Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials

L. H. Verhey, A. Signori, D. L. Arnold, A. Bar-Or, A. D. Sadovnick, R. A. Marrie, B. Banwell, M. P. Sormani
<span title="2013-08-21">2013</span> <i title="Ovid Technologies (Wolters Kluwer Health)"> <a target="_blank" rel="noopener" href="" style="color: black;">Neurology</a> </i> &nbsp;
Objective: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints. Methods: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting
more &raquo; ... of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters. Results: Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (q), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative q, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction. Conclusion: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration. Neurology â 2013;81:1215-1221 GLOSSARY AIC 5 Akaike information criterion; ARR 5 annualized relapse rate; DMT 5 disease-modifying therapy; MS 5 multiple sclerosis; NB 5 negative binomial; NBT 5 negative binomial time to event; TTFR 5 time to first relapse; ZINB 5 zero-inflated negative binomial; ZIP 5 zero-inflated Poisson.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1212/wnl.0b013e3182a6cb9b</a> <a target="_blank" rel="external noopener" href="">pmid:23966255</a> <a target="_blank" rel="external noopener" href="">pmcid:PMC3795606</a> <a target="_blank" rel="external noopener" href="">fatcat:7x2tir5awrcdnhczpetlkokaoq</a> </span>
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