Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART)

Area of Science:

• Neurology
• Clinical Trials
• Biostatistics

Background:

• Motor neuron disease (MND) is a progressive neurodegenerative condition.
• The MND-SMART trial is a multi-centre, randomized controlled trial for MND patients.
• It initially compares memantine and trazodone against placebo, with future treatments planned.

Purpose of the Study:

• To evaluate the efficacy of investigational treatments for motor neuron disease.
• To assess the impact of memantine and trazodone on functional outcomes and overall survival.
• To establish a flexible platform for introducing new MND therapies.

Main Methods:

• A platform, multi-arm, multi-stage randomized controlled trial design.
• Participants (up to 531) are randomized 1:1:1 to placebo or investigational treatments.
• Co-primary outcomes include the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) and overall survival, analyzed in stages.

Main Results:

• The statistical analysis plan details methods for analyzing longitudinal ALS-FRS-R data and survival.
• Normal linear mixed models will be used for ALS-FRS-R analysis.
• Pairwise type 1 error rates will be controlled for distinct treatment comparisons.

Conclusions:

• The statistical analysis plan addresses complexities like multiple testing and interim analyses.
• The plan balances bias minimization, power maximization, and clinically interpretable results.
• This framework ensures rigorous evaluation of MND treatments within the MND-SMART trial.