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    Clinical Trial Results:
    An extension study to CQTI571A2301 to evaluate the long-term safety,tolerability and efficacy of oral QTI571 (imatinib) in the treatment of severe pulmonaryarterial hypertension: IMPRES Extension.

    Summary
    EudraCT number
    2009-018167-26
    Trial protocol
    AT   ES   DE   BE   GB   IT   FR  
    Global end of trial date
    16 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    16 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQTI571A2301E1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01117987
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    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
    16 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of QTI571
    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
    15 Apr 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    144
    EEA total number of subjects
    63
    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)
    125
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The following screening procedures were performed within 2 weeks of extension study enrollment (first drug assignment): - Screening safety laboratories, electrocardiogram (ECG) and 6MWD performed at Visit 1 if not performed in the previous 4 weeks. - Echocardiogram was performed at Visit 1 if not performed in the previous 8 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Core Imatinib
    Arm description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.
    Arm type
    Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    QTI571
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants, who received imatinib 200 mg in the core study, CQTI571A2301 (NCT00902174), and completed the core study, received imatinib 200 mg every day (qd) in the extension. Participants, who were randomized to receive imatinib 400 mg in the core study and completed the core study, received imatinib 400 mg qd in the extension. Participants, who terminated early from the core study or who were randomized to placebo and completed the core study, started the extension with imatinib 200 mg qd. After 2 weeks, the dose was increased to 400 mg qd if tolerated.

    Arm title
    Core Placebo
    Arm description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.
    Arm type
    Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    QTI571
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    To preserve the blind of the core study until the core study CQTI571A2301 was completed, participants received a blinded study drug package containing a 70-tablet bottle of imatinim and 70-tablet bottle of matching placebo

    Number of subjects in period 1
    Core Imatinib Core Placebo
    Started
    66
    78
    Completed
    5
    4
    Not completed
    61
    74
         Subject no longer requires study drug
    1
    -
         Lack of efficacy
    3
    4
         Adverse event, serious fatal
    5
    10
         Administrative problems
    25
    22
         Adverse event, non-fatal
    19
    26
         Consent withdrawn by subject
    5
    10
         Protocol deviation
    -
    1
         Abnormal test procedure result
    2
    -
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core Imatinib
    Reporting group description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.

    Reporting group title
    Core Placebo
    Reporting group description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.

    Reporting group values
    Core Imatinib Core Placebo Total
    Number of subjects
    66 78 144
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    53 72 125
        From 65-84 years
    13 6 19
        85 years and over
    0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    49.3 ± 15.52 45.7 ± 13.31 -
    Gender, Male/Female
    Units: Participants
        Female
    57 63 120
        Male
    9 15 24

    End points

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    End points reporting groups
    Reporting group title
    Core Imatinib
    Reporting group description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.

    Reporting group title
    Core Placebo
    Reporting group description
    Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated.

    Primary: Number of participants with adverse events, serious adverse events and deaths

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    End point title
    Number of participants with adverse events, serious adverse events and deaths [1]
    End point description
    Adverse event monitoring was conducted throughout the study.
    End point type
    Primary
    End point timeframe
    204 weeks
    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: statistical analysis not prespecified for this outcome measure.
    End point values
    Core Imatinib Core Placebo
    Number of subjects analysed
    66
    78
    Units: Participants
        Adverse events (non-serious and serious)
    62
    76
        Serious adverse events
    40
    53
        Deaths
    6
    10
    No statistical analyses for this end point

    Secondary: Change from core study baseline in Six-Minute Walk Distance (6MWD)

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    End point title
    Change from core study baseline in Six-Minute Walk Distance (6MWD)
    End point description
    A six minute walk test (6MWT) was performed in accordance with the guidleines of the American Thoracic Society (2002).
    End point type
    Secondary
    End point timeframe
    core study baseline, extension baseline, 12 weeks, 24 weeks, 48 weeks, 72 weeks, 96 weeks, 120 weeks, 144 weeks, 156 weeks, 204 weeks
    End point values
    Core Imatinib Core Placebo
    Number of subjects analysed
    66
    78
    Units: meters
    arithmetic mean (standard deviation)
        Extension baseline (n=61,77)
    42.98 ± 55.209
    4.91 ± 62.629
        Week 12 (n=58,57)
    48.75 ± 60.887
    16.25 ± 64.992
        Week 24 (n=54,53)
    44.71 ± 45.506
    19.34 ± 71.675
        Week 48 (n=47,42)
    45.81 ± 72.15
    29.18 ± 65.198
        Week 72 (n=40,39)
    49.54 ± 76.019
    56.46 ± 111.13
        Week 96 (n=38,35)
    66.64 ± 71.08
    41.03 ± 54.495
        Week 120 (n=32,29)
    83.19 ± 67.855
    37.43 ± 60.087
        Week 144 (n=27,21)
    67.7 ± 64
    39.45 ± 79.356
        Week 156 (n=21,18)
    72.6 ± 67.972
    30.17 ± 66.856
        Week 204 (n=4,3)
    96.88 ± 42.048
    4.5 ± 25.608
    No statistical analyses for this end point

    Secondary: Percentage of participants with incidence of clinical worsening events

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    End point title
    Percentage of participants with incidence of clinical worsening events
    End point description
    Clinical worsening events included death, overnight hospitalization for worsening of PAH, worsening of World Health Organization (WHO) functional class by at least one level (drop in WHO ), 15% decrease in the 6MWD as compared to baseline confirmed by two 6MWTs at two consecutive study visits (6MWD reduction), and drop in WHO & 6MWD reduction. Some participants have fulfilled more than one criterion. Therefore, the sum of individual components may be higher than the total number of participants with clinical worsening.
    End point type
    Secondary
    End point timeframe
    204 weeks
    End point values
    Core Imatinib Core Placebo
    Number of subjects analysed
    66
    78
    Units: Percentage of participants
    number (not applicable)
        Total participants with clinical worsening
    50
    46.2
        Death (all deaths)
    7.6
    12.8
        Hospitalization for worsening of PAH
    33.3
    28.2
        Drop in WHO
    24.2
    19.2
        6MWD reduction
    12.1
    19.2
        Drop in WHO and 6MWD reduction
    1.5
    3.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo tablets
    Reporting group description
    Placebo tablets

    Reporting group title
    Imatinib 100mg tablets
    Reporting group description
    Imatinib 100mg tablets

    Serious adverse events
    Placebo tablets Imatinib 100mg tablets
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 78 (67.95%)
    40 / 66 (60.61%)
         number of deaths (all causes)
    10
    5
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Craniotomy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain death
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Complications of transplanted lung
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophil percentage increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematocrit decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    N-terminal prohormone brain natriuretic peptide
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    8 / 78 (10.26%)
    5 / 66 (7.58%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoeic attack
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 66 (6.06%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    8 / 78 (10.26%)
    6 / 66 (9.09%)
         occurrences causally related to treatment / all
    3 / 10
    1 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    7 / 78 (8.97%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal erosion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital oedema
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroedema
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Telangiectasia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic sclerosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 66 (7.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 66 (4.55%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo tablets Imatinib 100mg tablets
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 78 (92.31%)
    55 / 66 (83.33%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    6
    2
    Hypotension
         subjects affected / exposed
    3 / 78 (3.85%)
    6 / 66 (9.09%)
         occurrences all number
    3
    10
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 66 (1.52%)
         occurrences all number
    4
    1
    Chest discomfort
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    5
    2
    Asthenia
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 66 (6.06%)
         occurrences all number
    2
    4
    Fatigue
         subjects affected / exposed
    11 / 78 (14.10%)
    9 / 66 (13.64%)
         occurrences all number
    12
    12
    Pyrexia
         subjects affected / exposed
    5 / 78 (6.41%)
    9 / 66 (13.64%)
         occurrences all number
    6
    13
    Oedema peripheral
         subjects affected / exposed
    32 / 78 (41.03%)
    21 / 66 (31.82%)
         occurrences all number
    48
    40
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    5
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    5
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 66 (6.06%)
         occurrences all number
    1
    5
    Fall
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 66 (6.06%)
         occurrences all number
    1
    4
    Ligament sprain
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 66 (7.58%)
         occurrences all number
    3
    5
    Blood creatinine increased
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 66 (6.06%)
         occurrences all number
    4
    5
    Weight increased
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    6
    7
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    5
    5
    Pericardial effusion
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Palpitations
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 66 (6.06%)
         occurrences all number
    4
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 78 (14.10%)
    16 / 66 (24.24%)
         occurrences all number
    12
    25
    Dyspnoea
         subjects affected / exposed
    6 / 78 (7.69%)
    10 / 66 (15.15%)
         occurrences all number
    6
    12
    Hypoxia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    4
    2
    Epistaxis
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 66 (9.09%)
         occurrences all number
    9
    7
    Nasal congestion
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 66 (7.58%)
         occurrences all number
    2
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 78 (1.28%)
    8 / 66 (12.12%)
         occurrences all number
    1
    17
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    4
    2
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    7 / 78 (8.97%)
    6 / 66 (9.09%)
         occurrences all number
    7
    6
    Anaemia
         subjects affected / exposed
    8 / 78 (10.26%)
    5 / 66 (7.58%)
         occurrences all number
    9
    6
    Iron deficiency anaemia
         subjects affected / exposed
    6 / 78 (7.69%)
    5 / 66 (7.58%)
         occurrences all number
    7
    5
    Leukopenia
         subjects affected / exposed
    9 / 78 (11.54%)
    1 / 66 (1.52%)
         occurrences all number
    19
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 78 (6.41%)
    9 / 66 (13.64%)
         occurrences all number
    10
    13
    Headache
         subjects affected / exposed
    24 / 78 (30.77%)
    12 / 66 (18.18%)
         occurrences all number
    27
    26
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    23 / 78 (29.49%)
    11 / 66 (16.67%)
         occurrences all number
    32
    15
    Conjunctival haemorrhage
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    9
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 66 (6.06%)
         occurrences all number
    3
    4
    Abdominal pain
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 66 (9.09%)
         occurrences all number
    6
    8
    Abdominal pain upper
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    7
    2
    Constipation
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 66 (4.55%)
         occurrences all number
    5
    3
    Abdominal discomfort
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 66 (3.03%)
         occurrences all number
    6
    2
    Nausea
         subjects affected / exposed
    39 / 78 (50.00%)
    21 / 66 (31.82%)
         occurrences all number
    58
    31
    Gastritis
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Dyspepsia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    5
    4
    Diarrhoea
         subjects affected / exposed
    27 / 78 (34.62%)
    18 / 66 (27.27%)
         occurrences all number
    36
    31
    Vomiting
         subjects affected / exposed
    25 / 78 (32.05%)
    14 / 66 (21.21%)
         occurrences all number
    34
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 66 (4.55%)
         occurrences all number
    4
    3
    Rash
         subjects affected / exposed
    13 / 78 (16.67%)
    7 / 66 (10.61%)
         occurrences all number
    13
    8
    Pruritus
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 66 (1.52%)
         occurrences all number
    6
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 66 (9.09%)
         occurrences all number
    4
    9
    Arthralgia
         subjects affected / exposed
    12 / 78 (15.38%)
    5 / 66 (7.58%)
         occurrences all number
    17
    6
    Muscle spasms
         subjects affected / exposed
    12 / 78 (15.38%)
    8 / 66 (12.12%)
         occurrences all number
    15
    15
    Musculoskeletal pain
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 66 (6.06%)
         occurrences all number
    2
    4
    Pain in extremity
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 66 (9.09%)
         occurrences all number
    6
    10
    Myalgia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    6
    3
    Fluid overload
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 66 (1.52%)
         occurrences all number
    6
    1
    Decreased appetite
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 66 (3.03%)
         occurrences all number
    4
    2
    Hypokalaemia
         subjects affected / exposed
    10 / 78 (12.82%)
    5 / 66 (7.58%)
         occurrences all number
    14
    5
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 78 (0.00%)
    5 / 66 (7.58%)
         occurrences all number
    0
    5
    Infections and infestations
    Device related infection
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 66 (0.00%)
         occurrences all number
    8
    0
    Influenza
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 66 (7.58%)
         occurrences all number
    2
    6
    Nasopharyngitis
         subjects affected / exposed
    24 / 78 (30.77%)
    17 / 66 (25.76%)
         occurrences all number
    59
    54
    Pneumonia
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 66 (1.52%)
         occurrences all number
    4
    1
    Bronchitis
         subjects affected / exposed
    8 / 78 (10.26%)
    1 / 66 (1.52%)
         occurrences all number
    16
    2
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 78 (14.10%)
    6 / 66 (9.09%)
         occurrences all number
    13
    9
    Respiratory tract infection
         subjects affected / exposed
    7 / 78 (8.97%)
    3 / 66 (4.55%)
         occurrences all number
    12
    5
    Urinary tract infection
         subjects affected / exposed
    8 / 78 (10.26%)
    3 / 66 (4.55%)
         occurrences all number
    12
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2010
    Amendment 1: The protocol was amended to allow for additional safety monitoring, provide necessary clarifications and ensure alignment with the core protocol CQTI571A2301. To implement additional safety monitoring, three additional visits were added to the protocol changing the 6- month interval visits to 3-month intervals.
    19 Jul 2010
    Amendment 2: The protocol was amended to clarify the exclusion criterion for male and female contraception requirements and to specify an end date for the study.
    26 Jul 2011
    Amendment 3: The protocol was amended to unblind patients and site staff to the QTI571 dose strength and allow for patients to administer open-label study medication. This planned amendment followed the database lock and unblinding of the treatment assignments in the core protocol CQTI571A2301. Prior to this amendment, extension study medication was supplied in a blinded fashion to patients to prevent knowledge of the QTI571 dose level. This was done in order to maintain the blinding of the core protocol CQTI571A2301. Following this database lock, it is no longer necessary to have patients administer placebo study medication and maintain blinding in the extension study. In addition, the requirements for restarting study drug after a drop in platelets was amended. At the request of the French Health Authority, a specific country requirement was added, wherein, patients in this country can only resume when platelet count is above 75,000/mm3, even though the baseline count may have been lower. This requirement was implemented globally however has come to be overly restrictive for many patients in other countries whose platelet count was below the restart requirement at baseline. Since this requirement was only specific to France, the protocol will now allow patients in other countries to be restarted on drug when the platelet count has returned to baseline levels if less than 75,000/mm3 at study start.
    20 Mar 2012
    Amendment 4: The protocol was amended to obtain survival follow-up information on extension patients and core protocol CQTI571A2301 patients who did not enroll in the extension study. This information is being collected for additional safety monitoring of all patients involved in the core and extension trials. Survival follow-up information will be collected every six months after the patients’ last study visit for up to 3 years up until the time of study database lock for this extension protocol.
    25 Jul 2012
    Amendment 5: The protocol was amended to clarify the process for the collection of survival follow-up information from subjects in the United States only, as per local regulations. This information is being collected for additional safety monitoring of all patients involved in the core and extension trials. Survival follow-up information will be collected every six months after the patients’ last study visit for up to 3 years up until the time of study database lock for this extension protocol. Local regulations in the United States also permit obtaining publically available survival information without patient consent. Survival information will be collected from public databases, in the United States only, for subjects whose consent can not be obtained.
    06 Dec 2012
    Amendment 6: The protocol was amended to update language regarding the packaging of the study drug by removing the specifics of open-label study drug provided in 140-tablet bottles. This change will allow for alternative packaging to be used in this study. In addition text was deleted if not pertinent to a section, referred to in previous sections or not relevant to provide in the protocol.
    11 Jan 2013
    Amendment 7: The protocol was amended to extend the study duration by one additional year, thereby changing the overall study duration to four years for the approximate 74 ongoing patients out of 144 patients enrolled. This extension in study duration will consist of two additional visits of 6-month frequency with reduced assessments. A physical exam, echocardiogram, and dipstick urine test will not be required as part of the new study visits. Additionally, NTproBNP lab assessment, six-minute walk test and Borg Scale will be performed at one of the 2 new study visits only. Following 3 years of study treatment with imatinib, patients are considered stable and echocardiography will not be required except for the final study visit. The echocardiogram should be performed as clinically indicated as part of standard of care. The assessment schedule and other relevant protocol sections have been updated accordingly. Extending the study by one additional year will allow patients to continue to participate in this extension study and avoid treatment interruption. The protocol stated co-medications that are inhibitors, inducers or substrates of CYP3A4 and CYP2D6 should be used with caution. A statement was added in this amendment to also avoid grapefruit juice and other foods that inhibit CYP3A4 while taking imatinib as these foods may increase the plasma concentration of imatinib.
    24 Apr 2013
    Amendment 8: The protocol was amended to revise the information on concomitant use of imatinib and oral vitamin K antagonists in PAH patients. This is based on updated information on the risk of bleeding events, especially subdural hematoma, and the need for these events to receive careful evaluation in PAH patients – as the risk of subdural hematoma is increased in patients taking imatinib and oral vitamin K antagonists concomitantly.

    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.
    In 2013,Novartis discontinued the development program of imatinib in pulmonary arterial hypertension (PAH) due to requirement of regulatory authorities for additional data to secure marketing approval in PAH;all global extension studies were closed
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