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.
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.
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 (ϑ), 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 ϑ, 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.
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.
"The Steering Committee of the International Pediatric MS Study Group also recommended several measures of cognitive function, which examine attention, functioning, verbal learning and memory, language, and general intelligence . Sample size calculations for clinical trials of pediatric-onset MS have recently been proposed and may aid in planning phase II and III trials powered on clinical and MRI endpoints . "
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials.
[Show abstract][Hide abstract] ABSTRACT: We summarize MRI measures currently available to assess treatment efficacy and safety in multiple sclerosis (MS) clinical trials and discuss novel metrics that could enter the clinical arena in the near future.
In relapsing remitting MS, MRI measures of disease activity (new T2 and gadolinium-enhancing lesions) provide a good surrogacy of treatment effect on relapse rate and disability progression; however, their value in progressive MS remains elusive. For the progressive disease forms, these measures need to be combined with quantities assessing the extent of irreversible tissue loss, which have already been introduced in some clinical trials (e.g., evolution of active lesions into permanent black holes and brain atrophy). Novel measures (e.g., quantification of gray matter and spinal cord atrophy) have demonstrated a great value in explaining patients' clinical outcome, but still need to be fully validated. Despite showing promise, evaluations of cortical lesions, of microscopic tissue abnormalities, and of functional cortical reorganization are still some way off for monitoring of treatment effects.
Trial outcomes in MS should include measures of inflammation and neurodegeneration, which should be combined according to the disease clinical phenotype, phase of the study, and the supposed mechanism of action of the drug tested.
Current opinion in neurology 06/2014; 27(3):290-9. DOI:10.1097/WCO.0000000000000095 · 5.31 Impact Factor
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