The protocol for a phase 2A, multi centre, double-blind, randomized, placebo-controlled, parallel-group study to assess the effect of 12 weeks treatment with oral PXS-4728A on microglia activation, as measured by positron emission tomography, in participants with isolated rapid eye movement sleep behaviour disorder

Introduction Isolated REM-sleep behaviour disorder (iRBD) is a well-described prodromal feature of synuclein diseases, including Parkinson’s disease (PD), dementia with Lewy bodies and, less frequently, multiple system atrophy. Neuroinflammation has been reported in iRBD and is potentially a major contributor to synuclein accumulation and propagation. Positron emission tomography (PET) imaging of the translocator protein (TSPO) overexpressed by activated microglia has been used to demonstrate neuroinflammation in both iRBD and manifest PD. Although immune-modulating therapies have not shown direct benefit in PD, there are to date no reported trials in prodromal disease. This paper describes the protocol for the first immune-modulating drug trial in iRBD, which could provide evidence for an early neuroprotective intervention strategy in prodromal PD. Methods and analysis This is a phase IIa, randomised, double-blind, placebo-controlled, parallel-group trial of the small molecule PXS-4728A in iRBD. Forty participants with definitive iRBD, one or more features of Parkinsonism, impaired olfaction and/or impaired colour vision will be randomised 3:1 (treatment: placebo) for a 12-week treatment period, followed by a 12-week washout. The primary outcome will assess the effect of PXS-4728A on neuroinflammation, measured by PET using the TSPO radioligand [ 11 C]-PK11195 across nigro-striato-cortical regions in the treatment arm (within-arm) from baseline to week 12. Between-arm differences will be treated as exploratory. Drug safety and tolerability will also be assessed as a primary outcome. Secondary outcomes include further regional and whole-brain analysis of [ 11 C]-PK11195 binding. Exploratory outcomes will assess change in clinical scales of prodromal symptoms (motor and non-motor), biological markers from blood and CSF, and digital biomarkers (actigraphy, motor and cognitive). Study protocol registration https://clinicaltrials.gov/study/NCT05904717 ; Identifier, NCT05904717.