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    Clinical Trial Results:
    A Phase II Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of VS 6063 in Subjects with Malignant Pleural Mesothelioma

    Summary
    EudraCT number
    		 2013-001033-40
    Trial protocol
    		 GB   BE   ES   SE   NL   NO   PL   IT  
    Global end of trial date
    04 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2016
    First version publication date
    30 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VS-6063-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01870609
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Verastem Inc
    Sponsor organisation address
    117 Kendrick Street, Suite 500, Needham, MA, United States, MA 02494
    Public contact
    Mahesh Padval, Verastem Inc, 001 7812924217, info@verastem.com
    Scientific contact
    Mahesh Padval, Verastem Inc, 001 7812924217, info@verastem.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were to compare the overall survival (OS) in subjects with malignant pleural mesothelioma (MPM) receiving defactinib or placebo, and to compare the progression free survival (PFS) in these subjects.
    Protection of trial subjects
    The study was performed in accordance with the protocol and the European Community CPMP guidelines of GCP for Trials on Medicinal Products and applicable regulatory requirements and in accordance with regulations and statutory instruments for the administration of radioactive substances. The study was in keeping with the requirements of the “Declaration of Helsinki” as adopted by the World Medical Association (WMA) General Assembly and with its subsequent amendments. An independent data and safety monitoring committee was established to oversee the study to ensure patients' safety in this placebo-controlled trial.
    Background therapy
    		 No background therapy was specified. Prophylactic medications were permitted for use as needed if nausea was found to occur with administration of study drug and could not be managed with small amounts of food.
    Evidence for comparator
    		 This was a placebo-controlled study. No active comparator was planned.
    Actual start date of recruitment
    25 Sep 2013
    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
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 138
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Norway: 2
    Worldwide total number of subjects
    344
    EEA total number of subjects
    239
    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)
    110
    From 65 to 84 years
    231
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 449 subjects were screened and 344 were randomised and treated in 72 centres worldwide between 25 Sep 2013 and 04 Dec 2015, including 42 in the EU.

    Pre-assignment
    Screening details
    		 Male and female subjects aged at least 18 years, with histologically-proven MPM, evaluable disease according to RECIST v1.1, with ongoing confirmed partial or complete response to one previous chemotherapy regimen (at least 4 cycles), with last dose of chemotherapy administered at most 6 weeks previously, and a life expectancy of at least 3 months.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Defactinib was formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg. A matched placebo control was also provided. The placebo was the same color, shape, and composition, but contained no active ingredients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Defactinib
    Arm description
    		 Defactinib was taken orally twice daily in continuous 21 day cycles. The dose of defactinib was 400 mg (2 × 200 mg) twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Defactinib
    Investigational medicinal product code
    VS-6063
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Defactinib was taken orally twice daily in continuous 21 day cycles. The dose of defactinib was 400 mg (2 × 200 mg) twice daily.

    Arm title
    		 Placebo
    Arm description
    		 Placebo was taken orally twice daily in continuous 21 day cycles.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was taken orally twice daily in continuous 21 day cycles.

    Number of subjects in period 1
    		Defactinib Placebo
    Started
    173
    171
    Completed
    173
    171
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    As described for baseline period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Defactinib
    Arm description
    		 As defined for baseline period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Defactinib
    Investigational medicinal product code
    VS-6063
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg twice daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily

    Arm title
    		 Placebo
    Arm description
    		 As defined for baseline period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 200mg tablet taken twice daily

    Number of subjects in period 2
    		Defactinib Placebo
    Started
    173
    171
    Completed
    0
    0
    Not completed
    173
    171
         Adverse event, serious fatal
    55
    58
         Termination of study
    112
    109
         Unknown
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Defactinib
    Reporting group description
    		 Defactinib was taken orally twice daily in continuous 21 day cycles. The dose of defactinib was 400 mg (2 × 200 mg) twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was taken orally twice daily in continuous 21 day cycles.

    Reporting group values
    		 Defactinib Placebo Total
    Number of subjects
    		 173 171 344
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 56 54 110
        From 65-84 years
    		 114 117 231
        85 years and over
    		 3 0 3
    Age continuous
    Data reported at enrolment
    Units: years
        arithmetic mean (standard deviation)
    		 67.7 ± 8.33 67.6 ± 8.67 -
    Gender categorical
    Units: Subjects
        Female
    		 28 28 56
        Male
    		 145 143 288
    Karnofsky performance score
    Baseline Karnofsky performance score
    Units: Subjects
        70
    		 6 6 12
        80
    		 49 48 97
        90
    		 82 84 166
        100
    		 36 33 69
    Race
    Race of randomised subjects
    Units: Subjects
        White
    		 149 149 298
        Black
    		 1 1 2
        Asian
    		 22 20 42
        Other
    		 1 1 2
    Primary disease location
    The location of primary tumour
    Units: Subjects
        Ipsilateral
    		 26 14 40
        Parietal pleura
    		 91 90 181
        Visceral pleura
    		 9 24 33
        Lung parenchyma
    		 4 2 6
        Mediastinal
    		 12 9 21
        Other
    		 31 29 60
        Unknown
    		 0 3 3
    Metastasis location
    Location of metastatic tumours for subjects with metastases
    Units: Subjects
        Lung
    		 6 10 16
        Mediastinum
    		 2 3 5
        Liver
    		 3 2 5
        Adrenal
    		 1 1 2
        Bone
    		 0 3 3
        Other
    		 31 25 56
        None
    		 130 127 257
    TNM stage
    TNM classification of malignant tumours
    Units: Subjects
        Stage I
    		 2 2 4
        Stage IA
    		 4 8 12
        Stage IB
    		 11 10 21
        Stage II
    		 27 31 58
        Stage III
    		 66 58 124
        Stage IV
    		 47 49 96
        Unknown
    		 16 13 29
    Body mass index
    Data reported at baseline
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 25.63 ± 3.838 26.2 ± 4.592 -
    Time since diagnosis
    Time since original histopathological diagnosis of MPM
    Units: Months
        arithmetic mean (standard deviation)
    		 6.1 ± 5.4 6.7 ± 5.66 -
    Overall quality of life score
    Lung cancer Symptom scale modified for mesothelioma
    Units: Score
        median (full range (min-max))
    		 79.31 (9 to 100) 77.63 (31 to 100) -
    Quality of life - pain
    Lung cancer Symptom scale modified for mesothelioma
    Units: Score
        median (full range (min-max))
    		 92.5 (1 to 100) 92 (15 to 100) -
    Quality of life - dyspnoea
    Lung cancer Symptom scale modified for mesothelioma
    Units: Score
        median (full range (min-max))
    		 81.5 (7 to 100) 77 (6 to 100) -

    End points

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    End points reporting groups
    Reporting group title
    Defactinib
    Reporting group description
    		 Defactinib was taken orally twice daily in continuous 21 day cycles. The dose of defactinib was 400 mg (2 × 200 mg) twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was taken orally twice daily in continuous 21 day cycles.
    Reporting group title
    Defactinib
    Reporting group description
    		 As defined for baseline period

    Reporting group title
    Placebo
    Reporting group description
    		 As defined for baseline period

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    Time to disease progression or death
    End point type
    Primary
    End point timeframe
    From baseline to termination of the study
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    173
    171
    Units: Months
        median (confidence interval 95%)
    4.11 (2.79 to 5.55)
    4.04 (2.79 to 4.17)
    Statistical analysis title
    		 Duration of PFS
    Statistical analysis description
    The primary analysis of PFS was based on the stratified log-rank test, and used Kaplan-Meier methods for estimation of summary statistics. The median duration of PFS was estimated based on the 50th percentile of the Kaplan-Meier distribution. If applicable, p-values for the log-rank test were computed.
    Comparison groups
    Defactinib v Placebo
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.967
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.711
         upper limit
    		 1.316
    Notes
    [1] - The primary analysis of PFS was based on the stratified log-rank test, and used Kaplan-Meier methods for estimation of summary statistics. Hazard ratio with respect to relapse or death and 95% CI was calculated using Cox’s proportional hazard model, stratified by Merlin status.

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Duration of overall survival; subjects still alive at the time point of analysis or who dropped out prior to study end were censored at the day they were last known to be alive.
    End point type
    Secondary
    End point timeframe
    Baseline to termination of the study
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    173
    171
    Units: Months
        median (confidence interval 95%)
    12.68 (9.33 to 20.99)
    13.57 (9.49 to 21.16)
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Response to study drug according to RECIST v1.1 where objective response rate included subjects with complete or partial responses. Best objective response was categorised as complete response, partial response, stable disease, or progressive disease.
    End point type
    Secondary
    End point timeframe
    From baseline to termination of the study
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    173
    171
    Units: Subjects
        Complete/partial response
    7
    5
        Complete response
    0
    0
        Partial response
    7
    5
        Stable disease
    101
    104
        Progressive disease
    46
    50
    Statistical analysis title
    		 Difference in best objective response rate
    Statistical analysis description
    Frequencies and proportions of best objective responses were presented overall. Proportions of subjects with results of complete response, PR, SD, and PD were to be compared between the treatment arms, accounting for randomization strata using a Cochran Mantel-Haenszel chi-square test.
    Comparison groups
    Defactinib v Placebo
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5093
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Overall quality of life score

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    End point title
    		 Overall quality of life score
    End point description
    Lung cancer Symptom scale modified for mesothelioma
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    123
    112
    Units: score
        median (full range (min-max))
    70.88 (16 to 100)
    76.06 (18 to 100)
    No statistical analyses for this end point

    Secondary: Quality of life - pain

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    End point title
    		 Quality of life - pain
    End point description
    Lung cancer Symptom scale modified for mesothelioma
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    123
    112
    Units: Score
        median (full range (min-max))
    81 (12 to 100)
    84 (6 to 100)
    No statistical analyses for this end point

    Secondary: Quality of life - dyspnoea

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    End point title
    		 Quality of life - dyspnoea
    End point description
    Lung cancer Symptom scale modified for mesothelioma
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Defactinib Placebo
    Number of subjects analysed
    123
    112
    Units: Score
        median (full range (min-max))
    70 (3 to 100)
    73.5 (13 to 100)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time that the subject provided informed consent through and including 30 calendar days after the last administration of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Defactinib
    Reporting group description
    		 Defactinib was taken orally twice daily in continuous 21 day cycles. The dose of defactinib was 400 mg (2 × 200 mg) twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was taken orally twice daily in continuous 21 day cycles.

    Serious adverse events
    		 Defactinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 173 (10.98%)
    13 / 171 (7.60%)
         number of deaths (all causes)
    6
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    4 / 173 (2.31%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Cancer pain
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis malignant
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 173 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 173 (0.58%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 173 (0.58%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Defactinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    161 / 173 (93.06%)
    139 / 171 (81.29%)
    Investigations
    Blood creatinine decreased
         subjects affected / exposed
    12 / 173 (6.94%)
    6 / 171 (3.51%)
         occurrences all number
    12
    6
    Blood bilirubin increased
         subjects affected / exposed
    15 / 173 (8.67%)
    1 / 171 (0.58%)
         occurrences all number
    15
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 173 (6.94%)
    4 / 171 (2.34%)
         occurrences all number
    12
    4
    Paraesthesia
         subjects affected / exposed
    9 / 173 (5.20%)
    3 / 171 (1.75%)
         occurrences all number
    9
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 173 (17.34%)
    27 / 171 (15.79%)
         occurrences all number
    30
    27
    Oedema peripheral
         subjects affected / exposed
    22 / 173 (12.72%)
    13 / 171 (7.60%)
         occurrences all number
    22
    13
    Non-cardiac chest pain
         subjects affected / exposed
    11 / 173 (6.36%)
    14 / 171 (8.19%)
         occurrences all number
    11
    14
    Chest pain
         subjects affected / exposed
    11 / 173 (6.36%)
    13 / 171 (7.60%)
         occurrences all number
    11
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 173 (5.20%)
    3 / 171 (1.75%)
         occurrences all number
    9
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    42 / 173 (24.28%)
    19 / 171 (11.11%)
         occurrences all number
    42
    19
    Diarrhoea
         subjects affected / exposed
    41 / 173 (23.70%)
    15 / 171 (8.77%)
         occurrences all number
    41
    15
    Constipation
         subjects affected / exposed
    21 / 173 (12.14%)
    16 / 171 (9.36%)
         occurrences all number
    21
    16
    Vomiting
         subjects affected / exposed
    19 / 173 (10.98%)
    11 / 171 (6.43%)
         occurrences all number
    19
    11
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    30 / 173 (17.34%)
    24 / 171 (14.04%)
         occurrences all number
    30
    24
    Cough
         subjects affected / exposed
    24 / 173 (13.87%)
    17 / 171 (9.94%)
         occurrences all number
    24
    17
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 173 (4.05%)
    11 / 171 (6.43%)
         occurrences all number
    7
    11
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    14 / 173 (8.09%)
    0 / 171 (0.00%)
         occurrences all number
    14
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    8 / 173 (4.62%)
    8 / 171 (4.68%)
         occurrences all number
    8
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 173 (11.56%)
    5 / 171 (2.92%)
         occurrences all number
    20
    5
    Musculoskeletal pain
         subjects affected / exposed
    6 / 173 (3.47%)
    12 / 171 (7.02%)
         occurrences all number
    6
    12
    Back pain
         subjects affected / exposed
    10 / 173 (5.78%)
    4 / 171 (2.34%)
         occurrences all number
    10
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 173 (6.36%)
    4 / 171 (2.34%)
         occurrences all number
    11
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 173 (17.92%)
    13 / 171 (7.60%)
         occurrences all number
    31
    13

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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