Is It Possible to Conduct a Multi-Arm Multi-Stage Platform Trial in Parkinson’s Disease: Lessons Learned from Other Neurodegenerative Disorders and Cancer

Abstract

Many potential disease modifying therapies have been identified as suitable for clinical evaluation in Parkinson's disease (PD). Currently, the evaluation of compounds in phase II and phase III clinical trials in PD are set up in isolation, a process that is lengthy, costly and lacks efficiency. This review will introduce the concept of a multi-arm, multi-stage (MAMS) trial platform which allows for the assessment of several potential therapies at once, transitioning seamlessly from a phase II safety and efficacy study to a phase III trial by means of an interim analysis. At the interim checkpoint, ineffective arms are dropped and replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions. MAMS trial platforms already exist for prostate, renal and oropharyngeal cancer and are currently being developed for progressive multiple sclerosis (PMS) and motor neuron disease (MND) within the UK. As a MAMS trial will evaluate many potential treatments it is of critical importance that a widely endorsed core protocol is developed which will investigate outcomes and objectives meaningful to patients. This review will discuss the challenges of drug selection, trial design, stratification and outcome measures and will share strategies implemented in the planned MAMS trials for MND and PMS that may be of interest to the PD field.

Seven Solutions for Neuroprotection in Parkinson's Disease

“…A first discovery phase includes a broad population with several subtypes followed by a validation phase considering only the best patient responders. Master protocols, including “basket trials,” “umbrella trials,” and “platform trials” use a trial network with shared infrastructure and are designed with multiple sub‐studies to evaluate one or more investigational drugs in one or more disease subtypes 66,67 . Following the same idea, multi‐arm, multi‐stage (MAMS) trials have been recently proposed to test many potential therapies currently in the pipeline in parallel (multi‐arm), transitioning seamlessly through various phases (multi‐stage), that is, from a phase II safety and efficacy study to a phase III trial, with the help of a platform 68 .…”

Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

“…We are aware of multiple further MAMS trials that are currently being considered or designed for the late-phase setting including, but not limited to, multiple sclerosis,52 Parkinson’s disease,53 HIV 54. We note that to date, there has been a lack of use for this design in areas such as cardiology.…”

Can Innovative Trial Designs in Orphan Diseases Drive Advancement of Treatments for Common Neurological Diseases?

“…To reach consensus on these issues in PD, a Delphi process is currently being developed to inform the design of a MAMS platform 47 . This method is an iterative approach whereby experts from different backgrounds, such as clinicians, funders, industry, academics, regulators, and patients, complete multiple rounds of iterative questionnaires based on previous responses to enable a process to arrive at a consensus 46 …”

“…As demonstrated in rare disease and oncology, multi‐arm, multi‐stage (MAMS) trial platforms promise to overcome challenges in conducting trials in areas of unmet needs, such as PD. A MAMS trial platform is being planned for PD in the United Kingdom with current efforts aimed at achieving consensus on (i) drug selection, (ii) an appropriate patient population for study, (iii) methodology for identifying disease modification and whether this is necessary, as well as (iv) effective and relevant outcome measures 46 . To reach consensus on these issues in PD, a Delphi process is currently being developed to inform the design of a MAMS platform 47 .…”