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    Clinical Trial Results:
    Adjuvant Urokinase in the Treatment of Malignant Pleural Effusion: The Third Therapeutic Intervention in Maligant Effusion Trial (TIME3-UK). A Randomised Controlled Trial to evaluate whether use of intrapleural Urokinase aids the drainage of multi-septated pleural effusion compared to placebo

    Summary
    EudraCT number
    		 2008-000586-26
    Trial protocol
    		 GB  
    Global end of trial date
    26 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jul 2016
    First version publication date
    22 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TIME3UK
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12852177
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
    Public contact
    Dr Eleanor Mishra, Oxford Respiratory Trials Unit University of Oxford Churchill Hospital Headington Oxford OX3 7LE, 01865 225205, eleanor.mishra@gmail.com
    Scientific contact
    Dr Eleanor Mishra, Oxford Respiratory Trials Unit University of Oxford Churchill Hospital Headington Oxford OX3 7LE, 01865 225205, eleanor.mishra@gmail.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
    22 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Mean daily breathlessness score over 28 days following randomisation (quantified by visual analogue scale (VAS) scores) 2. Time to pleurodesis failure (proportion requiring further pleural fluid drainage with deaths and loss to follow up censored, log rank test). Pleurodesis failure is defined as: either another ipsilateral pleural drainage procedure to control breathlessness or the patient has symptomatic pleural fluid recurrence but another ipsilateral pleural drainage procedure is not performed due to patient refusal, futility or other medical reason e.g. warfarinisation, poor performance status.
    Protection of trial subjects
    Patients were closely monitored for any adverse events following the administration of the IMP. Bleeding was the expected adverse event though this was not expected to be a common occurrence. Patients experiencing adverse events were treated according to best clinical practice.
    Background therapy
    		 Following the administration of the IMP and further clinical assessment (chest -xray and pleural fluid drainage charts) all patients underwent talc pleurodesis, administered according to clinical standard operational procedures.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Sep 2009
    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 Kingdom: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    16
    From 65 to 84 years
    49
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 71 patients were recruited into the trial from September 2009 to June 2014. All patients were recruited as in-patients from 12 centres across the United Kingdom.

    Pre-assignment
    Screening details
    		 Patients screened for the trial were those with a clinically confident diagnosis of pleural malignancy and a chest drain inserted for a pleural effusion. The total number of subjects screened was 692.

    Period 1
    Period 1 title
    Main Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Urokinase
    Arm description
    		 intrapleural Urokinase 100,000 IU. Product name: "Syner-KINASE® 100,000 IU" 3 doses given 8-14 hours apart
    Arm type
    		 Experimental

    Investigational medicinal product name
    Urokinase 100,000 I.U.
    Investigational medicinal product code
    B01A D04
    Other name
    Syner-KINASE® 100,000 IU
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Respiratory use
    Dosage and administration details
    Treatment (urokinase) limb Intra-pleural Urokinase (100,000 IU in 20mls normal saline) administered at intervals of between 8-14 hours apart for a total of 3 doses.

    Arm title
    		 Placebo
    Arm description
    		 intra-pleural placebo, diluted in 20ml normal saline solution
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Respiratory use
    Dosage and administration details
    Placebo limb Intra-pleural urokinase placebo (in 20mls normal saline) administered at intervals of between 8-14 hours apart for a total of 3 doses

    Number of subjects in period 1
    		Urokinase Placebo
    Started
    36
    35
    Completed
    35
    32
    Not completed
    1
    3
         other
    1
    1
         Chest drain fell out
    -
    1
         Trial drugs unavaliable
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Urokinase
    Reporting group description
    		 intrapleural Urokinase 100,000 IU. Product name: "Syner-KINASE® 100,000 IU" 3 doses given 8-14 hours apart

    Reporting group title
    Placebo
    Reporting group description
    		 intra-pleural placebo, diluted in 20ml normal saline solution

    Reporting group values
    		 Urokinase Placebo Total
    Number of subjects
    		 36 35 71
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 7 16
        From 65-84 years
    		 24 25 49
        85 years and over
    		 3 3 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.5 ± 10.48 71.5 ± 8.3 -
    Gender categorical
    Units: Subjects
        Female
    		 13 17 30
        Male
    		 23 18 41
    WHO Performance Status
    Units: Subjects
        0-2
    		 21 21 42
        3-4
    		 15 14 29
    Histological tissue type
    Units: Subjects
        Mesothelioma
    		 3 4 7
        Non-mesothelioma/unknown
    		 33 31 64
    Previous pleurodesis
    Units: Subjects
        No
    		 31 30 61
        Yes
    		 5 5 10
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients and will include all randomised patients on whom an outcome is available

    Subject analysis sets values
    		 ITT
    Number of subjects
    71
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    16
        From 65-84 years
    49
        85 years and over
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    70.5 ± 9.45
    Gender categorical
    Units: Subjects
        Female
    30
        Male
    41
    WHO Performance Status
    Units: Subjects
        0-2
    42
        3-4
    29
    Histological tissue type
    Units: Subjects
        Mesothelioma
    7
        Non-mesothelioma/unknown
    64
    Previous pleurodesis
    Units: Subjects
        No
    61
        Yes
    10

    End points

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    End points reporting groups
    Reporting group title
    Urokinase
    Reporting group description
    		 intrapleural Urokinase 100,000 IU. Product name: "Syner-KINASE® 100,000 IU" 3 doses given 8-14 hours apart

    Reporting group title
    Placebo
    Reporting group description
    		 intra-pleural placebo, diluted in 20ml normal saline solution

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients and will include all randomised patients on whom an outcome is available

    Primary: The average breathlessness score over 28 days

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    End point title
    		 The average breathlessness score over 28 days
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to day 28
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    30
    33
    63
    Units: Vas Score
        arithmetic mean (standard deviation)
    38.06 ± 28.36
    38.39 ± 25.13
    38.22 ± 26.66
    Statistical analysis title
    		 The average breathlessness score over 28 days
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.362
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.97
         upper limit
    		 4.37

    Primary: Time to pleurodesis failure, up to 12 months

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    End point title
    		 Time to pleurodesis failure, up to 12 months
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to month 12
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    35
    34
    69
    Units: Time to failure
        arithmetic mean (standard deviation)
    21.65 ± 9.2
    22.18 ± 17.49
    21.9 ± 13.31
    Statistical analysis title
    		 Time to pleurodesis failure, up to 12 months
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.648
    Method
    		 competing risk analysis
    Parameter type
    		 subdistriution hazard ratio (SHR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 2.72

    Secondary: All-cause mortality up to 12 months

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    End point title
    		 All-cause mortality up to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 12 months
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    35
    71
    Units: Days to death
    arithmetic mean (standard deviation)
        Died
    94.42 ± 99.05
    67.89 ± 68.25
    80.35 ± 84.51
    Statistical analysis title
    		 All-cause mortality up to 12 months
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.93

    Secondary: Length of hospital stay (measured as time from randomisation until discharge)

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    End point title
    		 Length of hospital stay (measured as time from randomisation until discharge)
    End point description
    End point type
    Secondary
    End point timeframe
    randomisation until discharge from hospital
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    35
    34
    69
    Units: Length of hospital stay in days
        arithmetic mean (standard deviation)
    6.15 ± 2.73
    8.67 ± 6.47
    7.35 ± 5
    Statistical analysis title
    		 Length of hospital stay
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 competing risk analysis
    Parameter type
    		 subdistribution hazard (SHR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.56

    Secondary: Patients self-reported overall quality of life at enrolment calculated from patient’s response to Q30 on the EORTC QLQ-30

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    End point title
    		 Patients self-reported overall quality of life at enrolment calculated from patient’s response to Q30 on the EORTC QLQ-30
    End point description
    End point type
    Secondary
    End point timeframe
    From enrolment, day 28, 3 months, 6 months and 12 months
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    34
    70
    Units: Quality of life
        arithmetic mean (standard deviation)
    39.39 ± 22.29
    34.23 ± 28.42
    36.88 ± 25.4
    Statistical analysis title
    		 Overall quality of life
    Statistical analysis description
    Patients self-reported overall quality of life at enrolment, day 28, 3 months, 6 months and 12 months calculated from patient’s response to Q30 on the EORTC QLQ-30 and transformed to a percentage
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.171
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.18
         upper limit
    		 17.89

    Secondary: The proportion of patients that had any systemic bleeding (from time of randomisation until day of pleurodesis)

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    End point title
    		 The proportion of patients that had any systemic bleeding (from time of randomisation until day of pleurodesis)
    End point description
    End point type
    Secondary
    End point timeframe
    from time of randomisation until day of pleurodesis
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    35
    71
    Units: Number of patients
        unobtainable
    0
    1
    1
        Systemic Bleeding
    0
    1
    1
        No systemic bleeding
    36
    33
    69
    No statistical analyses for this end point

    Secondary: The proportion of patients that had any new intrapleural bleeding (from time of randomisation until day of pleurodesis)

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    End point title
    		 The proportion of patients that had any new intrapleural bleeding (from time of randomisation until day of pleurodesis)
    End point description
    End point type
    Secondary
    End point timeframe
    from time of randomisation until day of pleurodesis
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    35
    71
    Units: Number of Patients
        New intrapleural bleeding
    0
    0
    0
        No new intrapleural bleeding
    36
    34
    70
        Unobtainable
    0
    1
    1
    No statistical analyses for this end point

    Secondary: The average amount patients were bothered by their breathlessness over 28 days

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    End point title
    		 The average amount patients were bothered by their breathlessness over 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    30
    33
    63
    Units: VAS score
        arithmetic mean (standard deviation)
    34.47 ± 28.95
    35.28 ± 29.36
    34.86 ± 28.91
    Statistical analysis title
    		 The average amount bothered by breathlessness
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.101
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.25
         upper limit
    		 1.36

    Secondary: Radiographic improvement in the area of the pleural effusion on day two (the day of pleurodesis)

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    End point title
    		 Radiographic improvement in the area of the pleural effusion on day two (the day of pleurodesis)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to day 2
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    26
    21
    47
    Units: Radiographic improvement
        arithmetic mean (standard deviation)
    22.62 ± 15.39
    44.23 ± 23.62
    33.27 ± 22.12
    Statistical analysis title
    		 Radiographic improvement in pleural effusion
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 co-efficient
    Point estimate
    -19.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.74
         upper limit
    		 -10.81

    Secondary: The proportion of patients achieving a clinically significant decrease in VAS (19mm) over 28 days.

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    End point title
    		 The proportion of patients achieving a clinically significant decrease in VAS (19mm) over 28 days.
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    24
    19
    43
    Units: Number of patients
        >=19 mm decrease
    6
    4
    10
        <19 mm decrease
    18
    15
    33
    Statistical analysis title
    		 proportion achieving clinical decrease in VAS
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.761
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Volume of pleural fluid drained (mls) whilst the drain is in situ

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    End point title
    		 Volume of pleural fluid drained (mls) whilst the drain is in situ
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to day 3
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    24
    19
    43
    Units: Volume of Fluid drained
        arithmetic mean (standard deviation)
    357.5 ± 643.72
    257.11 ± 402.28
    313.14 ± 546.65
    Statistical analysis title
    		 Volume of pleural fluid drained
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.237
    Method
    		 Regression, Linear
    Parameter type
    		 co-efficient
    Point estimate
    168.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -110.63
         upper limit
    		 447.94

    Secondary: Patients that have symptomatic pleural fluid recurrence but do not have another pleural drainage procedure

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    End point title
    		 Patients that have symptomatic pleural fluid recurrence but do not have another pleural drainage procedure
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to month 12
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    35
    71
    Units: Number of Patients
        Symptomatic and no drainage
    4
    0
    4
        Not : symptomatic and no drainage
    32
    35
    37
    No statistical analyses for this end point

    Secondary: Patients self-reported health status calculated from patient’s response to Q29 on the EORTC QLQ-30

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    End point title
    		 Patients self-reported health status calculated from patient’s response to Q29 on the EORTC QLQ-30
    End point description
    End point type
    Secondary
    End point timeframe
    From enrolment, day 28, 3 months, 6 months and 12 months
    End point values
    		 Urokinase Placebo ITT
    Number of subjects analysed
    36
    34
    70
    Units: Health Status
        arithmetic mean (standard deviation)
    37.75 ± 22.96
    36.4 ± 24.13
    37.09 ± 23.37
    Statistical analysis title
    		 Patients self-reported health status
    Comparison groups
    Urokinase v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.758
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.64
         upper limit
    		 11.87

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During days 0-3 inclusive all SAEs, excluding reactions to talc pleurodesis, were reported to the sponsor within 24 hours knowledge of the event. After day 3, only SAEs possibly be related to the trial drug were reported to the sponsor within 24 hours
    Adverse event reporting additional description
    During in-patient stay, AEs and SAEs were collected by research staff for days 0-3 and day 3 onwards until discharge from hospital. Following discharge from hospital, Adverse Events were captured at 4 weeks, 3 , 6 and 12 month follow-ups. SAEs were reported by patients and captured by research staff through monitoring admissions.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Urokinase
    Reporting group description
    		 intrapleural Urokinase 100,000 IU. Product name: "Syner-KINASE® 100,000 IU" White powder for solution for injection or infusion.

    Reporting group title
    Placebo
    Reporting group description
    		 intra-pleural placebo, diluted in 20ml normal saline solution

    Serious adverse events
    		 Urokinase Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 35 (8.57%)
         number of deaths (all causes)
    31
    35
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Death
    Additional description: In the protocol only deaths within the first 3 days are reported as SAEs. Deaths after this time were reported on the CRF forms.
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pleural infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Urokinase Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 35 (2.86%)
    Gastrointestinal disorders
    haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2009
    Protocol v1.1 -change of PI at the Oxford Centre for Respiratory Medicine. We propose to change from 30ml normal saline vials to 20ml vials as 30ml are unavailable in the UK and the use of the vials imported from the United Sates would increase the costs of the trial. We also propose to remove lateral CXR and the chest pain VAS questionnaire as these are not essential for the study. We have added the collection of blood and pleural fluid samples on day 1 and day 2 after the enrolment and we have removed “Baseline VAS Questionnaire” phrase from the discharge column and inserted it in the trial entry column as this is when the baseline VAS will be measured. We also propose to add a new questionnaire - "Multidimensional dyspnoea profile" (for Oxford site only) which is a validated questionnaire developed at Harvard Medical School
    24 Jun 2009
    Protocol v1.2 The CTA has been amended with the change of the packaging/labelling company to LC2 which will be responsible for the final QP release .
    26 Aug 2009
    SA03-Protocol v1.3 1. Amendment of the consent form and the Patient Information Sheet to include information about the Medical Research Information Service follow-up. 2. Removal of CRDQ questionnaire from the study. 3. Change of the MRC performance status to WHO performance status. 4. Change of the trial mobile phone number. 5. Addition of the second VAS breathlessness measurement at baseline (protocol & VAS booklet). 6. Addition of chemotherapy-naïve patients with small cell lung cancer, lymphoma or breast cancer to the exclusion list. 7. Change from 15ml of 2% lignocaine local anaesthetic to 30ml 1% lignocaine local anaesthetic - in the Appendix 2 SOP for the performance of talc pleurodesis. 8. Change of the clinical coordinator 9. Removal of the total blood white cell count <1.0 x 10^9 from the exclusion list. 10. Change of the definition of the pleurodesis failure. 11. Change of the definition of the primary outcomes.
    19 Nov 2009
    SA04- protocol v1.4 1. Redefinition of one of the primary endpoints and clarification of the pleurodesis efficacy definition. 2. Addition of "Known underlying trapped lung of sufficient severity that pleurodesis is futile" to the exclusion criteria and rewording of the exclusion criteria referring to chemotherapy responsive tumours. 3. Clarification of the day of pleurodesis (pleurodesis is performed on day 2 not on day 3) and the days when trial procedures are performed. 4. Modification of the analysis plan. 5. Change of the drug accountability procedures. 6. Deletion of "at discharge" phrase from the Follow-up table; deletion of "until death" from the patients' follow-up in the protocol and GP letter. 7. Inclusion of the list of the Trial Steering Committee and the Data Monitoring Committee members for the trial and confirmation of the CTA reference number. 8. Updating the confidentiality section in the PIS and consent
    25 Mar 2010
    Protocol V1.5 Removal of all references to the “Dyspnoea questionnaire” from the protocol as the Principal Investigator has deemed that this questionnaire does not serve the purpose it was designed for.
    19 Aug 2010
    Protocol v1.6 The eligibility criteria in the protocol is being changed from 'histocytologically proven cancer to 'clinically proven cancer'. Addition of VAS (breathlessness) data collection at 3, 6 & 12 months.
    03 Mar 2011
    Protocol v2.0 Change of CI
    15 Apr 2011
    Protocol v3.0 Widening of the following inclusion criteria with the following point to help increase the recruitment rate for the trial and to reflect current clinical practice. c. Radiologically proven pleural malignancy as diagnosed in normal clinical practice on thoracic CT in the absence of histocytological proof -A chest radiograph showing >15% hemithorax area occupied by effusion OR -Septated effusion on thoracic ultrasound with a basal parietal to visceral depth of >2cm Removal of the following exclusion criteria Highly chemotherapy responsive tumours (such as small cell lung cancer, lymphoma or breast cancer) unless the patient has already undergone chemotherapy
    29 Aug 2011
    Protocol v4.0 - Interval between drug doses confirmed as 8-14 hours apart. - Recommended timings for baseline VAS measurements given to ensure consistency throughout all trial sites
    11 Apr 2013
    Protocol v5.0 -Addition of text to confirm that patients may be contacted by telephone if they cannot attend a follow-up visit -Clarification of procedures regarding loss to follow-up and withdrawal -Re-wording of the safety reporting section to provide clarification on safety reporting procedures. -Removal of appendices (two SOPs). The ‘talc slurry pleurodesis’ is already supplied in the Investigator Site File. The SOP entitled ‘Assessment of a reported probable SAE’ is for ORTU use only and will be kept with the departmental SOPs.

    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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