The patient centric development of an inclusive multi-arm multi-stage trial for Parkinson disease

Abstract There is an urgent need to speed up clinical trials for potential disease-modifying therapies that slow progression of Parkinson’s disease. The Edmond J Safra Accelerating Clinical Trials in Parkinson’s Disease (EJS ACT-PD) initiative set out to develop a patient-centric and inclusive platform trial using an innovative multi-arm, multi-stage (MAMS) design. We describe the work of the EJS ACT-PD consortium, which included over 90 experts including people with Parkinson’s disease and care partners across six working groups. There were 5 key challenges: developing an efficient MAMS trial that meets regulatory requirements and is acceptable to people with Parkinson’s; mitigating participant heterogeneity; reducing the risk of simultaneous arm closures; introducing different treatment regimens into a MAMS trial; and maximising deliverability and accessibility of a MAMS trial. The final design was achieved through an iterative process and critical appraisal of data modelling exploring the impact of participant numbers per arm, trial durations and endpoints. Every aspect of the design was informed by people with Parkinson’s disease and care partners whose advice ensured acceptability, deliverability and accessibility. The EJS ACT-PD trial will start with one placebo and three treatment arms, each with 400 participants, with a primary endpoint at three years powered to detect a 30% reduction in rate of progression of MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I and II summed scores. Interim analyses will test for activity using the summed inverse variance weighted MDS-UPDRS Part I, II and remote part III scores. Ineffective arms will be closed, allowing participants to be re-randomised. Cost-effectiveness analysis is embedded. Further promising treatments will be added in future arms, subject to additional funding. To maximise accessibility and inclusivity, the trial will allow for study visits to be conducted remotely based on participant preference. National sites were selected to maximise accessibility and inclusive recruitment with core funded staff placed within experienced trial sites to support training and delivery at less experienced centres. By involving people with Parkinson’s and care partners as well as stakeholders with broad scientific expertise, we have developed an inclusive MAMS trial which captures all stages of disease with partial remote delivery and clear design rationales that will significantly speed up the testing of disease modifying therapies in Parkinson’s disease.