BACKGROUND:New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking.
OBJECTIVE:The objective of this paper is to report sample-size calculations for assessment of new lesion recovery.
METHODS:In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations.
RESULTS:In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions 15 mm3, as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%.
CONCLUSION:Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset.
This is a fundamentally important issue. Do we select individuals for study based on unmet need or select people that are most likely to show an effect?
We selected the latter with the optic neuritis trial was a six month trial involving about 95 early MSers. This study suggests one may require less than ten to find an effect. If we can show an effect in a few people with the best chance of seeing an effect, one can go into Progressive MS studies that will require more people, time and money.