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

Abstract

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 model 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. Therapies to treat pediatric-onset multiple sclerosis (MS) 1-4 are used off-label, because all approved pharmacologic agents for MS have been studied exclusively in adult patients. With the recent approval of the first oral disease-modifying therapies (DMTs) for MS 5,6 and several promising new therapies likely to be approved over the next 10 years, pediatric practitioners face the challenge of recommending suitable therapies for pediatric patients with MS despite a lack of evidence on safety and efficacy of these drugs in the pediatric population.7 Clinical trials for pediatric-onset MS are being planned, but data on appropriate trial endpoints and required sample sizes to inform trial design are lacking.Annualized relapse rate (ARR) is a common primary efficacy endpoint in clinical trials of adults with MS, and reduction in new T2 and gadolinium-enhancing lesions are frequently used secondary endpoints in phase III trials. 5,[8][9][10][11][12] Time to first relapse (TTFR) has recently been shown in adults with MS to be a feasible and powerful trial endpoint; using TTFR has the advantage of permitting patients initially randomized to placebo to be switched to active therapy at the time of first relapse.

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

“…A strength of the present study is that all patients were followed prospectively from initial clinical presentation with careful ascertainment of both clinical and MRI evidence of new disease activity, enabling reliable confirmation of when an initial clinical attack was the first clinical expression of MS. Although we cannot entirely exclude the risk of false‐negative diagnoses of monoADS (ie, individuals who may take a long time to have more disease activity to meet MS diagnostic criteria), this risk is likely to be minimal given the duration of follow‐up and the known natural history of pediatric MS, wherein the great majority of children with MS demonstrate clinical and/or MRI evidence of relapsing disease within 12 months of their first clinically evident attack …”

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

“…MRI detection of new lesions occurs in adult patients with multiple sclerosis at a far greater frequency than clinically appreciated relapses do, and thus new or enlarging T2 lesions have served as key outcome metrics in phase 2 adult multiple sclerosis trials. 126 An analysis 127 of lesion accrual in paediatric patients followed-up prospectively from first attack estimates the number of patients needed to show differences in treatment effect in a paediatric multiple sclerosis clinical trial. Secondary MRI metrics, such as brain volume, can also be measured, although the restricted extent of change in measurable brain volume in short duration trials and the potential confounders of acute relapse treatment and the corticosteroid-associated transient flux in brain volume must be considered.…”

Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis

“…As mentioned above, pediatric patients with MS tend to have a more inflammatory course within the first 2 years of onset [11], manifesting with more frequent clinical relapses and a higher brain T2-and T1-weighted lesion volume [31][32][33][34]. Patients with pediatric-onset MS generally maintain good recovery from relapses with minimal-to-no progression in disability within the first 10 years of disease onset; however, irreversible disability and secondary progression ultimately occur at a much earlier age than in adult-onset MS [35].…”