A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology

Our plain-English summary of A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology, by A.C. Bibby, N. Zahan-Evans, E. Keenan, et al (Pilot and Feasibility Studies, 2022).

The study

• Authors: A.C. Bibby, N. Zahan-Evans, E. Keenan, C. Comins, J.E. Harvey, H. Day, N.M. Rahman, J.E. Fallon, R. Gooberman-Hill, N.A. Maskell
• Journal: Pilot and Feasibility Studies
• Published: 2022;8(1):196
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology.

Methods: TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004,727-23) and the ISRCTN Register on 04 December 2017.

Results: Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses.

Conclusion: It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered.

Trial Registration: TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23 ) and the ISRCTN Register ( 10432197 ) on 04 December 2017.

© 2022. The Author(s).

In plain English

This small feasibility trial in England tested whether a 'trial within a cohort' design could work for giving bacterial products into the chest cavity of people with malignant pleural mesothelioma. Patients were drawn from an existing mesothelioma study (ASSESS-meso) at three hospitals and screened between January 2018 and November 2019. Eligible people were randomly assigned to a single dose of OK432 (killed Streptococcus pyogenes bacteria) or BCG (a weakened strain of Mycobacterium bovis) through an indwelling pleural catheter, or to usual care. Only seven people were eligible and randomised, against a target of 12 (58.3%). Two withdrew, an attrition rate of 28.6%, above the 10% limit. All seven already knew about the trial before randomisation, so control participants could not be kept unaware of it. All three people who received a bacterial product had a whole-body inflammatory reaction. The authors reported no difference in survival between groups in this very small sample. Participants and relatives generally found the trial acceptable. The authors concluded the design was not feasible in people with mesothelioma, and noted possible selection and survivorship bias.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicentre, three-arm, randomised feasibility trial using the 'trials within cohorts' (TwiC) design, with qualitative interviews
• Who was studied: Patients with malignant pleural mesothelioma being followed in the ASSESS-meso cohort at three hospitals in England, screened from January 2018 to November 2019. Forty-three cohort patients were followed at the recruiting centres, 41 were screened, and seven were randomised: three to BCG, one to OK432 and three to control. Six were male and all had epithelioid mesothelioma.
• Exposure: A single dose of OK432 (heat-treated, penicillin-killed, freeze-dried Streptococcus pyogenes group A2) or BCG (live-attenuated Mycobacterium bovis), given via an indwelling pleural catheter within 14 days of randomisation, compared with usual care. The dose was halved for high-risk participants after early adverse reactions. The trial did not study asbestos exposure as such.
• Main results:
  • Seven participants were randomised against a target of 12, a recruitment rate of 58.3%. This missed the 66% target.
  • Two of the seven randomised participants withdrew, one from the BCG arm and one from the control arm. This gave an attrition rate of 28.6%, breaching the limit of less than 10%.
  • Data completeness was 99.3%, with 60 missing values out of 8750 data points. This met the target of more than 90%.
  • Of the 41 cohort patients screened, only the seven randomised ever met the eligibility criteria. The commonest reason for ineligibility was the absence of a functioning indwelling pleural catheter (39 screen failures).
  • All seven participants knew about the trial before randomisation, so blinding of control participants could not be maintained.
  • All three participants who received OK432 or BCG had a systemic inflammatory response syndrome, and two were admitted to hospital. There were three serious adverse events, one in each arm, and no grade 4 or 5 events or deaths during the trial.
  • There was no difference in survival between those randomised to OK432 or BCG (median 18.1 months) and controls (median 29.0 months). The unadjusted hazard ratio was 2.1 (95% CI 0.2 to 24.5; p=0.56) and the adjusted hazard ratio was 1.7 (95% CI 0.1 to 31.0; p=0.73).
  • Pleurodesis was achieved by 3 of 4 people randomised to a bacterial product (75%) and 3 of 3 controls (100%).
  • Participants and family members interviewed considered the TwiC design and trial processes acceptable.
• The authors' conclusion: The authors concluded that it was possible to design a drug trial using the TwiC design and to obtain ethical and regulatory approval. However, the approach was not feasible in people with mesothelioma, and eligibility constraints made recruitment difficult.
• Limitations the authors state:
  • The trial was not designed to evaluate efficacy or other clinical outcomes.
  • Because of the small numbers, the OK432 and BCG groups were combined after the fact into one group.
  • The open-label design could have introduced assessment bias, especially in patient-reported measures.
  • Participants were not required to be recently diagnosed, so the results may reflect survivorship bias.
  • The trial population was not representative of the UK mesothelioma population.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Pleural Mesothelioma, Prognosis, Cohort Study, Indwelling Pleural Catheter, Clinical Trial.

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