MAMS Adaptive Trial Shows Promise for Future Progressive MS Treatments

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Nurulamin Noor, MD, discusses the advantages and challenges of a MAMS adaptive trial design for PMS.

Clinical trials have produced remarkable strides in the treatment of multiple sclerosis (MS) in recent decades, especially for patients with the relapsing-remitting form of the disease. For the estimated 15% of patients with progressive forms of MS (PMS), however, progress has been minimal in comparison. The substantial disability associated with PMS underscores the critical need for novel therapies to slow disease progression in this patient population.1

Some experts note that advances in PMS could materialize more quickly outside of the traditional framework for clinical trials. Specifically, they advocate for the use of multi-arm multi-stage (MAMS) adaptive platform trials to expedite the advancement of candidate PMS therapies from animal research to clinical trials.2

The COVID-19 pandemic led to an increase in MAMS trials3 due to the need to rapidly evaluate the effectiveness of various interventions, according to Nurulamin Noor, MD, gastroenterology trainee at Cambridge University Hospitals and doctoral candidate in the Medical Research Council Clinical Trials Unit at University College London in the United Kingdom.

Understanding the MAMS Adaptive Trial Design

“A MAMS adaptive platform trial allows multiple primary research questions to be asked rather than the single primary research question in a traditional 2-arm clinical trial,” explained Dr Noor, lead author of 2 recent papers on the topic.3,4 “This means that faster answers are achieved from 1 MAMS trial rather than multiple separate and competing 2-arm trials.”

In a March 2022 study published in Neurology, the UK MS Society Expert Consortium for Progression in MS Clinical Trials described how such a design could work for PMS research. Based on a review of phase 2 and phase 3 PMS trials, they proposed interim and final outcomes measures and design parameters for potential MAMS trials comparing 3 repurposed neuroprotective therapies for PMS to a standard treatment. In each area, a Patient and Public Involvement (PPI) strategy group contributed feedback to ensure that the trials would adequately address the needs of the PMS community.2

The proposed trial would involve 2 stages: The interim stage (stage 1) would include 123 participants per arm and an outcome measure of whole brain atrophy on MRI at 18 months. Therapies demonstrating adequate evidence of slowing brain atrophy would proceed to the final stage (stage 2), in which the outcome would be time to 6-month confirmed disability progression as indicated by a composite clinical score that includes the Expanded Disability Status Score, Timed 25-Foot Walk, and 9-Hole Peg Test.2

According to the paper, stage 2 would require 600 participants per arm to detect a hazard ratio of 0.75 for the final outcome with 90% power. At this stage, a trial examining one treatment would need to recruit approximately 1,900 participants and would run for roughly 6 years. “This is approximately two-thirds the size and half the time of separate two-arm phase II and III trials,” the authors wrote.2 “The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatment for PMS.”

The authors reported that the trial design was well-received by people with MS and suggest that the principles of the design may also have utility in testing therapies for other neurodegenerative conditions, including Alzheimer disease, Parkinson disease, and motor neuron disease.2

Octopus: The First-Ever MAMS Trial for PMS

Investigators plan to use this type of trial design in the MS Society-funded initiative Octopus, the first-ever MAMS trial for PMS, noting that MAMS trials offer the “flexibility to drop drugs that don’t look promising, and slot in new drugs as they’re discovered,” among other benefits. The research team, led by professors Jeremy Chataway and Max Parmar from University College London, is currently finalizing selection of therapies with the aim of starting patient recruitment in the near future.5

The Advantages of a MAMS Adaptive Trial

The main advantage of the MAMS design is the ability to investigate multiple interventions, Dr Noor noted. “Most of those interventions will not be beneficial, and that is fine, but [it’s] really important to know, as resources can then be focused elsewhere and effective treatments can be determined at a much faster rate.”

Challenges associated with this trial design include the more complex and time-consuming (12-18 months) planning and setup required, shorter setup times for therapies added to the platform during the course of the trial, and the “incredibly complicated statistics that underpin the design.”2,5

Based on MAMS trials conducted in other diseases4 such as cancer and infectious disease, collaboration and combining resources are the keys to success in conducting these studies, Dr Noor said.4 “Rather than having lots of competing 2-arm trials, it makes more sense for pharma companies to contribute to a smaller number of MAMS platform trials and work together to achieve answers for patients,” he stated. “Clearly every trial needs a lead organization, and this is typically where academia or patient charities can take the lead in helping coordinate and get lots of companies to contribute to a single MAMS platform.”


  1. Hollen CW, Paz Soldán MM, Rinker JR, II, Spain RI. The future of progressive multiple sclerosis therapiesFed Pract. 2020;37(Suppl 1):S43-S49.
  2. Li V, Leurent B, Barkhof F, et al. Designing multi-arm multistage adaptive trials for neuroprotection in progressive multiple sclerosis. Neurology. Published online March 23, 2022. doi:10.1212/WNL.0000000000200604
  3. Noor NM, Pett SL, Esmail H, et al. Adaptive platform trials using multi-arm, multi-stage protocols: getting fast answers in pandemic settingsF1000Res. Published online September 9, 2020. doi:10.12688/f1000research.26253.2
  4. Noor NM, Love SB, Isaacs T, Kaplan R, Parmar MKB, Sydes MR. Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials. BMJ Open. 2022;12(3):e055615. doi:10.1136/bmjopen-2021-055615
  5. Multiple Sclerosis Society (MS Society UK). Octopus. Accessed online April 19, 2022.