Strategic Research Coordinator, Ismar Haga, reports on the work of the MND SMART trial.
The MND SMART trial, a pioneering adaptive platform trial in the UK, evaluated the efficacy of memantine and trazodone in treating motor neuron disease (MND).
Despite prior indications of their potential neuroprotective effects, interim analyses revealed that neither drug significantly improved functional or survival outcomes compared to placebo, leading to their discontinuation from the trial. This innovative trial model demonstrated efficiency in rapidly assessing drug efficacy, underscoring the need for ongoing innovation in clinical trial designs to better address the urgent needs of MND patients.
Motor neuron disease (MND) refers to a group of progressive neurodegenerative diseases that are currently incurable, typically leading to death within 3-5 years of symptom onset. The only globally approved treatment for amyotrophic lateral sclerosis (ALS), a subtype of MND, is riluzole, which has limited efficacy. Other recent drugs have shown mixed results in clinical trials, highlighting an urgent need for effective treatments.
The MND SMART trial, led by Prof Siddharthan Chandran and Prof Suvankar Pal, employed an innovative phase 3, double-blind, placebo-controlled, multi-arm, multistage, randomized, adaptive platform approach. This trial design allowed the evaluation of multiple drugs against a single control group, early cessation of ineffective treatments, and the introduction of new drugs into ongoing trials. The trial aimed to efficiently determine the efficacy of treatments through stages, keeping only those showing potential benefits.
Memantine, used for Alzheimer’s disease, and trazodone, an antidepressant, were chosen for their potential neuroprotective effects based on mechanisms such as blocking excitotoxicity and modulating neuroinflammation. Despite plausible mechanisms and prior smaller studies suggesting safety, the trial aimed to rigorously evaluate their efficacy in MND using clinical function and survival as main outcomes.
Participants over 18 with various MND subtypes were enrolled from multiple UK centres. The trial featured broad inclusion criteria and a focus on reducing participant burden through features like liquid drug formulations and remote assessments. Safety and efficacy were thoroughly monitored through scheduled reviews by an independent committee.
Interim analyses showed that neither memantine nor trazodone significantly improved the functional or survival outcomes compared to placebo. This lack of significant benefit led to the discontinuation of these treatment arms.
The MND SMART trial underscores the importance of adaptive trials in quickly identifying effective treatments. Despite the negative results for memantine and trazodone, the trial methodology has proven successful in conclusively evaluating these drugs, saving time and resources compared to traditional approaches. This has implications for future drug research, stressing the need for continued innovation in clinical trial design to meet the urgent needs of MND patients.
