by Isabella Colonna
For December we have selected Pal S, Chataway J, Swingler R, Macleod MR, Carragher NO, Hardingham G, Selvaraj BT, Smith C, Wong C, Newton J, Lyle D, Stenson A, Dakin RS, Ihenacho A, Colville S, Mehta AR, Stallard N, Carpenter JR, Parker RA, Keerie C, Weir CJ, Virgo B, Morris S, Waters N, Gray B, MacDonald D, MacDonald E, Parmar MKB, Chandran S; MND SMART Investigators. Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial. Lancet Neurol. 2024 Nov;23(11):1097-1107. doi: 10.1016/S1474-4422(24)00326-0. Epub 2024 Sep 19. PMID: 39307154.
Motor neuron disease (MND) is a neurodegenerative condition with an average survival of 3-5 years after symptoms begin. So far, treatment options remain limited to riluzole (poor efficacy) and tofersen (targeting rare SOD1 mutations).
Our paper of the month highlights the findings of the stage 2 interim analysis from the first cycle of MND SMART, a phase 3, multi-arm, randomised, adaptive platform trial conducted across 20 centres in the UK. This innovative trial design aims to evaluate simultaneously and efficiently the safety and efficacy of multiple promising treatments, using a placebo control group. Key advantages of this model include the ability to discontinue treatments with little or no evidence of activity early on and to add new treatment groups within the same clinical trial. Unlike conventional two-arm studies, this trial approach is more efficient in terms of time, cost, and sample size requirements. Notably, MND patients and their caregivers played a pivotal role in shaping the trial, defining broad inclusion criteria, thereby increasing the generalisability of the results.
At the time of the analysis, 554 MND patients were randomly assigned to receive 20mg of memantine once daily (33%), 200mg of trazodone once daily (33%), or placebo (34%). Memantine, a non-competitive NMDA receptor antagonist commonly used for Alzheimer’s disease, has also shown potential in MND by reducing glutamate excitotoxicity, promoting autophagy, and mitigating inflammation, with evidence of delayed disease progression in SOD1 models. Trazodone, a serotonin antagonist and reuptake inhibitor antidepressant has demonstrated the ability to inhibit protein kinase RNA-like endoplasmic reticulum kinase (PERK) signalling, a key pathway in the unfolded protein response to misfolded proteins found in neurodegenerative diseases such as MND.
The results of the interim analysis showed that, compared to placebo, treatment with memantine and trazodone was well tolerated in MND patients but did not significantly impact the rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) or survival.
In summary, neither memantine nor trazodone demonstrated improved efficacy outcomes compared to placebo. However, the innovative design of this trial provided sufficiently robust results to rule out further testing of these drugs in MND at the studied dosages. This approach reduced the time, costs, and number of participants required to reach a definitive conclusion.
