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.

Keywords: Parkinson’s disease; adaptive clinical trial; clinical trial protocol; motor neuron disease; multiple sclerosis; outcome measure.

Fig.1

MAMS trial schematic. In this example, a five year phase III set up is shown that assumes one out of four tested interventions (D) show a positive signal at an interim analysis after 18 months. By the time one phase III conclusion has been reached, 12 study drugs will have been initiated into the trial, eight will have been terminated at the interim analysis stage, two will have shown sufficient evidence to be carried forward to phase III and two will be pending interim results in year six. (—analysis).

Fig.2

Methodology to investigate disease modification. The delayed start design is a two period trial design. In period one, patients are initially randomised into placebo (delayed start) and treatment arms (early start) at the end of which, the placebo group is switched to the study drug (period two). Both groups will receive the study drug for the remaining duration of the trial. Should a treatment be neuroprotective rather than symptomatic, the early start group should have a reduced progression rate as compared to placebo in period one, a significantly improved MDS-UPDRS score from baseline at the end of period two and an equal or reduced rate of disease progression in the early start group compared to the delayed start group in period two. Thus, such a design has three endpoints [31]. The wash out design is a two period design that evaluates a global change in the outcome measure of choice from baseline over a drug administration period and the maintenance of this change after the study drug is withdrawn (washed out).