Large Platform (MAMS) Trials Necessary for Parkinson’s, Review Argues

A clinical trial that’s multi-arm and multi-stage (MAMS) could quicken development of promising therapies for Parkinson’s disease (PD) by allowing multiple treatments to be tested simultaneously.

MAMS trials, most commonly used across cancers, may be a way of advancing work toward a first therapy that can delay or stop Parkinson’s progression, the researchers wrote, adding their goal is to “make a MAMS trial for PD possible in the near future.”

In a review article published in the Journal of Parkinson’s Disease, the U.K. scientists outlined considerations that both support and challenge a Parkinson’s MAMS trial. Their paper is titled, “Is It Possible to Conduct a Multi-Arm Multi-Stage Platform Trial in Parkinson’s Disease: Lessons Learned from Other Neurodegenerative Disorders and Cancer.”

Clinical trials are studies of investigational medicines in people, and are typically conducted in phases. Generally, earlier phases are concerned with establishing dosages and determining safety in relatively small groups of volunteers and patients, while later phases evaluate treatment effectiveness in larger patient groups.

Although clinical trials are necessary to determine whether a given treatment is safe and effective, the process is expensive and time-consuming, the paper noted. This can delay treatments getting to people that need them.

“The current way we do trials in Parkinson’s is too slow and inefficient. We need to develop new ways of doing trials such as the MAMS trial platform,” Camille Carroll, MD, PhD, a professor at the University of Plymouth and article co-author, said in a press release.

A MAMS trial design aims to ease some of these barriers by testing multiple treatments simultaneously — this is what “multi-arm” refers to. “Multi-stage” references interim analyses conducted throughout the course of the trial. The general idea is that, through these analyses, any treatment “arms” found to be ineffective can be stopped. At the same time, additional treatment arms can be added as new medications are developed, saving on resources.

Interim analyses also allows a single MAMS trial to function as both a Phase 2 and, later, a Phase 3 trial. This also saves on resources, because it reduces the number of patients necessary to generate statistically meaningful results (the “power” of the trial), and it halves the number of clinical trials that need to be planned, approved and financed.

MAMS trials have previously been conducted in disorders that include multiple sclerosis and cancer. For example, the STAMPEDE trial (NCT00268476) in advanced prostate cancer has enrolled over 11,000 participants, and is set to evaluate 10 different treatments.

Building on lessons learned in previous MAMS trials, the researchers highlight three “challenges” that will need to be overcome  to conduct one in Parkinson’s.

The first concerns the selection of investigational treatments for testing, as which treatments are included can substantially affect the trial design. For instance, MAMS trials usually have a single placebo group (called a trial arm), against which all other treatment arms are compared. However, not all placebos are equal — a treatment taken as a pill would usually have a pill placebo, whereas a treatment administered by injection would usually have an injected placebo. There may be a need for treatment standardization and/or multiple placebo arms in a MAMS trial for Parkinson’s.

The second challenge is finding appropriate outcomes to measure for the trial. In order to tell whether a treatment is working, it’s necessary to be able to reliably measure things like disease severity over time. The researchers reviewed numerous tools used to measure Parkinson’s motor and non-motor symptoms, as well as quality of life and other metrics, highlighting strengths and weaknesses of different individual tools.

The third challenge concerns the design of the trial itself. This largely concerns enrollment — that is, which patient groups should be allowed to participate in the trial. For example, Parkinson’s clinical trials often only enroll people who haven’t been treated before and are in early stages of disease to minimize heterogeneity that affects outcomes. But this limits the trial’s ability to generate data on how effective the treatment is in late disease stages.

Figuring out how to include a variety of patients, while accounting for person-to-person variability in a statistical sense, will be a major obstacle to overcome in the design of a MAMS clinical trial in Parkinson’s.

The researchers emphasized that designing such a trial will require the involvement of people with Parkinson’s themselves.

“Decisions on outcome measures, trial population and design need to be widely endorsed not only in the scientific community to encourage widespread collaboration on the programme, but also by patients as their support is crucial for success,” they wrote.

“We believe a MAMS trial for PD is possible and could dramatically speed up the search for a cure,” Carroll added. “Over the coming 12–18 months we will be working with the Cure Parkinson’s Trust and other organizations, nationally and internationally, to achieve this.”