Objective: The Edmond J Safra Accelerating Clinical Trials in Parkinson disease (PD) initiative (EJS ACT-PD) aims to accelerate the identification of disease modifying treatments for PD through a multiarm, multistage (MAMS) platform trial approach.

Background: While past failures in treatment selection might be related not only to the drugs studied, but also to trial design, patient selection and outcome measures, it is clear that future compounds prioritised for trials should: have well defined molecular actions, translate into a clinically meaningful benefit, have initial safety data, be easy to monitor for target engagement, and lack negative interactions with other drugs.

Method: A Treatment Selection Working Group (WG), created as part of EJS ACT-PD has been subdivided into 5 subgroups to systematically prioritise drugs according to mechanistic actions: mitochondrial dysfunction, inflammation, lysosomal dysfunction, protein aggregation/propagation, and others (e.g. leucine-rich repeat kinase 2 (LRRK2) inhibition). Each subgroup will select the most promising drugs based on pre-clinical, clinical and epidemiological evidence, pharmacological data and safety, and thus score each compound. The highest-ranking drugs will be further considered in terms of pragmatic issues, such as accessibility, freedom to operate, availability of placebo, to prioritise the final compounds to include in the trial.

Results: A list of drugs suitable for repurposing, previously prioritised by the International Linked Clinical Trials (iLCT) programme over the last 10 years, is available for consideration. Additional dossiers are being prepared to score drugs previously linked to possible disease-modifying effects in PD and other neurodegenerative conditions. Careful consideration will be given to the advantages of a single placebo arm suitable for all active arms, or whether randomisation to a specific treatment arm, prior to active drug versus placebo allocation may be necessary. This will depend on several factors (e.g. different routes of administration).

Conclusion: This strategy provides a systematised framework to identify and assess potential disease modifying treatments in PD. The systematic approach is essential to ensure transparency in the decisions reached and how to communicate this process to stakeholders and funders that will be needed to support the Platform.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/treatment-selection-in-multi-arm-multi-stage-clinical-trials-in-parkinson-disease-the-search-for-the-ideal-neuroprotective-drug/