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    Clinical Trial Results:
    The efficacy of Indwelling Pleural Catheter placement versus IPC placement PLUS sclerosant (talc) in patients with malignant pleural effusions managed exclusively as out-patients

    Summary
    EudraCT number
    		 2012-000599-40
    Trial protocol
    		 GB  
    Global end of trial date
    09 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2018
    First version publication date
    12 May 2018
    Other versions
    Summary report(s)
    		 supplementary material for publication
    protocols and analysis plans
    IPC-Plus NEJM paper

    Trial information

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    Trial identification
    Sponsor protocol code
    2795
    Additional study identifiers
    ISRCTN number
    		 ISRCTN73255764
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Trust
    Sponsor organisation address
    Southmead Hospital, Bristol, United Kingdom,
    Public contact
    Trial manager, Respiratory Research, North Bristol NHS Trust, emma.keenan@nbt.nhs.uk
    Scientific contact
    Trial coordinator, Academic Respiratory Unit, University of Bristol, rahul.bhatnagar@bristol.ac.uk
    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
    09 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The IPC-PLUS trial is a study to help determine the best way to manage patients who develop fluid around the lung as a result of cancer (malignant pleural effusion). The aim is to compare outcomes in two groups of patients. The first group will be treated with an indwelling pleural catheter (IPC, or tunnelled chest tube) to help drain away the fluid, and will then be given an inert placebo substance (saline) into the drain before being followed up. The second group will receive the same type of IPC to drain away the fluid, but will then be given an injection of sterile talc powder into the drain instead of placebo. Our primary objective is to determine whether introducing talc through the IPC leads to an improved rate of successful pleurodesis, whereby the two linings of the lung are stuck together to prevent further fluid build-up. This is a randomised controlled trial, which means patients will be randomly allocated to receive either the placebo injection or the talc injection
    Protection of trial subjects
    The study was reviewed and approved by an approved NHS ethics committee and by the MHRA Patients were seen on a frequent basis (every 2 weeks) An emergency phone number was provided to all participants and was available at all times
    Background therapy
    		 Insertion of an indwelling pleural catheter for the management of malignant pleural effusion
    Evidence for comparator
    		 Talc is the gold-standard pleurodesis agent used widely around the world. The dose and administration method for talc was matched to current UK standards. Saline was chosen as a comparator as there is no evidence that this has the ability to induce pleurodesis.
    Actual start date of recruitment
    28 May 2012
    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: 154
    Worldwide total number of subjects
    154
    EEA total number of subjects
    154
    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)
    56
    From 65 to 84 years
    90
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 18 sites from England and Scotland. Recruitment took place from June 2012 to September 2016

    Pre-assignment
    Screening details
    		 Patients with malignant pleural effusion suitable for IPC insertion identified from routine practice. Not eligible if pre-existing contraindication to pleurodesis (e.g. trapped lung) or if unable to comply with trial schedule

    Period 1
    Period 1 title
    Day 10 randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talc
    Investigational medicinal product code
    Other name
    Novatech Steritalc
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intrapleural use
    Dosage and administration details
    4 grams made into slurry with 50mls normal saline

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    50mls total

    Number of subjects in period 1
    		Intervention Control
    Started
    78
    76
    Completed
    77
    76
    Not completed
    1
    0
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Follow-up over 10 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talc
    Investigational medicinal product code
    Other name
    Novatech Steritalc
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intrapleural use
    Dosage and administration details
    4 grams made into slurry with 50mls normal saline

    Investigational medicinal product name
    0.9% saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    50mls total

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    50mls

    Number of subjects in period 2
    		Intervention Control
    Started
    77
    76
    Completed
    60
    52
    Not completed
    17
    24
         Adverse event, serious fatal
    7
    14
         Withdrawal from trial
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 78 76 154
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.7 ± 12.7 68.7 ± 10.1 -
    Gender categorical
    Units: Subjects
        Female
    		 44 39 83
        Male
    		 34 37 71
    ECOG performance status
    Units: Subjects
        PS0
    		 8 10 18
        PS1
    		 38 33 71
        PS2
    		 23 16 39
        PS3
    		 8 16 24
        Missing
    		 1 1 2
    Cancer types
    Units: Subjects
        Lung
    		 20 25 45
        Breast
    		 15 16 31
        Mesothelioma
    		 13 10 23
        Ovarian
    		 6 5 11
        Renal
    		 5 4 9
        Other
    		 19 16 35
    Lung entrapment of <25% at randomization
    Units: Subjects
        Yes
    		 16 14 30
        no
    		 62 62 124
    Number of pleural interventions in previous 3 months
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 1 (1 to 2) 1 (0 to 2) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Primary: Pleurodesis success at 5 weeks

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    End point title
    		 Pleurodesis success at 5 weeks
    End point description
    End point type
    Primary
    End point timeframe
    5 weeks post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    69
    70
    Units: Percentage
        Success
    30
    16
    Statistical analysis title
    		 Primary outcome
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 competing-risk time-to-event regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 3.92

    Secondary: Pleurodesis success at 10 weeks

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    End point title
    		 Pleurodesis success at 10 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    10 weeks post randomisation
    End point values
    		 Intervention Control
    Number of subjects analysed
    69
    70
    Units: percentage
        Success
    35
    19
    No statistical analyses for this end point

    Secondary: Pleurodesis success at 5 weeks (alternative)

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    End point title
    		 Pleurodesis success at 5 weeks (alternative)
    End point description
    End point type
    Secondary
    End point timeframe
    5 weeks
    End point values
    		 Intervention Control
    Number of subjects analysed
    67
    70
    Units: Percentage
        success
    28
    9
    No statistical analyses for this end point

    Secondary: Pleurodesis success at 10 weeks (alternative)

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    End point title
    		 Pleurodesis success at 10 weeks (alternative)
    End point description
    End point type
    Secondary
    End point timeframe
    10 weeks
    End point values
    		 Intervention Control
    Number of subjects analysed
    66
    69
    Units: Percentage
        success
    30
    11
    No statistical analyses for this end point

    Secondary: Volume of fluid over 10 weeks

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    End point title
    		 Volume of fluid over 10 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Over 10 weeks
    End point values
    		 Intervention Control
    Number of subjects analysed
    77
    76
    Units: millilitre(s)
        median (inter-quartile range (Q1-Q3))
    1350 (340 to 5680)
    3640 (845 to 7605)
    No statistical analyses for this end point

    Secondary: Additional procedures

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    End point title
    		 Additional procedures
    End point description
    End point type
    Secondary
    End point timeframe
    Over 10 weeks
    End point values
    		 Intervention Control
    Number of subjects analysed
    71
    73
    Units: Number
        Yes
    5
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From consent to trial exit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Locally determined
    Dictionary version
    n/a
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: All data regarding adverse events is available in the summary documents attached to this submission.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2012
    Clarification of randomisation target of 154 patients • All references to SF-36 QoL questionnaire removed • Added exclusion criteria: patients must have access to phone for investigator trial contact • Clarified sample collection and analysis • Clarified procedure pre-randomisation • Clarified that patients may also be excluded from randomisation for clinical reasons other than x-ray appearances • Updated summary tables and clarified pre-randomisation day nomenclature • Stipulated a time window in which patients must have first IPC drainage post-randomisation • Clarified time window in which pts may have follow-up appointments • Clarified wording in safety reporting section and highlighted expected minor side effects from talc • Updated members of trial steering committee • New sites added: Preston, Portsmouth, Bristol Royal Infirmary
    18 Dec 2012
    New sites added: Worcester, North Staffordshire, North Tyneside, Middlesbrough, South Manchester and Blackpool • Creation of letter and short trial summary for district nurses • Alteration to primary endpoint, changing minimal fluid volume required for pleurodesis from 20mLs to 50mLs • Change to time limit given to patients to consider PIS • Removed requirement that trial CXR must be taken posterior-anterior (PA) specifically • Trial flow chart updated allowed patients to have follow up appointments at satellite centres • Allowance for patients to be approached as an inpatient but management must be as an outpatient for trial • Clarifications to adverse event and serious adverse event reporting procedures
    01 Aug 2013
    New sites added: London, Mansfield, Stockton-on-Tees and Sheffield • Clarification of wording of primary endpoint, removal of duplicate secondary endpoint and addition of new secondary endpoint 4.0 01/08/2013 47 • Clarification of definition of trapped lung in trial flow chart and protocol • Addition of new QoL questionnaire (QLQ-C30) for all new trial participants • Expanded the use of pleural manometry to all centres • Removed need for 0.9% saline placebo to be sources from particular manufacturer • Updated wording of how the primary outcome will be analysed • Updated membership of trial steering committee
    01 Jan 2014
    New sites added: Northampton, Ayr, Cambridge, and Aintree • Change of inclusion criteria to require WHO performance of 2 or better to be eligible. 3 if goes to 2 after drainage. • Allow pts with previous pleurodesis as long as more than 56 days before trial entry • Relax follow-up visits by allowing day 42 and 56 to be carried out over telephone • Allow carers/relatives to perform chest drains after day 28 post randomisation visit • Extend recruitment period to May 2015 • Relaxation of manometry recordings from every 100 ml to every 100-200 ml • Updated membership of TSC
    09 Sep 2016
    Remove interim analysis • add cough, chest pain/discomfort following drainage to expected AEs • amend reporting procedure for mild cough, chest pain/discomfort • extend trial end date to 31/10/2016 • update R&I contact details for SAE reporting

    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.
    Only primary endpoint and major secondary endpoints are summarised here. For complete trial data and details of analyses, adverse events and all amendments, please refer to attachments.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29617585
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