A Trial of Intra-Pleural BacteriaL ImmunoTherapy In Malignant Pleural Mesothelioma (TILT) – A Randomised Feasibility Study Using The Trial Within A Cohort (TwiC) Methodology

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective front-line treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local i.e. intra-pleural immune modulators. 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. MethodsTILT was a multi-centre, 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 pre-specified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions were 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 2016-004727-23) and the ISRCTN Register on 04/12/2017. ResultsSeven 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. ConclusionDesign of a clinical trial of an investigational medicinal product based on the TwiC design and obtaining the necessary regulatory approvals was possible. 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.

Cerebral air embolism after indwelling pleural catheter insertion in a chronic hydropneumothorax secondary to epithelioid mesothelioma

A 75-year-old man with a history of epithelioid mesothelioma and a right-sided indwelling pleural catheter (IPC) presented with a history of a purulent fluid drainage via the IPC. The pleural fluid cultured Klebsiella oxytoca and Enterococcus faecalis. He was treated with a course of oral fluoroquinolone followed by uneventful IPC replacement. One and half hours postprocedure, the patient had a witnessed drop in conscious level accompanied by seizure like activity. Acute stroke was suspected and a CT head was performed. CT head revealed multiple serpiginous pockets of air along the cerebral fissure, with features that were highly suggestive of cerebral air embolism and multiple wedge-shaped areas of infarction involving the cerebral hemispheres. Further imaging revealed satisfactory position of the replaced IPC. The patient was admitted to the intensive care unit for high flow oxygen therapy and head down ventilation. However, his condition deteriorated and he died later.