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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of six months treatment with the tyrosine kinase inhibitor of STI571 for the treatment of pulmonary arterial hypertension.

    Summary
    EudraCT number
    2005-005569-12
    Trial protocol
    GB   DE   AT  
    Global end of trial date
    31 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Apr 2016
    First version publication date
    14 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSTI571E2203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00477269
    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
    31 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    • To assess the safety and tolerability of oral STI571 compared with placebo in patients with pulmonary arterial hypertension. • To evaluate efficacy of oral STI571 as measured by improvement in 6-minute walk test.
    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
    23 Jun 2006
    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
    United States: 8
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Germany: 30
    Worldwide total number of subjects
    59
    EEA total number of subjects
    51
    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)
    52
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Fifty-nine subjects were enrolled in the core trial and 22 continued into the extension phase. The original protocol allowed for compassionate use but a DMC recommended a protocol amendment for the extension. When extension phase was implemented, patients had already been treated for up to two years on compassionate use dose.

    Pre-assignment
    Screening details
    Sixty-one patients were screened and 59 enrolled.

    Period 1
    Period 1 title
    Core Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Core-STI571
    Arm description
    STI571 (Imatinib) was supplied in 100 mg capsules and was to have been administered orally with daily dose starting at 200 mg rising to 400 mg within two weeks. Dose may have been downtitrated from 400 to 200 mg one time during the trial.
    Arm type
    Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    STI571
    Other name
    Glivec, Gleevec
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Core study: STI571 was initiated at a dose level of 200 mg (two 100 mg capsules) per day for the first two weeks of treatment. If treatment was well tolerated, an up-titration to 400 mg (four 100 mg capsules) occurred. Patients then continued treatment for the next five months. If 400 mg was not well tolerated, one down-titration during the course of the study was permitted. STI571 was provided as 100 mg capsules, orally taken. Open label extension: STI571 was provided as 100 mg capsules for oral administration. Patients were instructed to take the study drug once daily with a meal and a large glass (8 oz/200 mL) of water to to not chew the medication, but to swallow it whole.

    Arm title
    Core-Placebo
    Arm description
    The appearance of placebo medication was identical to that of active drug.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching capsules to be administered the same as the STI571 experimental arm.

    Number of subjects in period 1
    Core-STI571 Core-Placebo
    Started
    28
    31
    Completed
    19
    23
    Not completed
    9
    8
         Adverse event, serious fatal
    3
    3
         Adverse event, non-fatal
    6
    4
         Consent withdrawn by subject
    -
    1
    Period 2
    Period 2 title
    Extension
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Extension-STI571
    Arm description
    Open label
    Arm type
    Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    STI571
    Other name
    Glivec, Gleevec
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Open label extension: STI571 was provided as 100 mg capsules for oral administration. Patients were instructed to take the study drug once daily with a meal and a large glass (8 oz/200 mL) of water to to not chew the medication, but to swallow it whole.

    Number of subjects in period 2 [1]
    Extension-STI571
    Started
    22
    Completed
    9
    Not completed
    13
         Abnormal laboratory value
    1
         Adverse event, serious fatal
    4
         Administrative problems
    2
         Adverse event, non-fatal
    4
         Unsatisfactory therapeutic effict
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This study was comprised of several treatment phases. Initially the study was a 6 month treatment period in patients with PAH. Once patients completed this phase they were given the opportunity to continue to receive imatinib via compassionate use. After advice from the DSMB, a formal extension phase was launched. Twenty-two patients were receiving imatinib via compassionate use and were enrolled into the extension phase of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Core-STI571
    Reporting group description
    STI571 (Imatinib) was supplied in 100 mg capsules and was to have been administered orally with daily dose starting at 200 mg rising to 400 mg within two weeks. Dose may have been downtitrated from 400 to 200 mg one time during the trial.

    Reporting group title
    Core-Placebo
    Reporting group description
    The appearance of placebo medication was identical to that of active drug.

    Reporting group values
    Core-STI571 Core-Placebo Total
    Number of subjects
    28 31 59
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    26 26 52
        From 65-84 years
    2 5 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.4 ± 15.3 44.2 ± 15.7 -
    Gender categorical
    Units: Subjects
        Female
    18 22 40
        Male
    10 9 19

    End points

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    End points reporting groups
    Reporting group title
    Core-STI571
    Reporting group description
    STI571 (Imatinib) was supplied in 100 mg capsules and was to have been administered orally with daily dose starting at 200 mg rising to 400 mg within two weeks. Dose may have been downtitrated from 400 to 200 mg one time during the trial.

    Reporting group title
    Core-Placebo
    Reporting group description
    The appearance of placebo medication was identical to that of active drug.
    Reporting group title
    Extension-STI571
    Reporting group description
    Open label

    Subject analysis set title
    STI571 Six Min Walk Day 32
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Day 32.

    Subject analysis set title
    STI571 Six Min Walk Week 8
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Week 8.

    Subject analysis set title
    STI571 Six Min Walk Week 12
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Week 12.

    Subject analysis set title
    STI571 Six Min Walk Week 16
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Week 16.

    Subject analysis set title
    STI571 Six Min Walk Week 20
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Week 20.

    Subject analysis set title
    STI571 Six Min Walk Week 24
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on STI571 at Week 24 (Study Completion).

    Subject analysis set title
    Placebo Six Min Walk Day 32
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Day 32.

    Subject analysis set title
    Placebo Six Min Walk Week 8
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Week 8.

    Subject analysis set title
    Placebo Six Min Walk Week 12
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Week 12.

    Subject analysis set title
    Placebo Six Min Walk Week 16
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Week 16.

    Subject analysis set title
    Placebo Six Min Walk Week 20
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Week 20.

    Subject analysis set title
    Placebo Six Min Walk Week 24
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients included in Six Minute Walk Test analysis group on Placebo at Week 24 (Study Completion).

    Primary: Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Core

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    End point title
    Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Core [1]
    End point description
    No statistical analysis provided for Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Core. All patients with all (serious and non -serious) adverse events, and death were reported. See Safety Section.
    End point type
    Primary
    End point timeframe
    6 months
    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 statistical analysis was planned for this primary outcome measure.
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Patients
        Patients with AE(s)
    27
    29
        Death
    3
    3
        SAE(s)
    12
    11
    No statistical analyses for this end point

    Primary: Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Extension

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    End point title
    Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Extension [2]
    End point description
    No formal statistical analysis was performed in the extension phase of this study so no analysis data sets were defined. All summaries are based on all patients enrolled. See Safety Section
    End point type
    Primary
    End point timeframe
    72 months
    Notes
    [2] - 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 statistical analysis was planned for this primary outcome measure.
    End point values
    Extension-STI571
    Number of subjects analysed
    22
    Units: Patients
        Any Adverse Event(s)
    22
        Death
    4
        Serious Adverse Event(s)
    16
    No statistical analyses for this end point

    Primary: Change From Baseline of Six Minute Walk Test - Total Distance Walked

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    End point title
    Change From Baseline of Six Minute Walk Test - Total Distance Walked
    End point description
    The Six Minute Walk test was carried out along a course, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Distance <500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance >800 meters (with no rests) suggests mild or no limitation. The intention to treat population (ITT) included all patients who received at least one dose of study medication. Evaluable patients required observations at both baseline and endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Week 24.
    End point values
    STI571 Six Min Walk Day 32 STI571 Six Min Walk Week 8 STI571 Six Min Walk Week 12 STI571 Six Min Walk Week 16 STI571 Six Min Walk Week 20 STI571 Six Min Walk Week 24 Placebo Six Min Walk Day 32 Placebo Six Min Walk Week 8 Placebo Six Min Walk Week 12 Placebo Six Min Walk Week 16 Placebo Six Min Walk Week 20 Placebo Six Min Walk Week 24
    Number of subjects analysed
    25
    23
    22
    19
    19
    21
    27
    24
    24
    23
    21
    12
    Units: Meters
        arithmetic mean (standard deviation)
    10.2 ± 53.7
    17 ± 55.6
    21 ± 36.2
    25.5 ± 43.1
    38.3 ± 42.5
    22 ± 63.1
    8.2 ± 27.5
    15.5 ± 40.8
    7.8 ± 50
    12.1 ± 47.9
    12.8 ± 60.4
    -1 ± 53.3
    Statistical analysis title
    Six Minute Walk Test - Total Distance Day 32
    Statistical analysis description
    The six minute walk tests at week 24 was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Day 32 v Placebo Six Min Walk Day 32
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8772
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.93
         upper limit
    25.61
    Statistical analysis title
    Six Min Walk -Total Distance Week 8
    Statistical analysis description
    The six minute walk tests at week 24 was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Week 8 v Placebo Six Min Walk Week 8
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9282
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.4
         upper limit
    29.98
    Statistical analysis title
    Six Min Walk -Total Distance Week 12
    Statistical analysis description
    The six minute walk tests for all time points was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Week 12 v Placebo Six Min Walk Week 12
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2877
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    13.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.19
         upper limit
    40.1
    Statistical analysis title
    Six Min Walk -Total Distance Week 16
    Statistical analysis description
    The six minute walk tests for all time points was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Week 16 v Placebo Six Min Walk Week 16
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3392
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    13.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.64
         upper limit
    41.48
    Statistical analysis title
    Six Min Walk -Total Distance Week 20
    Statistical analysis description
    The six minute walk tests for all time points was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Week 20 v Placebo Six Min Walk Week 20
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1507
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    24.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.28
         upper limit
    58.05
    Statistical analysis title
    Six Min Walk -Total Distance Week 24
    Statistical analysis description
    The six minute walk tests for all time points was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For this timepoint the differences between STI571 and placebo was estimated together with the 95% confidence intervals. The analysis was performed on intention to treat population.
    Comparison groups
    STI571 Six Min Walk Week 24 v Placebo Six Min Walk Week 24
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2134
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    21.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.03
         upper limit
    56.51

    Primary: Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods

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    End point title
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods
    End point description
    The Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. If the patient stopped the duration of each stop was recorded. The intention to treat population (ITT) included all patients who received at least one dose of study medication. Evaluable patients required observations at both baseline and endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    STI571 Six Min Walk Day 32 STI571 Six Min Walk Week 8 STI571 Six Min Walk Week 12 STI571 Six Min Walk Week 16 STI571 Six Min Walk Week 20 STI571 Six Min Walk Week 24 Placebo Six Min Walk Day 32 Placebo Six Min Walk Week 8 Placebo Six Min Walk Week 12 Placebo Six Min Walk Week 16 Placebo Six Min Walk Week 20 Placebo Six Min Walk Week 24
    Number of subjects analysed
    25
    23
    22
    19
    19
    21
    27
    24
    24
    23
    21
    12
    Units: Number of stops
        arithmetic mean (standard deviation)
    -0.2 ± 0.7
    -0.2 ± 0.7
    -0.3 ± 0.9
    -0.3 ± 0.8
    -0.4 ± 1
    -0.3 ± 0.8
    0.1 ± 0.4
    0 ± 0.4
    0.3 ± 0.9
    0 ± 0.2
    0.3 ± 1
    -0.1 ± 0.5
    Statistical analysis title
    Six Minute Walk Test-Number of Stops - Day 32
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Day 32
    Comparison groups
    STI571 Six Min Walk Day 32 v Placebo Six Min Walk Day 32
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0166
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    0.07
    Statistical analysis title
    Six Minute Walk Test-Number of Stops Week 8
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Week 8
    Comparison groups
    STI571 Six Min Walk Week 8 v Placebo Six Min Walk Week 8
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.24
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    0.14
    Statistical analysis title
    Six Minute Walk Test-Number of Stops Week 12
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Week 12
    Comparison groups
    STI571 Six Min Walk Week 12 v Placebo Six Min Walk Week 12
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0252
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.15
         upper limit
    -0.08
    Statistical analysis title
    Six Minute Walk Test-Number of Stops Week 16
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Week 16
    Comparison groups
    STI571 Six Min Walk Week 16 v Placebo Six Min Walk Week 16
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0755
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.67
         upper limit
    0.03
    Statistical analysis title
    Six Minute Walk Test-Number of Stops Week 20
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Week 20
    Comparison groups
    STI571 Six Min Walk Week 20 v Placebo Six Min Walk Week 20
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0297
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    -0.07
    Statistical analysis title
    Six Minute Walk -Number of Stops Completion
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods Study Completion
    Comparison groups
    STI571 Six Min Walk Week 24 v Placebo Six Min Walk Week 24
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1485
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.39
         upper limit
    0.06

    Primary: Change From Baseline of Six Minute Walk Test - Total Duration of Stops at Different Time Periods

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    End point title
    Change From Baseline of Six Minute Walk Test - Total Duration of Stops at Different Time Periods
    End point description
    The Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. If the patient stopped the duration of each stop was recorded. The intention to treat population (ITT) included all patients who received at least one dose of study medication. Evaluable patients required observations at both baseline and endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    STI571 Six Min Walk Day 32 STI571 Six Min Walk Week 8 STI571 Six Min Walk Week 12 STI571 Six Min Walk Week 16 STI571 Six Min Walk Week 20 STI571 Six Min Walk Week 24 Placebo Six Min Walk Day 32 Placebo Six Min Walk Week 8 Placebo Six Min Walk Week 12 Placebo Six Min Walk Week 16 Placebo Six Min Walk Week 20 Placebo Six Min Walk Week 24
    Number of subjects analysed
    25
    23
    22
    19
    19
    21
    27
    24
    24
    23
    21
    12
    Units: minutes
        arithmetic mean (standard deviation)
    -0.06 ± 0.19
    -0.03 ± 0.1
    -0.03 ± 0.1
    -0.03 ± 0.1
    -0.05 ± 0.15
    -0.02 ± 0.1
    0.12 ± 0.36
    0.07 ± 0.27
    0.19 ± 0.55
    0.06 ± 0.26
    0.12 ± 0.42
    0.03 ± 0.18
    Statistical analysis title
    Six Minute Walk Duration of stops [min] - Day 32
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] at Different Time Periods Day 32
    Comparison groups
    STI571 Six Min Walk Day 32 v Placebo Six Min Walk Day 32
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0301
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    -0.02
    Statistical analysis title
    Six Minute Walk Duration of stops [min] Week 8
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] Week 8
    Comparison groups
    Placebo Six Min Walk Week 8 v STI571 Six Min Walk Week 8
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1179
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    0.03
    Statistical analysis title
    Six Minute Walk Duration of stops [min] Week 12
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] Week 12
    Comparison groups
    STI571 Six Min Walk Week 12 v Placebo Six Min Walk Week 12
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0652
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    0.01
    Statistical analysis title
    Six Minute Walk Duration of stops [min] Week16
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] Week 16
    Comparison groups
    STI571 Six Min Walk Week 20 v Placebo Six Min Walk Week 16
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1826
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    0.04
    Statistical analysis title
    Six Minute Walk Duration of stops [min] Week 20
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] Week 20
    Comparison groups
    STI571 Six Min Walk Week 20 v Placebo Six Min Walk Week 20
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0863
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    0.03
    Statistical analysis title
    Six Min Walk Duration of stops [min] Week 24
    Statistical analysis description
    Change From Baseline of Six Minute Walk Test -Total duration of stops [min] Study Completion
    Comparison groups
    STI571 Six Min Walk Week 24 v Placebo Six Min Walk Week 24
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1896
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.03

    Primary: Change From Baseline of Six Minute Walk Test - Total Distance Walked at week 8

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    End point title
    Change From Baseline of Six Minute Walk Test - Total Distance Walked at week 8
    End point description
    20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Distance <500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance >800 meters (with no rests) suggests mild or no limitation. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline, week 8
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    23
    24
    Units: Meters
    arithmetic mean (standard deviation)
        week 8 (n=23,24)
    17 ± 55.6
    15.5 ± 40.8
    Statistical analysis title
    Six Minute Walk Test - Total Distance at Week 8
    Statistical analysis description
    The six minute walk tests at week 24 was analyzed using an analysis of covariance (ANCOVA) model including treatment (STI571 or placebo) as fixed effect and value at baseline as covariate. For all time-points the differences between STI571 and placebo will be estimated together with the 95% confidence intervals. The analysis will be performed on intention to treat population.
    Comparison groups
    Core-STI571 v Core-Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9282
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.4
         upper limit
    29.98

    Secondary: Number of Patients With Pulmonary Hypertension (PAH) Assessd by World Health Organization (WHO) Classification on Physical Activity

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    End point title
    Number of Patients With Pulmonary Hypertension (PAH) Assessd by World Health Organization (WHO) Classification on Physical Activity
    End point description
    PAH assessed according to the WHO classification: Class I Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II Patients with PAH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III Patients with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV Patients with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. The intention to treat population (ITT) will include all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Participants
        Baseline: WHO Class IV (n=27,30)
    2
    1
        Baseline: WHO Class III (n=27,30)
    14
    22
        Baseline: WHO Class II (n=27,30)
    11
    7
        Day 32: WHO Class IV (n=27,30)
    3
    3
        Day 32: WHO Class III (n=27,30)
    11
    21
        Day 32: WHO Class II (n=27,30)
    13
    6
        Week 8: WHO Class IV (n=24,27)
    3
    1
        Week 8: WHO Class III (n=24,27)
    9
    20
        Week 8: WHO Class II (n=24,27)
    12
    6
        Week 12: WHO Class IV (n=23,27)
    0
    1
        Week 12: WHO Class III (n=23,27)
    12
    17
        Week 12: WHO Class II (n=23,27)
    11
    9
        Week 16: WHO Class IV (n=22,27)
    0
    1
        Week 16: WHO Class III (n=22,27)
    11
    18
        Week 16: WHO Class II (n=22,27)
    11
    7
        Week 16: WHO Class I (n=22,27)
    0
    1
        Week 20: WHO Class IV (n=19,24)
    0
    1
        Week 20: WHO Class III (n=19,24)
    10
    14
        Week 20: WHO Class II (n=19,24)
    8
    9
        Week 20: WHO Class I (n=19,24)
    1
    0
        Week 24: WHO Class IV (n=21,25)
    1
    2
        Week 24: WHO Class III (n=21,25)
    12
    13
        Week 24: WHO Class II (n=21,25)
    8
    10
    No statistical analyses for this end point

    Secondary: Borg Score-Oxygen Saturation(SaO2) During the Six Minutes Walk Test at Different Time Periods

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    End point title
    Borg Score-Oxygen Saturation(SaO2) During the Six Minutes Walk Test at Different Time Periods
    End point description
    Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. The test was terminated if the patient became too distressed or if their SaO2% fell below 60%. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Percentage of Oxygen Saturation
    arithmetic mean (standard deviation)
        Baseline: Resting (n= 28, 29)
    94.3 ± 4.6
    93.4 ± 4.7
        Baseline: End of Test (n= 28, 28)
    87.9 ± 12.4
    87.9 ± 8.2
        Baseline: 2 minutes after end of test (n=26, 26)
    93 ± 7
    92 ± 6.2
        Day 32: Resting (n= 25, 28)
    94.5 ± 4
    92.4 ± 6.3
        Day 32: End of Test (n= 25, 28)
    89 ± 11.2
    87.2 ± 12.8
        Day 32: 2 minutes after end of test (n= 25, 26)
    94.8 ± 4.6
    92.7 ± 7.1
        Week 8: Resting (n= 23, 25)
    95.1 ± 3.3
    93.2 ± 6.1
        Week 8: End of Test (n= 23, 24)
    90.9 ± 6.7
    87.9 ± 11.9
        Week 8: 2 minutes after end of test (n= 23, 23)
    94.4 ± 5.3
    93.1 ± 7.8
        Week 12: Resting (n= 22, 25)
    95.1 ± 4.8
    93.9 ± 5.6
        Week 12: End of Test (n= 20, 24)
    89.8 ± 9.2
    89.6 ± 8.9
        Week 12: 2 minutes after end of test (n= 19, 22)
    92.7 ± 8.9
    94.2 ± 5.6
        Week 16: Resting (n= 19, 24)
    95 ± 5
    94.1 ± 5.1
        Week 16: End of Test (n= 18, 23)
    87.9 ± 13.1
    88.1 ± 9.8
        Week 16: 2 minutes after end of test (n= 19, 19)
    94.6 ± 6
    93.3 ± 8
        Week 20: Resting (n= 19, 22)
    94 ± 4.7
    93.7 ± 5
        Week 20: End of Test (n= 18, 21)
    87.5 ± 13.2
    87.6 ± 9.1
        Week 20: 2 minutes after end of test (n= 19, 21)
    93.8 ± 7.1
    93.4 ± 7.4
        Week 24: Resting (n= 20, 22)
    95.5 ± 3.4
    94.3 ± 4.6
        Week 24: End of Test (n= 20, 21)
    89.9 ± 7.1
    89.3 ± 8.4
        Week 24: 2 minutes after end of test (n= 20, 21)
    94.8 ± 4.3
    94.8 ± 3.9
    No statistical analyses for this end point

    Secondary: Borg Score-Systolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods

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    End point title
    Borg Score-Systolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods
    End point description
    Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Systolic blood pressure (mmHg) were recorded before the test at resting, at the end of the test and two minutes after the end of the test. The intention to treat population (ITT) included all patients who received at least one dose of study medication
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: Resting (n= 26, 28)
    111.3 ± 14.2
    104.6 ± 13.2
        Baseline: End of Test (n= 21, 26)
    119.9 ± 19.3
    118.3 ± 18
        Baseline: 2 minutes after end of test (n=25, 27)
    120 ± 18.3
    110.4 ± 13.6
        Day 32: Resting (n= 25, 27)
    111.4 ± 9.6
    106 ± 12.3
        Day 32: End of Test (n= 22, 22)
    126.5 ± 17.3
    122.3 ± 18.6
        Day 32: 2 minutes after end of test (n= 25, 26)
    119.6 ± 12.6
    113.8 ± 14.9
        Week 8: Resting (n= 22, 24)
    108.9 ± 12.3
    107.3 ± 13.5
        Week 8: End of Test (n= 19, 20)
    124.6 ± 16.1
    119.9 ± 17.1
        Week 8: 2 minutes after end of test (n= 23, 24)
    115.2 ± 13.6
    114.5 ± 13.7
        Week 12: Resting (n= 22, 23)
    106.5 ± 11.5
    107.7 ± 13.8
        Week 12: End of Test (n= 17, 19)
    122.2 ± 17
    118.8 ± 22.9
        Week 12: 2 minutes after end of test (n= 20, 22)
    115.9 ± 14.2
    115.9 ± 14.9
        Week 16: Resting (n= 19, 22)
    106.7 ± 9.7
    105.7 ± 12.5
        Week 16: End of Test (n= 15,18)
    117.2 ± 12.3
    119.8 ± 13.5
        Week 16: 2 minutes after end of test (n= 19, 22)
    114.6 ± 13.8
    112.6 ± 15.8
        eek 20: Resting (n= 19, 20)
    106.5 ± 7
    109.1 ± 12.1
        Week 20: End of Test (n= 16,17)
    122.4 ± 13.3
    119.9 ± 19.3
        Week 20: 2 minutes after end of test (n= 19, 20)
    115.5 ± 14
    115.1 ± 15.1
        Week 24: Resting (n= 20, 21
    110.6 ± 15.6
    108.2 ± 15.7
        Week 24: End of Test (n= 16, 17)
    126.9 ± 23.6
    116.8 ± 14.9
        Week 24: 2 minutes after end of test (n= 20, 19)
    118.2 ± 18.6
    111.1 ± 10.6
    No statistical analyses for this end point

    Secondary: Borg Score-Diastolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods

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    End point title
    Borg Score-Diastolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods
    End point description
    Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Diastolic blood pressure (mmHg) were recorded before the test at resting, at the end of the test and two minutes after the end of the test. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: Resting (n= 26, 28)
    68.2 ± 10.2
    67.9 ± 8.9
        Baseline: End of Test (n= 21, 26)
    75.1 ± 10.8
    69.5 ± 11.9
        Baseline: 2 minutes after end of test (n=25, 27)
    71.6 ± 9.8
    67.9 ± 9.6
        Day 32: Resting (n= 25, 27)
    69.6 ± 10.4
    68.4 ± 8.8
        Day 32: End of Test (n= 22, 22)
    78.2 ± 12.3
    75.2 ± 11.2
        Day 32: 2 minutes after end of test (n= 25, 26)
    72.5 ± 9.1
    70.7 ± 9.4
        Week 8: Resting (n= 22, 24)
    67.7 ± 11.8
    68.8 ± 9
        Week 8: End of Test (n= 19, 20)
    74.8 ± 10.8
    74 ± 10.9
        Week 8: 2 minutes after end of test (n= 23, 24)
    71.2 ± 10.3
    72.2 ± 11.7
        Week 12: Resting (n= 22, 23)
    65.5 ± 8.3
    70.6 ± 11.6
        Week 12: End of Test (n= 17, 19)
    75.6 ± 11.5
    72.4 ± 14.3
        Week 12: 2 minutes after end of test (n= 20, 22)
    73.1 ± 8.9
    72 ± 13.7
        Week 16: Resting (n= 19, 22)
    67.7 ± 9.9
    66.7 ± 7.7
        Week 16: End of Test (n= 15,18)
    72.7 ± 9.2
    76.7 ± 8.6
        Week 16: 2 minutes after end of test (n= 19, 22)
    71.4 ± 11
    70.5 ± 8
        Week 20: Resting (n= 19, 20)
    67.2 ± 8
    69.8 ± 8.8
        Week 20: End of Test (n= 16,17)
    72.9 ± 8.7
    72.9 ± 8.1
        Week 20: 2 minutes after end of test (n= 19, 20)
    71.9 ± 9.2
    72.7 ± 9.8
        Week 24: Resting (n= 20, 21)
    69.7 ± 10.3
    70.7 ± 10.9
        Week 24: End of Test (n= 16, 17)
    74.1 ± 10.7
    72.3 ± 10.9
        Week 24: 2 minutes after end of test (n= 20, 19)
    71.3 ± 10.1
    72.9 ± 9.5
    No statistical analyses for this end point

    Secondary: Borg Score-Heart Rate (HR) During the Six Minutes Walk Test at Different Time Periods

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    End point title
    Borg Score-Heart Rate (HR) During the Six Minutes Walk Test at Different Time Periods
    End point description
    Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Heart Rate (bpm) were recorded before the test at resting, at the end of the test and two minutes after the end of the test. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Baseline: Resting (n= 28, 29)
    80.8 ± 13
    87.9 ± 12.7
        Baseline: End of Test (n= 28, 29)
    106.3 ± 23.9
    112.3 ± 20.4
        Baseline: 2 minutes after end of test (n=26, 26)
    84.2 ± 16.9
    94.1 ± 14.6
        Day 32: Resting (n= 25, 28)
    80.7 ± 14.3
    83.6 ± 15.7
        Day 32: End of Test (n= 25, 28)
    108.4 ± 19.1
    113.1 ± 19.5
        Day 32: 2 minutes after end of test (n= 25, 26)
    89.2 ± 17
    90.6 ± 14.1
        Week 8: Resting (n= 23, 25)
    80.3 ± 9.6
    81.1 ± 11.2
        Week 8: End of Test (n= 23, 24)
    109.5 ± 21.4
    110.3 ± 26.4
        Week 8: 2 minutes after end of test (n= 23, 23)
    85.3 ± 15.7
    88.9 ± 13.2
        Week 12: Resting (n= 22, 25)
    76.5 ± 13.2
    85.1 ± 13.2
        Week 12: End of Test (n= 20, 25)
    105.3 ± 26.2
    113 ± 26.5
        Week 12: 2 minutes after end of test (n= 19, 22)
    83.8 ± 17.8
    89.4 ± 15.7
        Week 16: Resting (n= 19, 24)
    76.5 ± 13.2
    84.4 ± 12.9
        Week 16: End of Test (n= 18, 23)
    102.8 ± 25.6
    117.9 ± 24.3
        Week 16: 2 minutes after end of test (n= 19, 21)
    85.8 ± 21
    85.5 ± 14.4
        Week 20: Resting (n= 19, 22)
    75.3 ± 13.8
    80.2 ± 9.6
        Week 20: End of Test (n= 18,22)
    109.2 ± 26.8
    118 ± 24.5
        Week 20: 2 minutes after end of test (n= 19, 21)
    83.3 ± 17.4
    87.3 ± 11.4
        Week 24: Resting (n= 20, 22)
    79.5 ± 13.8
    83.6 ± 8.6
        Week 24: End of Test (n= 20, 21)
    110.2 ± 18.1
    116.8 ± 21.7
        Week 24: 2 minutes after end of test (n= 20, 21)
    87.9 ± 17.5
    88.9 ± 11.8
    No statistical analyses for this end point

    Secondary: Borg Score Breathlessness During the Six Minutes Walk Test at Different Time Periods

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    End point title
    Borg Score Breathlessness During the Six Minutes Walk Test at Different Time Periods
    End point description
    Borg Score during Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Borg Score of Breathlessness was recorded using the following score of 0 to 10, how breathless do you feel? 0 is nothing at all and 10 is maximal breathlessness. The intention to treat population (ITT) will include all patients who received at least one dose of study medication
    End point type
    Secondary
    End point timeframe
    Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: Resting (n= 26, 27)
    68.2 ± 10.2
    67.9 ± 8.9
        Baseline: End of Test (n= 27, 29)
    75.1 ± 10.8
    69.5 ± 11.9
        Baseline: 2 minutes after end of test (n=24, 26)
    71.6 ± 9.8
    67.9 ± 9.6
        Day 32: Resting (n= 25, 27)
    69.6 ± 10.4
    68.4 ± 8.8
        Day 32: End of Test (n= 25, 28)
    78.2 ± 12.3
    75.2 ± 11.2
        Day 32: 2 minutes after end of test (n= 25, 26)
    72.5 ± 9.1
    70.7 ± 9.4
        Week 8: Resting (n= 23, 24)
    67.7 ± 11.8
    68.8 ± 9
        Week 8: End of Test (n= 23, 25)
    74.8 ± 10.8
    74 ± 10.9
        Week 8: 2 minutes after end of test (n= 23, 24)
    71.2 ± 10.3
    72.2 ± 11.7
        Week 12: Resting (n= 22, 24)
    65.5 ± 8.3
    70.6 ± 11.6
        Week 12: End of Test (n= 22, 25)
    75.6 ± 11.5
    72.4 ± 14.3
        Week 12: 2 minutes after end of test (n= 22, 23)
    73.1 ± 8.9
    72 ± 13.7
        Week 16: Resting (n= 19, 23)
    67.7 ± 9.9
    66.7 ± 7.7
        Week 16: End of Test (n= 18, 23)
    72.7 ± 9.2
    76.7 ± 8.6
        Week 16: 2 minutes after end of test (n= 19, 23)
    71.4 ± 11
    70.5 ± 8
        Week 20: Resting (n= 19, 21)
    67.2 ± 8
    69.8 ± 8.8
        Week 20: End of Test (n= 18,22)
    72.9 ± 8.7
    72.9 ± 8.1
        Week 20: 2 minutes after end of test (n= 18, 20)
    71.9 ± 9.2
    72.7 ± 9.8
        Week 24: Resting (n= 20, 21)
    69.7 ± 10.3
    70.7 ± 10.9
        Week 24: End of Test (n= 20, 21)
    74.1 ± 10.7
    72.3 ± 10.9
        Week 24: 2 minutes after end of test (n= 20, 20)
    71.3 ± 10.1
    72.9 ± 9.5
    No statistical analyses for this end point

    Secondary: Mean Pulmonary Artery Pressure (PAP) at Baseline and Study Completion

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    End point title
    Mean Pulmonary Artery Pressure (PAP) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including right Pulmonary Arterial Pressure (PAP). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Pulmonary Artery Pressure mmHg
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=27,28)
    61.7 ± 15.6
    59.2 ± 11.6
        Baseline every 2 mins breathing NO (1st) (n=20,20)
    61.6 ± 18.7
    55.7 ± 12
        Baseline every 2 mins breathing NO (2nd) (n=17,18)
    58.1 ± 16.7
    53.3 ± 11.5
        Baseline 5 mins after NO administration (n=20,14)
    60.9 ± 16.2
    56.9 ± 10.8
        Baseline 15 mins after NO administration(n=19,19)
    60.3 ± 16
    56.5 ± 10.3
        Week 24 breathing ambient air (n=20,22)
    52.5 ± 11.4
    55.5 ± 11.6
        Week 24 every 2 mins breathing NO (1st) (n=10,13)
    50.9 ± 17.5
    55.1 ± 13.9
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    46.2 ± 18.1
    53.9 ± 14
        Week 24 5 mins after NO administration (n=10,12)
    47 ± 15.8
    57.5 ± 12.8
        Week 24 15 mins after NO administration (n=10,14)
    48.1 ± 13.7
    57.2 ± 12.4
    No statistical analyses for this end point

    Secondary: Mean Pulmonary Artery Wedge Pressure (PAWP) at Baseline and Study Completion

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    End point title
    Mean Pulmonary Artery Wedge Pressure (PAWP) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including right Pulmonary Arterial Pressure (PAP). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=26,28)
    9 ± 2.6
    7.6 ± 2.3
        Baseline every 2 mins breathing NO (1st) (n=20,17)
    9.5 ± 2
    7.7 ± 2.9
        Baseline every 2 mins breathing NO (2nd) (n=17,16)
    9.4 ± 2.2
    7.8 ± 3.4
        Baseline 5 mins after NO administration (n=19,12)
    9.5 ± 2.7
    7.8 ± 2.9
        Baseline 15 mins after NO administration(n=18,17)
    9.6 ± 2.4
    8.1 ± 2.6
        Week 24 breathing ambient air (n=19,22)
    8.4 ± 3.2
    8.6 ± 2.8
        Week 24 every 2 mins breathing NO (1st) (n=9,13)
    7.9 ± 3.1
    10.2 ± 3.7
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    7 ± 3.4
    10 ± 3.7
        Week 24 5 mins after NO administration (n=10,12)
    7.1 ± 3.1
    10.3 ± 3.3
        Week 24 15 mins after NO administration (n=10,14)
    6.7 ± 2.8
    10.4 ± 3.6
    No statistical analyses for this end point

    Secondary: Mean Systolic Arterial Pressure (SAP) at Baseline and Study Completion

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    End point title
    Mean Systolic Arterial Pressure (SAP) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including right Pulmonary Arterial Pressure (PAP). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=26,28)
    110.3 ± 19.5
    108.2 ± 15.4
        Baseline every 2 mins breathing NO (1st) (n=20,19)
    108.3 ± 18.9
    106.9 ± 18
        Baseline every 2 mins breathing NO (2nd) (n=17,17)
    109.9 ± 19.1
    105.4 ± 18.1
        Baseline 5 mins after NO administration (n=21,15)
    106 ± 17.7
    107.1 ± 18.6
        Baseline 15 mins after NO administration(n=19,19)
    109.5 ± 20.3
    106.9 ± 16.7
        Week 24 breathing ambient air (n=20,22)
    108 ± 19.8
    106.9 ± 18.8
        Week 24 every 2 mins breathing NO (1st) (n=10,13)
    103.9 ± 17.5
    102.9 ± 20.4
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    104.8 ± 18.3
    103.6 ± 19.2
        Week 24 5 mins after NO administration (n=9,12)
    103.4 ± 18.7
    104 ± 20
        Week 24 15 mins after NO administration (n=10,14)
    103.8 ± 21.4
    107.3 ± 18.3
    No statistical analyses for this end point

    Secondary: Mean Heart Rate (HR) at Baseline and Study Completion

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    End point title
    Mean Heart Rate (HR) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Heart Rate (HR). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=27,28)
    77.3 ± 7.5
    84.9 ± 13
        Baseline every 2 mins breathing NO (1st) (n=20,19)
    75.9 ± 12.9
    84.4 ± 15.5
        Baseline every 2 mins breathing NO (2nd) (n=17,17
    75.2 ± 13.6
    83.3 ± 13.2
        Baseline 5 mins after NO administration (n=19,15)
    73.2 ± 10.2
    84.3 ± 13.9
        Baseline 15 mins after NO administration(n=18,19)
    76.2 ± 9
    85.1 ± 13.8
        Week 24 breathing ambient air (n=20,22)
    76.6 ± 8.6
    83 ± 12.8
        Week 24 every 2 mins breathing NO (1st) (n=9,13)
    76.3 ± 10.1
    82.5 ± 15.3
        Week 24 every 2 mins breathing NO (2nd) (n=8,11)
    76.6 ± 10.3
    82.8 ± 16.7
        Week 24 5 mins after NO administration (n=9,12)
    75.7 ± 10.2
    79.3 ± 10.4
        Week 24 15 mins after NO administration (n=10,14)
    73.2 ± 8.3
    82.9 ± 10.5
    No statistical analyses for this end point

    Secondary: Mean Cardiac Output (CO) at Baseline and Study Completion

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    End point title
    Mean Cardiac Output (CO) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Cardiac Output (CO). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: L/min
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=27,28)
    4.2 ± 1.33
    4.09 ± 1.44
        Baseline every 2 mins breathing NO (1st) (n=19,20)
    4.02 ± 1.32
    4.22 ± 1.64
        Baseline every 2 mins breathing NO (2nd) (n=17,18)
    3.98 ± 1.16
    4.43 ± 1.8
        Baseline 5 mins after NO administration (n=19,14)
    4.2 ± 1.16
    4.71 ± 1.95
        Baseline 15 mins after NO administration(n=18,19)
    3.87 ± 1.03
    4.47 ± 2.15
        Week 24 breathing ambient air (n=20,22)
    4.9 ± 1.21
    4.35 ± 1.57
        Week 24 every 2 mins breathing NO (1st) (n=10,13)
    4.8 ± 1.26
    4.67 ± 2.27
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    4.79 ± 1.31
    4.62 ± 2.26
        Week 24 5 mins after NO administration (n=10,12)
    4.63 ± 1.21
    4.65 ± 1.99
        Week 24 15 mins after NO administration (n=10,14)
    4.48 ± 1.21
    4.46 ± 1.98
    No statistical analyses for this end point

    Secondary: Mean Pulmonary Vascular Resistance (PVR) at Baseline and Study Completion

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    End point title
    Mean Pulmonary Vascular Resistance (PVR) at Baseline and Study Completion
    End point description
    he right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Vascular Resistance (PVR). The were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. PVR calculated according to the equation:PVR = (PAP – PCWP)/CO. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: dyn*s/cm^5
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=27,27)
    1124.4 ± 460
    1118.3 ± 486.7
        Baseline every 2 mins breathing NO (1st) (n=19,17)
    1180.9 ± 520.8
    1067.9 ± 509.1
        Baseline every 2 mins breathing NO (2nd) (n=17,16)
    1064.6 ± 458.9
    982.8 ± 483.9
        Baseline 5 mins after NO administration (n=19,11)
    1131.5 ± 491.2
    1160.4 ± 510
        Baseline 15 mins after NO administration(n=18,16)
    1181.9 ± 498.7
    1132.9 ± 461
        Week 24 breathing ambient air (n=19,21)
    729.9 ± 230.1
    1017 ± 369.1
        Week 24 every 2 mins breathing NO (1st) (n=9,14)
    706.9 ± 285.5
    1000.6 ± 501.5
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    687.4 ± 276.3
    1033.6 ± 546.2
        Week 24 5 mins after NO administration (n=10,12)
    717.2 ± 271.6
    987.8 ± 370.4
        Week 24 15 mins after NO administration (n=10,14)
    776.1 ± 286.8
    1042.5 ± 388.4
    No statistical analyses for this end point

    Secondary: Mean Systemic Vascular Resistance (SVR) at Baseline and Study Completion

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    End point title
    Mean Systemic Vascular Resistance (SVR) at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Systemic Vascular Resistance (SVR). These were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. SVR was calculated according to the equation: SVR = (Paorta – Pright atrium)/CO. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: dyn*s/cm^5
    arithmetic mean (standard deviation)
        Baseline breathing ambient air (n=26,26)
    1674.4 ± 761.2
    1764.8 ± 481.9
        Baseline every 2 mins breathing NO (1st) (n=18,15)
    1778.2 ± 709.5
    1769.7 ± 457
        Baseline every 2 mins breathing NO (2nd) (n=16,14)
    1807.3 ± 615.1
    1664.7 ± 472
        Baseline 5 mins after NO administration (n=18,11)
    1609.2 ± 593.4
    1666.6 ± 488.6
        Baseline 15 mins after NO administration(n=17,15)
    1976.3 ± 877.5
    1748.4 ± 499.3
        Week 24 breathing ambient air (n=18,21)
    1427.2 ± 446.8
    1667.9 ± 357.8
        Week 24 every 2 mins breathing NO (1st) (n=9,13)
    1344.2 ± 474.8
    1579.3 ± 386.8
        Week 24 every 2 mins breathing NO (2nd) (n=9,11)
    1367.9 ± 601.7
    1592.5 ± 389
        Week 24 5 mins after NO administration (n=9,12)
    1419.7 ± 566.6
    1503.9 ± 305.3
        Week 24 15 mins after NO administration (n=10,14)
    1431.7 ± 524.4
    1629.3 ± 355.6
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - PaO2 at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - PaO2 at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PaO2 levels at baseline and Study completion Week 24. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline n=22,21
    63.36 ± 14.33
    63.75 ± 12.02
        Week 24 n=16,17
    72.49 ± 14.09
    70.13 ± 16.72
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - PvO2 at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - PvO2 at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PvO2 levels at baseline and Study completion Week 24. The intention to treat population (ITT) included all patients who received at least one dose of study medication
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline n=14,14
    33.16 ± 4.62
    34.7 ± 4.75
        Week 24 n=11,11
    35.56 ± 3.8
    32.65 ± 4.18
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - Arterial Saturation at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - Arterial Saturation at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including Arterial Saturation levels at baseline and Study completion Week 24. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Percentage of saturation
    arithmetic mean (standard deviation)
        Baseline n=19,16
    87.99 ± 9.19
    91.81 ± 4.05
        Week 24 n=14,15
    92.89 ± 4.5
    91.78 ± 3.36
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - Venous Saturation at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - Venous Saturation at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including Venous Saturation levels at baseline and Study completion Week 24. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: Percentage of saturation
    arithmetic mean (standard deviation)
        Baseline n=17,14
    57.96 ± 10.48
    60.84 ± 6.61
        Week 24 n=13,13
    65.11 ± 6.91
    57 ± 9.18
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - pH at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - pH at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including pH levels at baseline and Study completion Week 24. The pH scale measures how acidic or basic a substance is. It ranges from 0 to 14. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. The intention to treat population (ITT) included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: pH scale
    arithmetic mean (standard deviation)
        Baseline n=24,23
    7.43 ± 0.04
    7.44 ± 0.05
        Week 24 n=17,17
    7.44 ± 0.05
    7.46 ± 0.05
    No statistical analyses for this end point

    Secondary: Blood Gas Measurement - PaCO2 at Baseline and Study Completion

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    End point title
    Blood Gas Measurement - PaCO2 at Baseline and Study Completion
    End point description
    The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PaCO2 levels at baseline and Study completion Week 24. The intention to treat population (ITT) included all patients who received at least one dose of study medication
    End point type
    Secondary
    End point timeframe
    Baseline, and Study completion (Week 24)
    End point values
    Core-STI571 Core-Placebo
    Number of subjects analysed
    28
    31
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline n=23,21
    32.7 ± 4.4
    30.02 ± 4.76
        Week 24 n=16,17
    33.36 ± 5.11
    30.23 ± 3.55
    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
    16.1
    Reporting groups
    Reporting group title
    Core - STI571
    Reporting group description
    STI571 (Imatinib) was supplied in 100 mg capsules and was to have been administered orally with daily dose starting at 200 mg rising to 400 mg within two weeks. Dose may have been downtitrated from 400 to 200 mg one time during the trial.

    Reporting group title
    Extension - STI571
    Reporting group description
    Open label.

    Reporting group title
    Core - Placebo
    Reporting group description
    The appearance of placebo medication was identical to that of active drug.

    Serious adverse events
    Core - STI571 Extension - STI571 Core - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 28 (42.86%)
    16 / 22 (72.73%)
    11 / 31 (35.48%)
         number of deaths (all causes)
    3
    4
    3
         number of deaths resulting from adverse events
    0
    0
    1
    Vascular disorders
    Arterial rupture
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 28 (0.00%)
    7 / 22 (31.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 22 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Right ventricular failure
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 22 (4.55%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery aneurysm
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 22 (4.55%)
    3 / 31 (9.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 22 (4.55%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 22 (13.64%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Core - STI571 Extension - STI571 Core - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 28 (92.86%)
    21 / 22 (95.45%)
    25 / 31 (80.65%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 22 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    2
    0
    4
    Haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Chest discomfort
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 22 (18.18%)
    3 / 31 (9.68%)
         occurrences all number
    2
    7
    4
    Fatigue
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 22 (13.64%)
    4 / 31 (12.90%)
         occurrences all number
    3
    4
    4
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 22 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    2
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 22 (4.55%)
    3 / 31 (9.68%)
         occurrences all number
    1
    2
    3
    General physical health deterioration
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    1
    3
    0
    Oedema
         subjects affected / exposed
    1 / 28 (3.57%)
    8 / 22 (36.36%)
    0 / 31 (0.00%)
         occurrences all number
    2
    16
    0
    Oedema peripheral
         subjects affected / exposed
    7 / 28 (25.00%)
    9 / 22 (40.91%)
    5 / 31 (16.13%)
         occurrences all number
    13
    14
    7
    Pyrexia
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 22 (18.18%)
    0 / 31 (0.00%)
         occurrences all number
    2
    7
    0
    Pain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 22 (18.18%)
    0 / 31 (0.00%)
         occurrences all number
    1
    4
    0
    Sleep disorder
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 22 (18.18%)
    0 / 31 (0.00%)
         occurrences all number
    2
    4
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Investigations
    Blood amylase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    1 / 31 (3.23%)
         occurrences all number
    0
    4
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    1
    Blood potassium decreased
         subjects affected / exposed
    3 / 28 (10.71%)
    6 / 22 (27.27%)
    0 / 31 (0.00%)
         occurrences all number
    4
    7
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    1
    5
    0
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    0
    5
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    1 / 31 (3.23%)
         occurrences all number
    0
    4
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Lipase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 22 (18.18%)
    0 / 31 (0.00%)
         occurrences all number
    1
    4
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences all number
    2
    1
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Palpitations
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 22 (18.18%)
    4 / 31 (12.90%)
         occurrences all number
    9
    7
    5
    Pericardial effusion
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    1
    Tachycardia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 28 (7.14%)
    7 / 22 (31.82%)
    6 / 31 (19.35%)
         occurrences all number
    2
    9
    6
    Dyspnoea
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 22 (13.64%)
    5 / 31 (16.13%)
         occurrences all number
    2
    6
    6
    Nasal congestion
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    0
    6
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 28 (10.71%)
    5 / 22 (22.73%)
    3 / 31 (9.68%)
         occurrences all number
    4
    6
    3
    Headache
         subjects affected / exposed
    10 / 28 (35.71%)
    4 / 22 (18.18%)
    6 / 31 (19.35%)
         occurrences all number
    14
    4
    10
    Eye disorders
    Eye swelling
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences all number
    4
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    0
    Vertigo
         subjects affected / exposed
    4 / 28 (14.29%)
    8 / 22 (36.36%)
    4 / 31 (12.90%)
         occurrences all number
    4
    12
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    2
    3
    1
    Ascites
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 22 (18.18%)
    1 / 31 (3.23%)
         occurrences all number
    0
    4
    1
    Abdominal pain
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Diarrhoea
         subjects affected / exposed
    6 / 28 (21.43%)
    9 / 22 (40.91%)
    3 / 31 (9.68%)
         occurrences all number
    10
    12
    3
    Constipation
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 22 (9.09%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    2
    Gastritis
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 22 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 22 (18.18%)
    2 / 31 (6.45%)
         occurrences all number
    3
    5
    3
    Nausea
         subjects affected / exposed
    14 / 28 (50.00%)
    8 / 22 (36.36%)
    5 / 31 (16.13%)
         occurrences all number
    17
    11
    5
    Vomiting
         subjects affected / exposed
    6 / 28 (21.43%)
    3 / 22 (13.64%)
    1 / 31 (3.23%)
         occurrences all number
    10
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Periorbital oedema
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Pruritus
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 22 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    5
    0
    4
    Rash
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    3
    4
    0
    Swelling face
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 28 (17.86%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    6
    6
    0
    Muscle spasms
         subjects affected / exposed
    4 / 28 (14.29%)
    3 / 22 (13.64%)
    0 / 31 (0.00%)
         occurrences all number
    4
    3
    0
    Back pain
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 22 (9.09%)
    4 / 31 (12.90%)
         occurrences all number
    4
    3
    4
    Musculoskeletal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 22 (4.55%)
    3 / 31 (9.68%)
         occurrences all number
    3
    2
    3
    Myalgia
         subjects affected / exposed
    0 / 28 (0.00%)
    5 / 22 (22.73%)
    1 / 31 (3.23%)
         occurrences all number
    0
    6
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 22 (18.18%)
    0 / 31 (0.00%)
         occurrences all number
    0
    4
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 22 (18.18%)
    2 / 31 (6.45%)
         occurrences all number
    1
    5
    2
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    5 / 22 (22.73%)
    1 / 31 (3.23%)
         occurrences all number
    0
    10
    1
    Bronchitis
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    0
    5
    1
    Cystitis
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    1
    Helicobacter infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    Oral candidiasis
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 28 (21.43%)
    14 / 22 (63.64%)
    8 / 31 (25.81%)
         occurrences all number
    6
    30
    9
    Herpes simplex
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    6 / 28 (21.43%)
    11 / 22 (50.00%)
    1 / 31 (3.23%)
         occurrences all number
    7
    50
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    7 / 22 (31.82%)
    0 / 31 (0.00%)
         occurrences all number
    0
    9
    0
    Sinusitis
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2006
    Additional biomarker assessments for Brain Natriuretic Peptide (BNP) and specialist assessments (multiple inert gas elimination technique and blood gases) were to be conducted in at least one of the participating centers. The amendment also clarified and corrected inconsistencies in the protocol text and updated the names and contact details of responsible study personnel.
    15 Jun 2006
    Right Heart Catheritization procedure could have been performed within one month of the patient receiving the first dose rather than at the baseline visit. A Data Safety Monitoring Board was to be implemented to address the recommendations of the German national regulatory authority, BfArM which was requested during the protocol approval process. Patient diary cards were issued to paitients for monitoring of weight. Additional criteria for patient withdrawal from study which included reduction/downtitration in dose was added. An interim analysis was planned of the first 30 patients that completed 3 months of treatment to povide an interim risk-benefit evaluation based on blinded data. No formal statistical testing will be applied.
    19 Sep 2006
    Documention of the procedure for reporting Serious Adverse events at the Austrian site (Site 003) was added. This new site was set up after finalization of the study protocol.
    15 Feb 2007
    Following review of the IND submission the FDA requested that further information concerning the methodology used for genotyping of the exploratory biomarker samples and gene expression be included. Additional text has been added to sections 7.6.1 Genetic polymorphism and 7.6.2 Gene expression in peripheral blood cells.
    01 Oct 2007
    An interim analysis was added for patients who had completed at least 2 months treatment for a blinded analysis of the Six Minute Walk Test and hemodynamic parameter data. Exclusion Criteria was modified to exclude any pre-existing condition associated with chronic hypoxia that may have contributed to the severity of Pulmonary Arterial Hypertension.
    12 Mar 2008
    The study design was modified to include an extension period for follow up safety (two years) which formalized the compassionate use that had been available for patients. This was recommended by the Data Safety Monitoriong Board to monitor the safety of long term use of imatinib. The results from the extension study were reported independently from the results of the core study.
    19 May 2008
    The completion of the clinical phase of the core study enabled un-blinding of all data. Due to the open-label design of the extension study, the ongoing safety review (previously performed in the core study by the independent Data Safety Monitoring Committee) was performed by Novartis until the final study results were available. This review of SAE reports was continued (to be reported as per the core study) to ensure oversight of safety in the extension study. However, if the core study was found to be positive then an external (to Novartis) expert, independent of the study, was to review SAE reports. Simplifications to the data collected in the CRF were made, with the remaining data only maintained as source documents. The Week 1 visit, as well as weeks 2 and 3 visits, became optional for those patients already receiving compassionate Glivec.
    09 Dec 2008
    The duration of this extension study was increased to 5 years or until STI571 was approved and marketed for this patient population. It emerged that thyroid disorders may result from the use of imatinib, therefore, monitoring of thyroid stimulating hormone was included at each visit. Right heart catheterization was removed. Since the safety profile of this drug in this population has been better established with completion of the core study, the visit frequency for safety monitoring was reduced to every 6 months.
    03 Apr 2009
    Amendment 12 was rejected by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK based on the study end being until STI571 was approved for treating pulmonary arterial hypertension and this not being an acceptable scientific endpoint. This was hanged to a duration of 5 years..
    23 Jun 2009
    This protocol was amended following review by the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM) to define the function of the data safety monitoring board. A Data Safety Monitoring Board (DSMB) was formed to review the data collected in the extension study. The DSMB reviewed serious adverse events every 3 months until the study was completed and reviewed all available safety data every six months in relation to the benefit of STI571 in pulmonary arterial hypertension. If any new safety concerns arose with prolonged dosing, a Novartis review board or the DSMB determined whether any changes were required to the protocol.
    18 Apr 2013
    Due to the submission of a marketing authorization for STI571, an interim CSR to the extension study was written to enable accurate reporting of data. This amendment detailed the interim access to data required for the CSR. Advice received from the Data Safety Monitoring Board suggested closer monitoring of patient’s Echocardiograms. This included making the Echocardiogram assessments mandatory every 6 months. The protocol was changed to reflect this requirement.
    06 May 2013
    The protocol was amended to revise the information on concomitant use of imatinib and oral Vitamin K antagonists in PAH patients. This was 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. The risk of subdural hematoma was increased in patients taking imatinib and oral Vitamin K antagonists concomitantly. This amendment will increase this extension period from 5 to 6 years. This extension will provide drug to patients who continue to benefit until a new study is started into which the patients can be enrolled (CQTI571A2304).
    26 Jun 2013
    The protocol was amended to revise information on concomitant use of imatinib and oral vitamin K antagonists in PAH patients. The concomitant use of imatinib and oral vitamin K antagonists was no longer permitted in the study. This was based on health authority feedback which advised that patients must be discontinued if they were receiving concomitant oral vitamin K antagonist therapy. To comply with this request, Novartis amended the study protocol accordingly and added additional discontinuation criterion.
    14 Aug 2013
    The protocol was amended to revise information on further extension of the trial from 5 years to 6 years. This additional extension was not approved by the German health authority and was not applicable to German sites. This amendment detailed the areas of the protocol that were not applicable to Germany.

    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.
    Novartis withdrew marketing for QTI571 filed in US, Europe, Japan, and Switzerland in 2012 for the treatment of PAH following discussion with the FDA and CHMP. Core study was completed, Novartis terminated extension study in PAH on 20 Nov 2013.
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