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    Clinical Trial Results:
    A Trial of Intra-pleuraL OK-432 Therapy in mesothelioma (TILT): A feasibility study using the ‘trial within a cohort’ methodology

    Summary
    EudraCT number
    		 2016-004727-23
    Trial protocol
    		 GB  
    Global end of trial date
    19 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jan 2021
    First version publication date
    23 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3850
    Additional study identifiers
    ISRCTN number
    		 ISRCTN10432197
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Trust
    Sponsor organisation address
    Southmead Hospital, Bristol, United Kingdom, BS10 5NB
    Public contact
    Research & Innovation, North Bristol NHS Trust, 0044 1174149329, researchsponsor@nbt.nhs.uk
    Scientific contact
    Research & Innovation, North Bristol NHS Trust, 0044 1174149329, researchsponsor@nbt.nhs.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
    25 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to answer the question “Is it possible (feasible) to undertake a trial within a cohort to investigate the effect of OK432, administered directly into the chest in people with mesothelioma, and is it acceptable to patients and relatives?” This research will determine whether a full-scale version of the trial is possible. If it is, the results of this research will inform the design of the subsequent full-scale trial. The long-term goal is to determine whether OK432 is an effective treatment for mesothelioma, and whether the trial within a cohort design is appropriate for mesothelioma trials.
    Protection of trial subjects
    Known safety risks were minimised where possible by excluding high risk patients and using close patient monitoring to identify adverse events as soon as possible. The TwiC (Trial within a Cohort) design was discussed with the PPI group and seen as preferable to traditional randomised methods as patients would only be informed of the intervention once selected to receive it. The number of trial visits was also discussed with the PPI group to balance the need for clinical follow up with patient burden. To minimise potential distress to patients participating in the qualitative interviews a topic guide was developed in collaboration with the PPI group to ensure acceptability.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2018
    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: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    0
    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)
    2
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled between 30/01/2018 and 30/11/2019 and recruitment was based at three NHS sites in the UK.

    Pre-assignment
    Screening details
    		 There were 43 patients in the cohort during the recruitment period at the trial sites of which 7 met the eligibility criteria.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 All participants
    Arm type
    		 Baseline

    Investigational medicinal product name
    OncoTice
    Investigational medicinal product code
    BCG
    Other name
    Bacillus Calmette-Guérin (BCG)
    Pharmaceutical forms
    Powder and solvent for intravesical solution
    Routes of administration
    Intrapleural use
    Dosage and administration details
    BCG original dose: 0.4-1.6 x 10^7 CFU instilled intra-pleurally via indwelling pleural catheter BCG dose reduced to 0.2-0.8 x 10^7 CFU after urgent safety measure passed

    Investigational medicinal product name
    OK432
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    Original dose 10 Klinishe Einheirt (KE) delivered intra-pleurally via indwelling pleural catheter Dose reduced to 5KE after urgent safety measure.

    Number of subjects in period 1
    		All participants
    Started
    7
    Completed
    7
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    A key tenet of the TwiC design is that participants are only informed about the trial intervention once they have been selected to receive it, whilst controls are blinded to the existence of the trial.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 IMP-BCG
    Arm description
    		 BCG is a live attenuated, low-virulence strain of Mycobacterium bovis prepared from a culture of Bacillus Calmette-Guérin (OncoTice, Merck Sharp & Dohme Ltd, Netherlands).
    Arm type
    		 Experimental

    Investigational medicinal product name
    OncoTice
    Investigational medicinal product code
    BCG
    Other name
    Bacillus Calmette-Guérin (BCG)
    Pharmaceutical forms
    Powder and solvent for intravesical solution
    Routes of administration
    Intrapleural use
    Dosage and administration details
    BCG original dose: 0.4-1.6 x 10^7 CFU instilled intra-pleurally via indwelling pleural catheter BCG dose reduced to 0.2-0.8 x 10^7 CFU after urgent safety measure passed

    Arm title
    		 Control
    Arm description
    		 Eligible patients from the longitudinal, observational cohort study. A key tenet of the TwiC design is that participants are only informed about the trial intervention once they have been selected to receive it, whilst controls are blinded to the existence of the trial.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 IMP-OK432
    Arm description
    		 OK432 consists of heat-treated, penicillin-killed, freeze-dried Streptococcus pyogenes group A2 (Picibanil, Chugai Pharmaceutical Ltd, Japan).
    Arm type
    		 Experimental

    Investigational medicinal product name
    OK432
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    Original dose 10 Klinishe Einheirt (KE) delivered intra-pleurally via indwelling pleural catheter Dose reduced to 5KE after urgent safety measure.

    Arm title
    		 All participants
    Arm description
    		 -
    Arm type
    		 All participants

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 IMP- both
    Arm description
    		 Patients who received either OK432 or BCG
    Arm type
    		 Experimental

    Investigational medicinal product name
    OncoTice
    Investigational medicinal product code
    BCG
    Other name
    Bacillus Calmette-Guérin (BCG)
    Pharmaceutical forms
    Powder and solvent for intravesical solution
    Routes of administration
    Intrapleural use
    Dosage and administration details
    BCG original dose: 0.4-1.6 x 10^7 CFU instilled intra-pleurally via indwelling pleural catheter BCG dose reduced to 0.2-0.8 x 10^7 CFU after urgent safety measure passed

    Investigational medicinal product name
    OK432
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intrapleural use
    Dosage and administration details
    Original dose 10 Klinishe Einheirt (KE) delivered intra-pleurally via indwelling pleural catheter Dose reduced to 5KE after urgent safety measure.

    Number of subjects in period 2
    		IMP-BCG Control IMP-OK432 All participants IMP- both
    Started
    3
    3
    1
    7
    4
    Completed
    2
    2
    1
    7
    3
    Not completed
    1
    1
    0
    0
    1
         declined to participate
    1
    1
    -
    -
    1

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 7 7
    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
        median (full range (min-max))
    		 73 (60 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 6 6
    Asbestos exposure
    Units: Subjects
        None recalled
    		 1 1
        Transient
    		 1 1
        Light/passive
    		 1 1
        Heavy/active
    		 4 4
    Duration of symptoms
    Units: Subjects
        < 1 month
    		 3 3
        1-3 months
    		 1 1
        > 3 months
    		 2 2
        Not recorded
    		 1 1
    Method of diagnosis
    Units: Subjects
        CT-guided biopsy
    		 1 1
        Medical thoracoscopy
    		 5 5
        VATS
    		 1 1
    Laterality
    Units: Subjects
        Left
    		 2 2
        Right
    		 5 5
    Tumour histology
    Units: Subjects
        Epithelioid
    		 7 7
    Brims prognostic score
    Units: Subjects
        1 (best prognosis)
    		 1 1
        02
    		 5 5
        03
    		 0 0
        4 (worst prognosis)
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 All participants
    Reporting group title
    IMP-BCG
    Reporting group description
    		 BCG is a live attenuated, low-virulence strain of Mycobacterium bovis prepared from a culture of Bacillus Calmette-Guérin (OncoTice, Merck Sharp & Dohme Ltd, Netherlands).

    Reporting group title
    Control
    Reporting group description
    		 Eligible patients from the longitudinal, observational cohort study. A key tenet of the TwiC design is that participants are only informed about the trial intervention once they have been selected to receive it, whilst controls are blinded to the existence of the trial.

    Reporting group title
    IMP-OK432
    Reporting group description
    		 OK432 consists of heat-treated, penicillin-killed, freeze-dried Streptococcus pyogenes group A2 (Picibanil, Chugai Pharmaceutical Ltd, Japan).

    Reporting group title
    All participants
    Reporting group description
    		 -

    Reporting group title
    IMP- both
    Reporting group description
    		 Patients who received either OK432 or BCG

    Primary: Recruitment rate

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    End point title
    		 Recruitment rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    Randomisation
    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 analyses planned - a feasibility trial
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: Participants
        Target
    12
        Randomised
    7
    No statistical analyses for this end point

    Primary: Attrition Rate

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    End point title
    		 Attrition Rate [2]
    End point description
    Attrition was defined as participants who declined to receive an IMP following randomisation or who declined or failed to complete follow up in the cohort if allocated to control.
    End point type
    Primary
    End point timeframe
    Final follow up
    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 analyses planned - a feasibility trial
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: Participants
        Randomised
    7
        Completed
    5
    No statistical analyses for this end point

    Secondary: Number of control participants who were unblinded

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    End point title
    		 Number of control participants who were unblinded
    End point description
    End point type
    Secondary
    End point timeframe
    Final follow up
    End point values
    		 Control
    Number of subjects analysed
    3
    Units: Participants
        Number of control patients
    3
        Number of control patients who were unblinded
    3
    No statistical analyses for this end point

    Secondary: Survival

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    End point title
    		 Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Survival was calculated as date of diagnosis with MPM to date of death, as recorded on the death certificate. Surviving participants were censored on 02/06/2020 (7.5 months after final patient visit)
    End point values
    		 Control IMP- both
    Number of subjects analysed
    3
    4
    Units: months
        median (inter-quartile range (Q1-Q3))
    29 (5.2 to 45.0)
    18.1 (12.1 to 23.3)
    No statistical analyses for this end point

    Secondary: Radiological tumour response rates

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    End point title
    		 Radiological tumour response rates
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and final follow up (week 12)
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: Participants
        progressive disease
    3
        stable disease
    4
    No statistical analyses for this end point

    Secondary: Pleural fluid drainage volumes

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    End point title
    		 Pleural fluid drainage volumes
    End point description
    End point type
    Secondary
    End point timeframe
    Until final follow up at 12 weeks
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: ml
        arithmetic mean (full range (min-max))
    436.7 (0 to 1500)
    No statistical analyses for this end point

    Secondary: Successful pleurodesis

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    End point title
    		 Successful pleurodesis
    End point description
    End point type
    Secondary
    End point timeframe
    Censored from cohort on 02/06/2020
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: Participants
    6
    No statistical analyses for this end point

    Secondary: Time to pleurodesis

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    End point title
    		 Time to pleurodesis
    End point description
    End point type
    Secondary
    End point timeframe
    Final follow up at 12 weeks
    End point values
    		 All participants
    Number of subjects analysed
    6 [3]
    Units: days
        median (inter-quartile range (Q1-Q3))
    42 (30 to 132)
    Notes
    [3] - 6 patients achieved pleurodesis
    No statistical analyses for this end point

    Secondary: Breathlessness

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    End point title
    		 Breathlessness
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 3, 6 and 12
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: mm
        median (inter-quartile range (Q1-Q3))
    18.3 (8.3 to 25)
    No statistical analyses for this end point

    Secondary: Chest pain

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    End point title
    		 Chest pain
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and weeks 3, 6 and 12
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: mm
        median (inter-quartile range (Q1-Q3))
    4.7 (1.5 to 11.2)
    No statistical analyses for this end point

    Secondary: Sweats

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    End point title
    		 Sweats
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and weeks 3, 6 and 12
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: mm
        median (inter-quartile range (Q1-Q3))
    2.2 (0.3 to 7.9)
    No statistical analyses for this end point

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and weeks 3, 6 and 12
    End point values
    		 All participants
    Number of subjects analysed
    7
    Units: mm
        median (inter-quartile range (Q1-Q3))
    80 (76.9 to 81.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation until datalock (participants continued to be monitored for adverse events when they had returned to the cohort)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1.36.4
    Reporting groups
    Reporting group title
    OK432
    Reporting group description
    		 -

    Reporting group title
    IMP-BCG
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Serious adverse events
    		 OK432 IMP-BCG Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
    Additional description: Fever, malaise and anorexia with raised inflammatory markers.
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural infection bacterial
    Additional description: Infection of indwelling pleural catheter
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 OK432 IMP-BCG Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    2 / 2 (100.00%)
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
    Additional description: Fever, malaise and raised inflammatory markers
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pleural infection bacterial
    Additional description: Infected indwelling pleural catheter, treated as outpatient.
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pain
    Additional description: Rib pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2017
    Addition of BCG arm
    25 Jul 2018
    Updated BCG SmPC Change to CTA to use Pharmaceutical Solutions as QP
    21 Jan 2019
    Urgent Safety Measure to allow half dose IMP

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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