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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence

    Summary
    EudraCT number
    2017-000322-35
    Trial protocol
    GB   IT  
    Global end of trial date
    18 Jul 2022

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Sep 2023
    First version publication date
    03 Aug 2023
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ACE-536-MF-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03194542
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of luspatercept for the treatment of anemia in subjects with MPN-associated myelofibrosis with and without RBC-transfusion dependence.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Nov 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Italy: 29
    Worldwide total number of subjects
    95
    EEA total number of subjects
    36
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    74
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The target study population included participants with myeloproliferative neoplasm (MPN)-associated myelofibrosis and anemia with and without RBC-transfusion dependence.

    Pre-assignment
    Screening details
    95 participants were treated in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Anemia Only
    Arm description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 mg/kg. Participants may have the dose level increased in a stepwise manner beyond the starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no more than 168 mg) during the Treatment Period.

    Arm title
    Cohort 2: RBC-Transfusion Dependent
    Arm description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 mg/kg. Participants may have the dose level increased in a stepwise manner beyond the starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no more than 168 mg) during the Treatment Period.

    Arm title
    Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Arm description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 mg/kg. Participants may have the dose level increased in a stepwise manner beyond the starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no more than 168 mg) during the Treatment Period.

    Arm title
    Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Arm description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 mg/kg. Participants may have the dose level increased in a stepwise manner beyond the starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no more than 168 mg) during the Treatment Period.

    Number of subjects in period 1
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Started
    22
    21
    14
    38
    Completed
    0
    0
    0
    0
    Not completed
    22
    21
    14
    38
         Adverse event, serious fatal
    1
    2
    -
    5
         Rollover to Long-term follow-up
    1
    1
    -
    5
         Consent withdrawn by subject
    2
    1
    5
    4
         Physician decision
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    2
    -
    5
         Progressive Disease
    1
    -
    1
    1
         Participant to Receive Bone Marrow Transplant
    1
    -
    -
    -
         Per Protocol Repeat Blasts of 10%
    1
    -
    1
    -
         Did not meet clinical benefit criteria
    8
    10
    2
    8
         Loss of Response
    4
    2
    3
    4
         Lack of efficacy
    2
    2
    2
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Anemia Only
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 2: RBC-Transfusion Dependent
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib) Total
    Number of subjects
    22 21 14 38 95
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    5 2 7 5 19
        From 65-84 years
    16 18 7 33 74
        85 years and over
    1 1 0 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    69 ± 8.87 73.9 ± 5.71 65.4 ± 8.45 71.3 ± 5.80 -
    Sex: Female, Male
    Units: Participants
        Female
    9 6 7 15 37
        Male
    13 15 7 23 58
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    2 1 3 1 7
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 0 1 2 3
        White
    16 18 10 30 74
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    4 2 0 5 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 0 0 1 3
        Not Hispanic or Latino
    16 19 14 32 81
        Unknown or Not Reported
    4 2 0 5 11

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Anemia Only
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 2: RBC-Transfusion Dependent
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Primary: The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period

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    End point title
    The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period [1]
    End point description
    The number of participants that achieved anemia response as it relates to hemoglobin (Hgb) increase and red blood cell (RBC)-transfusion independence is defined below: Cohorts 1 (anemia only) and 3A: The number of participants achieving ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion from Day 1 up through and including Day 168. Cohorts 2 (RBC-transfusion dependent) and 3B: The number of participants who become RBC-transfusion free over any consecutive 84-day period from Day 1 up through and including Day 168. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.
    End point type
    Primary
    End point timeframe
    Any consecutive “rolling” 84-day period from Day 1 through and including Day 168
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics planned for this endpoint
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Participants
    3
    2
    2
    10
    No statistical analyses for this end point

    Secondary: Time to Anemia Response During the Primary Treatment Period

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    End point title
    Time to Anemia Response During the Primary Treatment Period
    End point description
    Time to anemia response follows the definitions below: Cohorts 1 (anemia only) and 3A: Time between first administration of luspatercept and the first hemoglobin increase of ≥ 1.5 g/dL from baseline that starts a consecutive 84-day period of consecutive increase ≥ 1.5 g/dL without RBC transfusions. Cohorts 2 (RBC-transfusion dependent) and 3B: Time between first administration of luspatercept and the first day of an RBC transfusion-free period of 84 days. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.
    End point type
    Secondary
    End point timeframe
    From first dose up to first onset of anemia response (calculated from Day 1 through and including Day 168)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    3
    2
    2
    10
    Units: Days
        arithmetic mean (standard deviation)
    57.3 ± 14.36
    2.0 ± 0.00
    63.5 ± 30.41
    30.7 ± 27.22
    No statistical analyses for this end point

    Secondary: Duration of Anemia Response

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    End point title
    Duration of Anemia Response
    End point description
    The duration of anemia response is defined as the duration of time from first day of longest response to the last day of longest response. Participants who achieved and maintained the anemia response at the time of the analysis are censored at the efficacy cutoff date. For Cohorts 1 and 3A, an anemia responder was defined as a subject with ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion. For Cohorts 2 and 3B, an anemia responder was defined as a subject who becomes RBC transfusion free over any consecutive 84-day period. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.
    End point type
    Secondary
    End point timeframe
    From first dose through last day of longest response (calculated from Day 1 through end of treatment, up to approximately 232 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    3
    2
    2
    10
    Units: Days
        arithmetic mean (standard deviation)
    457.7 ± 611.20
    623.0 ± 29.70
    88.5 ± 6.36
    534.7 ± 527.67
    No statistical analyses for this end point

    Secondary: The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only)

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    End point title
    The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only) [2]
    End point description
    Frequency of RBC transfusion is defined as the mean number of RBC units transfused per participant every 4 weeks (28 days). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.
    End point type
    Secondary
    End point timeframe
    From Day 1 through end of treatment (up to approximately 232 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: Endpoint is specific to certain study arms
    End point values
    Cohort 2: RBC-Transfusion Dependent Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    21
    38
    Units: RBC Units
    arithmetic mean (standard deviation)
        Primary Treatment Period
    2.76 ± 1.967
    1.49 ± 1.345
        Entire Treatment Period
    2.70 ± 2.040
    1.52 ± 1.365
    No statistical analyses for this end point

    Secondary: The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only)

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    End point title
    The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only) [3]
    End point description
    The number of participants who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period. Baseline is defined as average number of RBC units per 28 days over the 84 days period on or prior to the C1D1 date. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and from Day 1 through end of treatment (up to approximately 232 weeks).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint is specific to certain study arms
    End point values
    Cohort 2: RBC-Transfusion Dependent Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    21
    38
    Units: Participants
        Primary Treatment Period
    10
    19
        Entire Treatment Period
    10
    20
    No statistical analyses for this end point

    Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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    End point title
    The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
    End point description
    Symptoms response improvement will be assessed using the number of participants who achieve ≥ 50% reduction in fatigue symptoms. Fatigue is 1 out of 10 total symptoms scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Participants
        Primary Treatment Period (Last Available)
    4
    2
    4
    10
        Entire Treatment Period (Last Available)
    4
    1
    4
    7
        Primary Treatment Period (Mean)
    5
    1
    3
    5
        Entire Treatment Period (Mean)
    4
    0
    3
    5
    No statistical analyses for this end point

    Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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    End point title
    The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
    End point description
    TSS includes 10 items - worst fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers, scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). For participants who completed at least six of these 10 items, the MPN-SAF TSS was computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus had a possible range of 0 to 100. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Participants
        Primary Treatment Period (Last Available)
    2
    2
    2
    9
        Entire Treatment Period (Last Available)
    2
    1
    2
    7
        Primary Treatment Period (Mean)
    2
    2
    3
    6
        Entire Treatment Period (Mean)
    2
    2
    3
    6
    No statistical analyses for this end point

    Secondary: Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

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    End point title
    Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline
    End point description
    The Functional Assessment of Cancer Therapy – Anemia (FACT-An) questionnaire includes 47 items rating on a 5-point Likert scale from 0 (not at all) to 4 (very much) on five primary subscales: • Physical well-being (sum of 7 items, score range from 0-28) • Social/Family well-being (sum of 7 items, score range from 0-28) • Emotional well-being (sum of 6 items, score range from 0-24) • Functional well-being (sum of 7 items, score range from 0-28) • Anemia-related symptoms (sum of 20 items, score range from 0-80) A total score for the FACT-An can be calculated by summing the five primary subscales with a score range from 0-188. Higher scores representing better quality of life. Baseline is defined as the last value on or before the first dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 169 and End of treatment (up to approximately 232 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    9 [4]
    9 [5]
    8 [6]
    14 [7]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 169
    -10.4 ± 13.23
    -15.7 ± 14.24
    -9.4 ± 9.24
    5.0 ± 21.77
        End of Treatment
    -15.9 ± 18.35
    -16.6 ± 16.80
    -12.6 ± 10.03
    -14.2 ± 21.98
    Notes
    [4] - Day 169 (n= 9) End of Treatment (n=9)
    [5] - Day 169 (n= 9) End of Treatment (n=8)
    [6] - Day 169 (n= 5) End of Treatment (n=8)
    [7] - Day 169 (n= 14) End of Treatment (n=14)
    No statistical analyses for this end point

    Secondary: Mean change in EQ-5D-5L Utility Score Compared to Baseline

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    End point title
    Mean change in EQ-5D-5L Utility Score Compared to Baseline
    End point description
    The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index for this analysis will be derived using the United Kingdom (UK) value sets based on UK time trade-off (TTO) valuation techniques and will use the Decision Support Unit (DSU) model to cross-walk to the EQ-5D-3L value set from the UK to derive a single index value. The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility.
    End point type
    Secondary
    End point timeframe
    Day 169 and End of treatment (up to approximately 232 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    11 [8]
    9 [9]
    8 [10]
    14 [11]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 169
    -0.043 ± 0.1466
    -0.063 ± 0.1152
    -0.126 ± 0.1246
    0.005 ± 0.1084
        End of Treatment
    -0.029 ± 0.1029
    -0.120 ± 0.1740
    -0.129 ± 0.1812
    -0.103 ± 0.2055
    Notes
    [8] - Day 169 (n= 11) End of Treatment (n=10)
    [9] - Day 169 (n= 9) End of Treatment (n=9)
    [10] - Day 169 (n= 6) End of Treatment (n=8)
    [11] - Day 169 (n= 14) End of Treatment (n=12)
    No statistical analyses for this end point

    Secondary: The Number of Participants Treatment-Emergent Adverse Events (TEAE)

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    End point title
    The Number of Participants Treatment-Emergent Adverse Events (TEAE)
    End point description
    TEAE is defined as any AEs that begin or worsen on or after the day of the first dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. An SAE is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or constitutes an important medical event. The severity/intensity of AEs will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.
    End point type
    Secondary
    End point timeframe
    From first dose through 42 days after the last dose (up to approximately 238 weeks)
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Participants
        TEAE
    21
    19
    13
    36
        Treatment-Related TEAE
    14
    5
    7
    19
        Serious TEAE
    8
    8
    4
    17
        Treatment-Related Serious TEAE
    1
    0
    0
    2
        TEAE Grade >=3
    9
    11
    4
    24
        Treatment-Related TEAE Grade >=3
    0
    1
    2
    7
        TEAE Leading to Dose Interruption
    2
    2
    3
    12
        Treatment-Related TEAE to Dose Interruption
    1
    1
    1
    4
        TEAE Leading to Dose Reduction
    1
    0
    2
    2
        Treatment-Related TEAE Leading to Dose Reduction
    1
    0
    2
    2
        TEAE Leading to Study Drug Withdrawn
    1
    2
    1
    5
        Treatment-Related TEAE to Study Drug Withdrawn
    0
    0
    0
    1
        TEAE Leading to Death
    1
    2
    0
    5
        Treatment-Related TEAE Leading to Death
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: CL/F (L/day)

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    End point title
    CL/F (L/day)
    End point description
    Apparent clearance
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: L/day
        geometric mean (geometric coefficient of variation)
    0.61 ± 51
    0.53 ± 31
    0.46 ± 34
    0.44 ± 38
    No statistical analyses for this end point

    Secondary: Ka (day-1)

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    End point title
    Ka (day-1)
    End point description
    First-order rate constant of absorption
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Day-1
        geometric mean (geometric coefficient of variation)
    0.3 ± 37
    0.28 ± 19
    0.29 ± 21
    0.28 ± 28
    No statistical analyses for this end point

    Secondary: V1/F (L)

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    End point title
    V1/F (L)
    End point description
    Apparent volume of distribution of the central compartment
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Liter
        geometric mean (geometric coefficient of variation)
    11.65 ± 53
    10.15 ± 31
    11.36 ± 34
    10.84 ± 39
    No statistical analyses for this end point

    Secondary: T1/2 (day)

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    End point title
    T1/2 (day)
    End point description
    Elimination half-life
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Day
        geometric mean (geometric coefficient of variation)
    13.28 ± 2.4
    13.3 ± 1.4
    16.96 ± 2.1
    16.98 ± 2.2
    No statistical analyses for this end point

    Secondary: Tmax (day)

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    End point title
    Tmax (day)
    End point description
    Time to reach the maximum concentration for the first dose (Cmax)
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Day
        median (full range (min-max))
    6.72 (4.84 to 10.01)
    7.38 (5.75 to 9.14)
    7.85 (6.17 to 9.54)
    7.96 (5.24 to 11.34)
    No statistical analyses for this end point

    Secondary: Cmax (µg/mL)

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    End point title
    Cmax (µg/mL)
    End point description
    Maximum concentration for the first dose
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    4.41 ± 39
    4.68 ± 20
    4.96 ± 23
    5.01 ± 30
    No statistical analyses for this end point

    Secondary: Cmax.ss (µg/mL)

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    End point title
    Cmax.ss (µg/mL)
    End point description
    Maximum concentration for the first dose (Cmax) at steady state for the starting dose
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    7.28 ± 42
    7.72 ± 21
    9.45 ± 24
    9.6 ± 32
    No statistical analyses for this end point

    Secondary: AUCss (day* µg/mL)

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    End point title
    AUCss (day* µg/mL)
    End point description
    Area under the concentration-time curve at the steady state for the starting dose
    End point type
    Secondary
    End point timeframe
    C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: day* µg/mL
        geometric mean (geometric coefficient of variation)
    123 ± 47
    132 ± 24
    168 ± 26
    171 ± 35
    No statistical analyses for this end point

    Secondary: Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A)

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    End point title
    Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A) [12]
    End point description
    Calculated based on average hemoglobin measurements collected during the treatment period.The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. The baseline RBC transfusion is defined as average number of RBC units/28 days over the 84 days period immediately prior to the C1D1 date.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 through end of treatment (up to approximately 232 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: Endpoint is specific to certain study arms
    End point values
    Cohort 1: Anemia Only Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    14
    Units: g/dL
    arithmetic mean (standard deviation)
        Primary Treatment Period
    0.795 ± 0.7697
    1.157 ± 0.5178
        Entire Treatment Period
    0.824 ± 0.8613
    1.172 ± 0.5992
    No statistical analyses for this end point

    Secondary: The Number of Participants with Antidrug Antibody (ADA) Measurements

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    End point title
    The Number of Participants with Antidrug Antibody (ADA) Measurements
    End point description
    The ADA status of a participant during treatment is determined based on the longitudinal ADA results as follows: Negative: All samples (baseline and post-baseline) are negative. Positive to treatment-emergent ADA: At least one post-baseline sample is positive if the baseline sample is negative, or at least one post-baseline sample is positive with a titer ≥ 4-fold of the baseline titer if the baseline sample is positive
    End point type
    Secondary
    End point timeframe
    C1D1 (pre- dose), C2D1, C4D1, C6D1, C8D1, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.
    End point values
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib) Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    21
    14
    38
    Units: Participants
        Positive
    1
    2
    2
    2
        Negative
    21
    19
    12
    36
    No statistical analyses for this end point

    Secondary: The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A)

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    End point title
    The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A) [13]
    End point description
    The number of participants with a Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period without an RBC transfusion. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as all non-missing Hgb records within 28 days on or prior to date of first dose (or date of enrollment if not treated).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 through end of treatment (up to approximately 232 weeks)
    Notes
    [13] - 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: Endpoint is specific to certain study arms
    End point values
    Cohort 1: Anemia Only Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Number of subjects analysed
    22
    14
    Units: Participants
        Primary Treatment Period
    5
    6
        Entire Treatment Period
    6
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs were assessed from first dose through 42 days after the last dose (up to approximately 238 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 1: Anemia Only
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 2: RBC-Transfusion Dependent
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Reporting group title
    Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Reporting group description
    Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

    Serious adverse events
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib) Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 22 (36.36%)
    8 / 21 (38.10%)
    17 / 38 (44.74%)
    4 / 14 (28.57%)
         number of deaths (all causes)
    6
    12
    13
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin squamous cell carcinoma recurrent
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic embolus
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Troponin T increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest wall haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral toxoplasmosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1: Anemia Only Cohort 2: RBC-Transfusion Dependent Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib) Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 22 (95.45%)
    19 / 21 (90.48%)
    33 / 38 (86.84%)
    13 / 14 (92.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 21 (14.29%)
    9 / 38 (23.68%)
    6 / 14 (42.86%)
         occurrences all number
    6
    3
    16
    6
    Hypotension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    4 / 38 (10.53%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    6
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 21 (14.29%)
    5 / 38 (13.16%)
    0 / 14 (0.00%)
         occurrences all number
    1
    3
    7
    0
    Chills
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    1
    Fatigue
         subjects affected / exposed
    4 / 22 (18.18%)
    5 / 21 (23.81%)
    6 / 38 (15.79%)
    2 / 14 (14.29%)
         occurrences all number
    4
    5
    12
    2
    Influenza like illness
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    3 / 14 (21.43%)
         occurrences all number
    1
    1
    1
    3
    Injection site pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    5 / 38 (13.16%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    5
    1
    Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    5 / 22 (22.73%)
    1 / 21 (4.76%)
    7 / 38 (18.42%)
    1 / 14 (7.14%)
         occurrences all number
    7
    1
    10
    1
    Early satiety
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 21 (23.81%)
    4 / 38 (10.53%)
    0 / 14 (0.00%)
         occurrences all number
    5
    6
    7
    0
    Dyspnoea
         subjects affected / exposed
    4 / 22 (18.18%)
    5 / 21 (23.81%)
    9 / 38 (23.68%)
    2 / 14 (14.29%)
         occurrences all number
    4
    5
    10
    3
    Epistaxis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    4 / 38 (10.53%)
    3 / 14 (21.43%)
         occurrences all number
    1
    2
    4
    3
    Sleep apnoea syndrome
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Depression
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    7 / 38 (18.42%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    10
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    0
    2
    Blood glucose increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    4 / 38 (10.53%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Fall
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    3 / 38 (7.89%)
    1 / 14 (7.14%)
         occurrences all number
    2
    4
    10
    3
    Lower limb fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    1
    Memory impairment
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 21 (4.76%)
    3 / 38 (7.89%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    3
    2
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    7 / 38 (18.42%)
    3 / 14 (21.43%)
         occurrences all number
    2
    2
    11
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 21 (14.29%)
    11 / 38 (28.95%)
    1 / 14 (7.14%)
         occurrences all number
    3
    3
    17
    1
    Splenomegaly
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 38 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    1
    0
    2
    Neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Anaemia
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    2
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    1
    Vomiting
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    2
    3
    Nausea
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 21 (14.29%)
    6 / 38 (15.79%)
    2 / 14 (14.29%)
         occurrences all number
    4
    3
    8
    2
    Mouth haemorrhage
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 21 (19.05%)
    11 / 38 (28.95%)
    4 / 14 (28.57%)
         occurrences all number
    4
    10
    17
    5
    Constipation
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    2
    2
    1
    1
    Abdominal pain
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 21 (9.52%)
    4 / 38 (10.53%)
    2 / 14 (14.29%)
         occurrences all number
    6
    2
    5
    2
    Skin and subcutaneous tissue disorders
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 21 (9.52%)
    3 / 38 (7.89%)
    3 / 14 (21.43%)
         occurrences all number
    3
    3
    3
    3
    Erythema
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Night sweats
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    2 / 38 (5.26%)
    3 / 14 (21.43%)
         occurrences all number
    3
    2
    3
    3
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    3 / 38 (7.89%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Acute kidney injury
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    1
    Arthralgia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    6 / 38 (15.79%)
    3 / 14 (21.43%)
         occurrences all number
    2
    0
    6
    3
    Back pain
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    2 / 14 (14.29%)
         occurrences all number
    4
    1
    2
    2
    Bone pain
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 21 (9.52%)
    4 / 38 (10.53%)
    3 / 14 (21.43%)
         occurrences all number
    5
    2
    5
    4
    Bursitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    3 / 38 (7.89%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Neck pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Neck mass
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    4 / 38 (10.53%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    4
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    2
    Abscess limb
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cystitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    5
    0
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Pyelonephritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    2 / 38 (5.26%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    2
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 21 (19.05%)
    3 / 38 (7.89%)
    1 / 14 (7.14%)
         occurrences all number
    2
    6
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    3 / 38 (7.89%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    3 / 38 (7.89%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    4
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 38 (2.63%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    2
    1
    Gout
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 38 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dehydration
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    3 / 38 (7.89%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    3
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    2 / 38 (5.26%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    5
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 21 (4.76%)
    1 / 38 (2.63%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 38 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2018
    Addition of exclusion criterion for a white blood count threshold. Addition of exclusion criterion for a platelet count threshold. Addition of exclusion criterion for subjects on anticoagulant therapy who are not under appropriate control or not on a stable dose of anticoagulant therapy for ≥ 8 weeks up to the enrollment date. Addition of exclusion criterion for subjects on anagrelide within 28 days immediately up to the enrollment date. Addition of exclusion criterion for subjects with a major bleeding event in the last 6 months prior to enrollment. Addition of secondary endpoint to capture changes in hemoglobin over the study compared to baseline in the absence of red blood cell (RBC) transfusions. Addition of minimum number of days between hemoglobin assessments as outlined within Inclusion Criterion 3A. Modified protocol criteria related to dose modification (dose delay, dose reductions, and discontinuation) measures to account for elevated white blood counts at the day of dosing.
    18 Dec 2018
    Clarification to collection of exploratory biomarkers in Section 1.4.4, Section 2 (Table 2) and Section 5 (Table 3)
    01 Aug 2019
    Expansion of Cohort 3 enrollment. Modifying Cohorts 2 and 3B inclusion criterion. Statistical considerations supporting Cohort 3 expansion. Addition of secondary endpoint to assess mean hemoglobin increase. Modifying dose titration criteria. Adapting clinical benefit criteria to allow subjects to continue in the Extension Phase. Addition of language supporting the ACE-536-LTFU-001 roll-over study. New starting dose level of 1.33 mg/kg. Amended Exclusion Criterion #3 for ruxolitinib dosing in Cohort 3. Added Section 10.9 Monitoring of Toxicity and Study Stopping Rules.
    19 Feb 2020
    Prolongation of Extension Phase of the Treatment Period.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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