End point title
    		 Number of participants with any treatment-emergent adverse event (TEAE) [22]
    End point description
    Adverse events were defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occurred after the participant’s signed informed consent was obtained. Abnormal laboratory values or test results occurring after informed consent constituted adverse events only if they induced clinical signs or symptoms, were considered clinically significant, required therapy (e.g., hematologic abnormality that required transfusion or hematological stem cell support), or required changes in study medication(s). TEAEs were defined as those AEs that started or worsened during the on-treatment period (either randomized or cross-over period).
    End point type
    Secondary
    End point timeframe
    up to approximately 318 weeks
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    158
    Units: participants
    165
    148
    No statistical analyses for this end point

    Secondary: AUCinf of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 AUCinf of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [23]
    End point description
    AUCinf was defined as the area under the concentration-time curve from time 0 to infinity. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    10
    Units: ng*hour/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    642 ± 32.7
        Day 15
    0 ± 0
    No statistical analyses for this end point

    Secondary: CL/F of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 CL/F of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [24]
    End point description
    CL/F was defined as the oral dose clearance of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: Liters/hour
    geometric mean (geometric coefficient of variation)
        Day 1
    15.6 ± 32.7
        Day 15
    15.2 ± 20.4
    No statistical analyses for this end point

    Secondary: tmax of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 tmax of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [25]
    End point description
    tmax was defined as the time to reach the maximum plasma concentration of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: hours
    median (full range (min-max))
        Day 1
    0.833 (0.417 to 4.08)
        Day 15
    1.00 (0.417 to 2.00)
    No statistical analyses for this end point

    Secondary: Vz/F of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 Vz/F of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [26]
    End point description
    Vz/F was defined as the apparent oral dose volume of distribution of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: Liters
    geometric mean (geometric coefficient of variation)
        Day 1
    54.0 ± 25.0
        Day 15
    50.9 ± 33.9
    No statistical analyses for this end point

    Secondary: t1/2 of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses

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    End point title
    		 t1/2 of ruxolitinib after single (Cycle 1 Day 1) and multiple (Cycle 1 Day 15) doses [27]
    End point description
    t1/2 was defined as the apparent terminal phase disposition half-life of ruxolitinib. Early enrolling participants (approximately the first 8 adult and first 4 adolescent participants) randomized to ruxolitinib arm followed an “extensive PK” sampling schedule. Subsequent participants randomized to ruxolitinib, any randomized participants receiving ruxolitinib after Cycle 6, and any randomized participants receiving BAT that cross over to ruxolitinib followed the “sparse PK” sampling schedule.
    End point type
    Secondary
    End point timeframe
    Extensive Sampling Schedule: Cycle 1 Days 1 and 15: predose; 0.5, 1, 1.5, 4, 6, and 9 hours post-dose. Sparse Sampling Schedule: Cycle 1 Days 1 and 15: predose; 1.5 hours post-dose
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib
    Number of subjects analysed
    20
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 1
    2.40 ± 28.9
        Day 15
    2.32 ± 19.8
    No statistical analyses for this end point

    Secondary: Utilization of medical resources

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    End point title
    		 Utilization of medical resources [28]
    End point description
    The percentage of participants with at least one submission to healthcare encounter was assessed.
    End point type
    Secondary
    End point timeframe
    up to approximately 318 weeks
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this arm.
    End point values
    		 Ruxolitinib Best Available Therapy
    Number of subjects analysed
    165
    158
    Units: percentage of participants
        number (not applicable)
    57.0
    65.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to when the last participant received the last dose (+30 days); up to approximately 318 weeks
    Adverse event reporting additional description
    Treatment-emergent adverse events, defined as adverse events that started or worsened during the on-treatment period (either Randomized or Cross-over Period), have been reported for the Safety Set, which included subjects who received at least one dose of drug. A total of 6 subjects in the BAT arm discontinued before receiving the first dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Ruxolitinib
    Reporting group description
    		 Ruxolitinib was administered orally twice per day at a dose of 10 milligrams (mg).

    Reporting group title
    Ruxolitinib Cross-Over Period
    Reporting group description
    		 Subjects from the BAT arm at the end of Cycle 6 crossed over to ruxolitinib treatment.

    Reporting group title
    Best Available Therapy
    Reporting group description
    		 Subjects received best available therapies (BATs), including, but not limited to, extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, and ibrutinib based on the investigator's decision.

    Serious adverse events
    		 Ruxolitinib Ruxolitinib Cross-Over Period Best Available Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 165 (52.12%)
    27 / 70 (38.57%)
    71 / 158 (44.94%)
         number of deaths (all causes)
    37
    10
    40
         number of deaths resulting from adverse events
    8
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Lung neoplasm
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin squamous cell carcinoma recurrent
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Hypotension
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poor peripheral circulation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Stenosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Pyrexia
         subjects affected / exposed
    11 / 165 (6.67%)
    3 / 70 (4.29%)
    7 / 158 (4.43%)
         occurrences causally related to treatment / all
    10 / 17
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Necrosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hyperthermia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Generalised oedema
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Reproductive system and breast disorders
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 165 (1.82%)
    2 / 70 (2.86%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Alveolar proteinosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Atelectasis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Hypoxia
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Pleural effusion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Pneumonitis
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 70 (0.00%)
    0 / 158 (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
    Pulmonary embolism
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 70 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Respiratory acidosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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 failure
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 70 (1.43%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    Pleuritic pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Agitation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Depression
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Blood creatinine increased
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Platelet count decreased
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 70 (1.43%)
    0 / 158 (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
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    White blood cell count decreased
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Injury, poisoning and procedural complications
    Anastomotic complication
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Femur fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Fall
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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 failure congestive
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Cardiac failure
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Aortic valve incompetence
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Encephalopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Intracranial pressure increased
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Neuralgia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Syncope
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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
    Atypical haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 165 (0.61%)
    3 / 70 (4.29%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 165 (2.42%)
    1 / 70 (1.43%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spleen disorder
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Pancytopenia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    0 / 158 (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
    Leukopenia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Splenic haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Corneal erosion
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Corneal perforation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Keratitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 165 (0.00%)
    2 / 70 (2.86%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Haematemesis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 70 (1.43%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 165 (1.82%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Pancreatitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Nausea
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral dysaesthesia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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 and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         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 impairment
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Urinary retention
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Osteonecrosis
         subjects affected / exposed
    4 / 165 (2.42%)
    1 / 70 (1.43%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 70 (0.00%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 70 (1.43%)
    0 / 158 (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
    Brain abscess
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Bacterial translocation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Anal abscess
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Adenovirus reactivation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Abscess limb
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aspergillus infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Fungal infection
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    0 / 158 (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
    Clostridium difficile infection
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryocanaliculitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Device related sepsis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Enterocolitis infectious
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Erysipelas
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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 bacteraemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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 infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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 zoster
         subjects affected / exposed
    4 / 165 (2.42%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Measles
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Meningitis cryptococcal
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Meningitis viral
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Metapneumovirus infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 165 (3.03%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Pneumococcal infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    24 / 165 (14.55%)
    5 / 70 (7.14%)
    18 / 158 (11.39%)
         occurrences causally related to treatment / all
    18 / 31
    0 / 5
    4 / 20
         deaths causally related to treatment / all
    4 / 5
    0 / 0
    2 / 3
    Pneumonia bacterial
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary nocardiosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 165 (1.21%)
    3 / 70 (4.29%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Sepsis
         subjects affected / exposed
    4 / 165 (2.42%)
    1 / 70 (1.43%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 165 (0.61%)
    2 / 70 (2.86%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Systemic mycosis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 70 (1.43%)
    0 / 158 (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
    Tracheitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Septic shock
         subjects affected / exposed
    2 / 165 (1.21%)
    1 / 70 (1.43%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    Urinary tract infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 70 (0.00%)
    0 / 158 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         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
    1 / 165 (0.61%)
    0 / 70 (0.00%)
    0 / 158 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 70 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    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 Ruxolitinib Cross-Over Period Best Available Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    158 / 165 (95.76%)
    62 / 70 (88.57%)
    132 / 158 (83.54%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    33 / 165 (20.00%)
    7 / 70 (10.00%)
    21 / 158 (13.29%)
         occurrences all number
    37
    7
    25
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 165 (2.42%)
    5 / 70 (7.14%)
    4 / 158 (2.53%)
         occurrences all number
    6
    6
    4
    Fatigue
         subjects affected / exposed
    25 / 165 (15.15%)
    7 / 70 (10.00%)
    15 / 158 (9.49%)
         occurrences all number
    26
    8
    19
    Oedema peripheral
         subjects affected / exposed
    13 / 165 (7.88%)
    4 / 70 (5.71%)
    18 / 158 (11.39%)
         occurrences all number
    14
    6
    21
    Pyrexia
         subjects affected / exposed
    34 / 165 (20.61%)
    9 / 70 (12.86%)
    16 / 158 (10.13%)
         occurrences all number
    43
    11
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 165 (15.15%)
    12 / 70 (17.14%)
    15 / 158 (9.49%)
         occurrences all number
    37
    13
    17
    Dyspnoea
         subjects affected / exposed
    19 / 165 (11.52%)
    5 / 70 (7.14%)
    10 / 158 (6.33%)
         occurrences all number
    21
    5
    11
    Rhinorrhoea
         subjects affected / exposed
    8 / 165 (4.85%)
    0 / 70 (0.00%)
    8 / 158 (5.06%)
         occurrences all number
    10
    0
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 165 (7.88%)
    1 / 70 (1.43%)
    8 / 158 (5.06%)
         occurrences all number
    14
    1
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    32 / 165 (19.39%)
    5 / 70 (7.14%)
    8 / 158 (5.06%)
         occurrences all number
    42
    8
    12
    Amylase increased
         subjects affected / exposed
    12 / 165 (7.27%)
    2 / 70 (2.86%)
    4 / 158 (2.53%)
         occurrences all number
    13
    2
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 165 (11.52%)
    3 / 70 (4.29%)
    6 / 158 (3.80%)
         occurrences all number
    28
    5
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 165 (7.27%)
    3 / 70 (4.29%)
    6 / 158 (3.80%)
         occurrences all number
    17
    4
    7
    Blood cholesterol increased
         subjects affected / exposed
    15 / 165 (9.09%)
    1 / 70 (1.43%)
    7 / 158 (4.43%)
         occurrences all number
    18
    1
    7
    Blood creatine phosphokinase increased
         subjects affected / exposed
    11 / 165 (6.67%)
    2 / 70 (2.86%)
    1 / 158 (0.63%)
         occurrences all number
    17
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    29 / 165 (17.58%)
    4 / 70 (5.71%)
    8 / 158 (5.06%)
         occurrences all number
    39
    4
    10
    Fibrin D dimer increased
         subjects affected / exposed
    9 / 165 (5.45%)
    0 / 70 (0.00%)
    0 / 158 (0.00%)
         occurrences all number
    10
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    19 / 165 (11.52%)
    3 / 70 (4.29%)
    7 / 158 (4.43%)
         occurrences all number
    28
    3
    7
    Lipase increased
         subjects affected / exposed
    10 / 165 (6.06%)
    3 / 70 (4.29%)
    4 / 158 (2.53%)
         occurrences all number
    14
    5
    4
    Platelet count decreased
         subjects affected / exposed
    19 / 165 (11.52%)
    1 / 70 (1.43%)
    11 / 158 (6.96%)
         occurrences all number
    27
    2
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 165 (10.30%)
    6 / 70 (8.57%)
    14 / 158 (8.86%)
         occurrences all number
    21
    7
    14
    Tremor
         subjects affected / exposed
    7 / 165 (4.24%)
    0 / 70 (0.00%)
    8 / 158 (5.06%)
         occurrences all number
    7
    0
    9
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    21 / 165 (12.73%)
    7 / 70 (10.00%)
    14 / 158 (8.86%)
         occurrences all number
    24
    10
    19
    Neutropenia
         subjects affected / exposed
    25 / 165 (15.15%)
    8 / 70 (11.43%)
    8 / 158 (5.06%)
         occurrences all number
    43
    12
    15
    Leukopenia
         subjects affected / exposed
    10 / 165 (6.06%)
    1 / 70 (1.43%)
    2 / 158 (1.27%)
         occurrences all number
    17
    2
    2
    Anaemia
         subjects affected / exposed
    56 / 165 (33.94%)
    15 / 70 (21.43%)
    25 / 158 (15.82%)
         occurrences all number
    101
    26
    38
    Eye disorders
    Dry eye
         subjects affected / exposed
    11 / 165 (6.67%)
    2 / 70 (2.86%)
    10 / 158 (6.33%)
         occurrences all number
    11
    3
    10
    Cataract
         subjects affected / exposed
    4 / 165 (2.42%)
    5 / 70 (7.14%)
    6 / 158 (3.80%)
         occurrences all number
    5
    5
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 165 (16.36%)
    6 / 70 (8.57%)
    23 / 158 (14.56%)
         occurrences all number
    31
    7
    31
    Constipation
         subjects affected / exposed
    14 / 165 (8.48%)
    5 / 70 (7.14%)
    10 / 158 (6.33%)
         occurrences all number
    14
    5
    10
    Nausea
         subjects affected / exposed
    19 / 165 (11.52%)
    3 / 70 (4.29%)
    21 / 158 (13.29%)
         occurrences all number
    20
    3
    24
    Vomiting
         subjects affected / exposed
    15 / 165 (9.09%)
    3 / 70 (4.29%)
    12 / 158 (7.59%)
         occurrences all number
    21
    3
    18
    Dyspepsia
         subjects affected / exposed
    4 / 165 (2.42%)
    4 / 70 (5.71%)
    4 / 158 (2.53%)
         occurrences all number
    4
    4
    4
    Abdominal pain
         subjects affected / exposed
    7 / 165 (4.24%)
    4 / 70 (5.71%)
    9 / 158 (5.70%)
         occurrences all number
    8
    4
    11
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 70 (1.43%)
    8 / 158 (5.06%)
         occurrences all number
    1
    1
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 165 (12.12%)
    7 / 70 (10.00%)
    13 / 158 (8.23%)
         occurrences all number
    26
    14
    14
    Back pain
         subjects affected / exposed
    18 / 165 (10.91%)
    5 / 70 (7.14%)
    10 / 158 (6.33%)
         occurrences all number
    18
    5
    10
    Myalgia
         subjects affected / exposed
    17 / 165 (10.30%)
    1 / 70 (1.43%)
    7 / 158 (4.43%)
         occurrences all number
    18
    1
    8
    Pain in extremity
         subjects affected / exposed
    10 / 165 (6.06%)
    1 / 70 (1.43%)
    5 / 158 (3.16%)
         occurrences all number
    10
    1
    5
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 165 (4.85%)
    6 / 70 (8.57%)
    11 / 158 (6.96%)
         occurrences all number
    9
    11
    11
    Urinary tract infection
         subjects affected / exposed
    13 / 165 (7.88%)
    4 / 70 (5.71%)
    9 / 158 (5.70%)
         occurrences all number
    21
    5
    17
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 165 (11.52%)
    12 / 70 (17.14%)
    15 / 158 (9.49%)
         occurrences all number
    22
    21
    23
    BK virus infection
         subjects affected / exposed
    9 / 165 (5.45%)
    3 / 70 (4.29%)
    2 / 158 (1.27%)
         occurrences all number
    9
    3
    2
    Bronchitis
         subjects affected / exposed
    7 / 165 (4.24%)
    7 / 70 (10.00%)
    3 / 158 (1.90%)
         occurrences all number
    8
    8
    5
    COVID-19
         subjects affected / exposed
    8 / 165 (4.85%)
    5 / 70 (7.14%)
    1 / 158 (0.63%)
         occurrences all number
    9
    6
    2
    Conjunctivitis
         subjects affected / exposed
    13 / 165 (7.88%)
    2 / 70 (2.86%)
    6 / 158 (3.80%)
         occurrences all number
    17
    2
    6
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    8 / 165 (4.85%)
    4 / 70 (5.71%)
    15 / 158 (9.49%)
         occurrences all number
    10
    5
    23
    Influenza
         subjects affected / exposed
    16 / 165 (9.70%)
    2 / 70 (2.86%)
    10 / 158 (6.33%)
         occurrences all number
    18
    2
    12
    Nasopharyngitis
         subjects affected / exposed
    17 / 165 (10.30%)
    1 / 70 (1.43%)
    10 / 158 (6.33%)
         occurrences all number
    24
    3
    14
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    15 / 165 (9.09%)
    2 / 70 (2.86%)
    22 / 158 (13.92%)
         occurrences all number
    25
    2
    47
    Hypophosphataemia
         subjects affected / exposed
    4 / 165 (2.42%)
    4 / 70 (5.71%)
    8 / 158 (5.06%)
         occurrences all number
    7
    9
    8
    Hypomagnesaemia
         subjects affected / exposed
    8 / 165 (4.85%)
    2 / 70 (2.86%)
    11 / 158 (6.96%)
         occurrences all number
    11
    2
    16
    Hyperuricaemia
         subjects affected / exposed
    9 / 165 (5.45%)
    2 / 70 (2.86%)
    1 / 158 (0.63%)
         occurrences all number
    9
    2
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    16 / 165 (9.70%)
    4 / 70 (5.71%)
    14 / 158 (8.86%)
         occurrences all number
    21
    6
    15
    Hyperkalaemia
         subjects affected / exposed
    12 / 165 (7.27%)
    5 / 70 (7.14%)
    4 / 158 (2.53%)
         occurrences all number
    14
    6
    4
    Hyperglycaemia
         subjects affected / exposed
    13 / 165 (7.88%)
    1 / 70 (1.43%)
    6 / 158 (3.80%)
         occurrences all number
    20
    1
    8
    Hypercholesterolaemia
         subjects affected / exposed
    13 / 165 (7.88%)
    8 / 70 (11.43%)
    2 / 158 (1.27%)
         occurrences all number
    15
    8
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2017
    The main purpose of the amendment was to extend the available patient population. Due to protracted enrollment and feedback from health authorities and investigators, several inclusion and exclusion criteria were revised. Additionally, with the recent approval of ibrutinib the original protocol-defined list of BAT options would not allow for a complete comparative assessment versus ruxolitinib. Therefore, adding ibrutinib to this list was necessary to reflect the complete list of treatment options for this patient population. Lastly, a Data Monitoring Committee was added based on health authority feedback to include an independent review group.
    07 Oct 2021
    The main purpose of the amendment was to restrict the use of live attenuated vaccines (specifically against SARS-CoV-2) in this population with immunocompromised state while on study treatment. Due to feedback from health authorities and based on a risk assessment, protocol language was revised for prohibited concomitant medication. These changes did not add risk to the subject population.

    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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