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
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EudraCT number |
2016-004727-23 |
Trial protocol |
GB |
Global end of trial date |
19 Nov 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jan 2021
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First version publication date |
23 Jan 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
3850
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Additional study identifiers
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ISRCTN number |
ISRCTN10432197 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
North Bristol NHS Trust
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Sponsor organisation address |
Southmead Hospital, Bristol, United Kingdom, BS10 5NB
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Public contact |
Research & Innovation, North Bristol NHS Trust, 0044 1174149329, researchsponsor@nbt.nhs.uk
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Scientific contact |
Research & Innovation, North Bristol NHS Trust, 0044 1174149329, researchsponsor@nbt.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Feb 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Nov 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Jan 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 7
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Worldwide total number of subjects |
7
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
2
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Arm title
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All participants | ||||||||||||||||||||||||||||||
Arm description |
All participants | ||||||||||||||||||||||||||||||
Arm type |
Baseline | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
OncoTice
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Investigational medicinal product code |
BCG
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Other name |
Bacillus Calmette-Guérin (BCG)
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Pharmaceutical forms |
Powder and solvent for intravesical solution
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Routes of administration |
Intrapleural use
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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
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Investigational medicinal product name |
OK432
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intrapleural use
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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.
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Period 2
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Period 2 title |
Overall trial
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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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
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Investigational medicinal product code |
BCG
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Other name |
Bacillus Calmette-Guérin (BCG)
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Pharmaceutical forms |
Powder and solvent for intravesical solution
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Routes of administration |
Intrapleural use
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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
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Arm title
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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
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intrapleural use
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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.
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Arm title
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All participants | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
All participants | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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IMP- both | ||||||||||||||||||||||||||||||
Arm description |
Patients who received either OK432 or BCG | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
OncoTice
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Investigational medicinal product code |
BCG
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Other name |
Bacillus Calmette-Guérin (BCG)
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Pharmaceutical forms |
Powder and solvent for intravesical solution
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Routes of administration |
Intrapleural use
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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
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Investigational medicinal product name |
OK432
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intrapleural use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All participants
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Reporting group description |
All participants | ||
Reporting group title |
IMP-BCG
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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
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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
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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
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Reporting group description |
- | ||
Reporting group title |
IMP- both
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Reporting group description |
Patients who received either OK432 or BCG |
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End point title |
Recruitment rate [1] | ||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Randomisation
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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 |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Final follow up
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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 |
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No statistical analyses for this end point |
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End point title |
Number of control participants who were unblinded | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Final follow up
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No statistical analyses for this end point |
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End point title |
Survival | ||||||||||||
End point description |
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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End point title |
Radiological tumour response rates | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and final follow up (week 12)
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No statistical analyses for this end point |
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End point title |
Pleural fluid drainage volumes | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Until final follow up at 12 weeks
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No statistical analyses for this end point |
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End point title |
Successful pleurodesis | ||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Censored from cohort on 02/06/2020
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No statistical analyses for this end point |
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End point title |
Time to pleurodesis | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Final follow up at 12 weeks
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Notes [3] - 6 patients achieved pleurodesis |
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No statistical analyses for this end point |
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End point title |
Breathlessness | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, weeks 3, 6 and 12
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No statistical analyses for this end point |
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End point title |
Chest pain | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
baseline and weeks 3, 6 and 12
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No statistical analyses for this end point |
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End point title |
Sweats | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
baseline and weeks 3, 6 and 12
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No statistical analyses for this end point |
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End point title |
Quality of Life | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
baseline and weeks 3, 6 and 12
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Randomisation until datalock (participants continued to be monitored for adverse events when they had returned to the cohort)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
SNOMED CT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1.36.4
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Reporting groups
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Reporting group title |
OK432
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IMP-BCG
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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30 Oct 2017 |
Addition of BCG arm |
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25 Jul 2018 |
Updated BCG SmPC
Change to CTA to use Pharmaceutical Solutions as QP |
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21 Jan 2019 |
Urgent Safety Measure to allow half dose IMP |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |