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.

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Journal
Brain Communications
Published
2026-09-21
DOI
https://doi.org/10.1093/braincomms/fcag349
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
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article

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

Michael Andrew Lawton, Sheila Wonnacott, Joy Duffen, Marie‐Louise Zeissler et al.
Brain Communications
Parkinson's Disease Mechanisms and Treatments
article

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

Michael Andrew Lawton, Sheila Wonnacott, Joy Duffen, Marie‐Louise Zeissler, Anna Jewell, Carl Counsell, Carroll Siu, Rebecca Croucher, Oliver Bandmann, Eric Deeson, Miriam Parry, Thomas Foltynie, David Trevor Dexter, Sandra Bartolomeu-Pires, Natasha Ratcliffe, Edwin Jabbari, Sonia Gandhi, Yoav Ben‐Shlomo, Romy Ellis‐Doyle, Camille Carroll, Priti Gros, Sue Whipps, Raj Khengar, Thomas R. Barber, Prasad Korlipara, Fleur Hudson, George K. Tofaris, Michèle Bartlett, Amit Batla, James R. Carpenter, Rimona Sharon Weil, Nikul Bakshi, David Breen, Dorothy Salathiel, Roger A. Barker, Rebecca Petty, Stephen Mullin, Kuhan Pushparatnam, Kate Hockey, Laurel Miller, Jodie Forbes, Alan Wong, Michele T M Hu, Dilan Athauda, Huw Morris, Emily Henderson, Anthony H V Schapira, Brook Huxford, Monty Silverdale, Karen Matthews, Kevin McFarthing, Georgia Mills, Helen Matthews, Veena Agarwal, Helen Collins, Sally Collins, Jennifer Allison, Susan Duty, Alan Whone, Joel Handley, Michael Lawton, Heather Mortiboys, Esther Sammler, Matthew Burnell, Kailash Bhatia, Christian Lambert, K Ray Chaudhuri, Thomas Barber, Vince Greaves, Lynn Rochester, Ashwani Jha, Li Wei, Caroline S Clarke, Jen Black, Shlomi Haar Millo, Alex Edwards, Anette Schrag, Mark J Edwards, Daniel van Wamelen, Alastair Noyce, Henrik Zetterberg, Simon R W Stott, Cristina Gonzalez-Robles, Paola Piccini, Caroline H Williams-Gray, Thomas Foltynie, Alison J Yarnall
article en

Abstract

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.

Brain Communications
King's College London (GB), University of Aberdeen (GB), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB), University of Bristol (GB), Clinical Research Institute (US), London School of Hygiene & Tropical Medicine (GB), Parkinson's UK (GB), NIHR Newcastle Biomedical Research Centre (GB), Expert System (Italy) (IT), Stem Cell Institute (PA), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), University of Newcastle Australia (AU), Newcastle University (GB), University of Plymouth (GB), Medical Research Council (GB)
Partnerships for the goals
Openalex Percentile: Top 11%
Parkinson's Disease Mechanisms and Treatments
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