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    Clinical Trial Results:
    A multicenter Phase II, open label, single arm study to evaluate the efficacy and safety of ruxolitinib in the treatment of anemic myelofibrosis subjects

    Summary
    EudraCT number
    		 2016-003552-75
    Trial protocol
    		 HU   GR   DE   ES   AT   BG   BE   IT  
    Global end of trial date
    15 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Feb 2020
    First version publication date
    29 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424A2411
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02966353
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Study Director, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Study Director, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the spleen length response rate at Week 24
    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
    31 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Turkey: 3
    Worldwide total number of subjects
    51
    EEA total number of subjects
    37
    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)
    20
    From 65 to 84 years
    28
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening evaluations were performed to determine the eligibility for the study and establish a baseline prior to dosing.

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

    Arms
    Arm title
    		 All Subjects
    Arm description
    		 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.
    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 10 mg b.i.d. (two 5-mg tablets of ruxolitinib taken orally) was self-administered as the starting dose for treatment. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction

    Number of subjects in period 1
    		All Subjects
    Started
    51
    Completed after data cutoff
    1 [1]
    Completed
    29
    Not completed
    22
         Adverse event, serious fatal
    4
         Consent withdrawn by subject
    7
         Physician decision
    3
         Adverse event, non-fatal
    4
         Protocol deviation
    2
         Progressive disease
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One participant completed one week after 30 days follow up for safety

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.

    Reporting group values
    		 All Subjects Total
    Number of subjects
    		 51 51
    Age Categorical
    Units:
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 20 20
        >=65 years
    		 31 31
    Sex: Female, Male
    Units:
        Female
    		 21 21
        Male
    		 30 30
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 48 48
        Asian
    		 3 3
    Type of myelofibrosis-n
    Units: Subjects
        Primary myelofibrosis
    		 34 34
        Post-polycythemia vera myelofibrosis
    		 6 6
        Post-essential thrombocythemia myelofibrosis
    		 11 11
    Bone Marrow Fibrosis Grade at Diagnosis
    Units: Subjects
        Grade 0
    		 0 0
        Grade 1
    		 6 6
        Grade 2
    		 26 26
        Grade 3
    		 18 18
        Missing
    		 1 1
    Constitutional symptoms
    Units: Subjects
        Present
    		 29 29
        Absent
    		 22 22
    Time since intial diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 32.9 ( 44.16 ) -
    Palpable spleen length (cm) below costal margin
    Units: spleen length - centimeters
        arithmetic mean (standard deviation)
    		 11.7 ( 6.20 ) -
    Hemoglobin level
    Units: g/dL
        arithmetic mean (standard deviation)
    		 88.6 ( 9.74 ) -
    Platelets
    Units: 10E9/L
        arithmetic mean (standard deviation)
    		 236.7 ( 176.88 ) -

    End points

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    End points reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.

    Primary: Percentage of participants with at least 50% reduction in spleen length from baseline at Week 24

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    End point title
    		 Percentage of participants with at least 50% reduction in spleen length from baseline at Week 24 [1]
    End point description
    Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
    End point type
    Primary
    End point timeframe
    Baseline up to week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal analysis was performed
    End point values
    		 All Subjects
    Number of subjects analysed
    50
    Units: percentage of participants
        number (confidence interval 95%)
    56.0 (41.3 to 70.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants with at least 50% reduction in spleen length from baseline at Week 48

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    End point title
    		 Percentage of participants with at least 50% reduction in spleen length from baseline at Week 48
    End point description
    Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 48
    End point values
    		 All Subjects
    Number of subjects analysed
    50
    Units: percentage of participants
        number (confidence interval 95%)
    36.0 (22.9 to 50.8)
    No statistical analyses for this end point

    Secondary: Percentage of participants by spleen length reduction from baseline category at Week 24 and Week 48

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    End point title
    		 Percentage of participants by spleen length reduction from baseline category at Week 24 and Week 48
    End point description
    The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0.
    End point type
    Secondary
    End point timeframe
    baseline, weeks 24 and 48
    End point values
    		 All Subjects
    Number of subjects analysed
    51
    Units: percentage of participants
    number (not applicable)
        Week 24 ≤ -50% n=43
    65.1
        Week 24 -50%, -25% n=43
    11.6
        Week 24 -25%, -5% n=43
    9.3
        Week 24 -5%, 5% n=43
    4.7
        Week 24 5%, 25% n=43
    9.3
        Week 24 25%, 50% n=43
    0
        Week 24 >50% n=43
    0
        Week 24 remained non-palpable n=43
    0
        Week 24 became palpable n=43
    0
        Week 48 ≤ -50% n=36
    50.0
        Week 48 -50%, -25% n=36
    22.2
        Week 48 -25%, -5% n=36
    16.7
        Week 48 -5%, 5% n=36
    5.6
        Week 48 5%, 25% n=36
    2.8
        Week 48 25%, 50% n=36
    2.8
        Week 48 >50% n=36
    0
        Week 48 remained non-palpable n=36
    0
        Week 48 became palpable n=36
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants with at least a 50% reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24

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    End point title
    		 Percentage of participants with at least a 50% reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24
    End point description
    The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable).
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 All Subjects
    Number of subjects analysed
    45
    Units: percentage of participants
    number (confidence interval 95%)
        MF-7 Total Symptom score
    51.1 (35.8 to 66.3)
        Modified MFSAF v2.0 Total symptom score
    55.6 (40.0 to 70.4)
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) at Week 24 and Week 48

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    End point title
    		 Patient Global Impression of Change (PGIC) at Week 24 and Week 48
    End point description
    The PGIC is comprised of a single question intended to measure a subject’s perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where ‘1’ equals very much improved and ‘7’ equals very much worse.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 48
    End point values
    		 All Subjects
    Number of subjects analysed
    51
    Units: Participants
        Week 24 n=41 Very much improved
    5
        Week 24 n=41 Much improved
    20
        Week 24 n=41 Minimally improved
    9
        Week 24 n=41 No change
    6
        Week 24 n=41 Minimally worse
    1
        Week 24 n=41 Much worse
    0
        Week 24 n=41 Very much worse
    0
        Week 48 n=33 Very much improved
    5
        Week 48 n=33 Much improved
    15
        Week 48 n=33 Minimally improved
    9
        Week 48 n=33 No change
    4
        Week 48 n=33 Minimally worse
    0
        Week 48 n=33 Much worse
    0
        Week 48 n=33 Very much worse
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants transfusion independency from baseline up to week 96

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    End point title
    		 Percentage of participants transfusion independency from baseline up to week 96
    End point description
    Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 96
    End point values
    		 All Subjects
    Number of subjects analysed
    50
    Units: percentage of participants
    number (not applicable)
        Transfusion dependent participants at baseline
    18.0
        Week 24 transfusion independent rate
    0.0
        Week 24 transfusion responder rate
    44.4
        Week 48 transfusion independent rate
    0.0
        Week 48 transfusion responder rate
    66.7
        Week 72 transfusion independent rate
    0.0
        Week 72 transfusion responder rate
    66.7
        Week 96 transfusion independent rate
    0.0
        Week 96 transfusion responder rate
    66.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 100 weeks
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 51 (33.33%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    Haemolytic anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 51 (84.31%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Keratoacanthoma
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    6
    Hypertension
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Peripheral venous disease
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 51 (11.76%)
         occurrences all number
    7
    Fatigue
         subjects affected / exposed
    5 / 51 (9.80%)
         occurrences all number
    5
    Oedema peripheral
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    4
    Chest discomfort
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Early satiety
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Oedema
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    4
    Epistaxis
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Catarrh
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Dyspnoea exertional
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Pneumonitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    4
    Pulmonary mass
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hallucination
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 51 (9.80%)
         occurrences all number
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 51 (9.80%)
         occurrences all number
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    5
    Blood creatinine increased
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 51 (11.76%)
         occurrences all number
    8
    Platelet count decreased
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    4
    Amylase increased
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    3
    Blood bilirubin increased
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Blood phosphorus increased
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Blood potassium increased
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Lipase increased
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Neutrophil count decreased
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Weight increased
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Limb injury
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    3
    Cardiac disorder
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Cognitive disorder
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Dysgeusia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Encephalopathy
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 51 (33.33%)
         occurrences all number
    51
    Thrombocytopenia
         subjects affected / exposed
    14 / 51 (27.45%)
         occurrences all number
    18
    Coagulopathy
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Haemorrhagic disorder
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Leukocytosis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Retinal vascular disorder
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    6 / 51 (11.76%)
         occurrences all number
    7
    Abdominal distension
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Aphthous ulcer
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Rectal haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    5
    Hyperhidrosis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Mucocutaneous haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    4
    Chronic kidney disease
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Dysuria
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Nocturia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Renal failure
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    4
    Muscle spasms
         subjects affected / exposed
    4 / 51 (7.84%)
         occurrences all number
    4
    Muscular weakness
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Bone pain
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Bursitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Connective tissue disorder
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Flank pain
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    5
    Oral herpes
         subjects affected / exposed
    3 / 51 (5.88%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 51 (9.80%)
         occurrences all number
    6
    Bacteraemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    4
    Dysentery
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Nasal herpes
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    2
    Otitis externa
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    2
    Viral infection
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Gout
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    3
    Haemosiderosis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hyperphosphataemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hyperuricaemia
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    5
    Hypocalcaemia
         subjects affected / exposed
    2 / 51 (3.92%)
         occurrences all number
    4
    Hypoglycaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1
    Lactic acidosis
         subjects affected / exposed
    1 / 51 (1.96%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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