Exploratory treatment trials in multiple sclerosis using MRI: sample size calculations for relapsing-remitting and secondary progressive subgroups using placebo controlled parallel groups
- aNMR Research Unit, Institute of Neurology, Queen Square, London, UK, bDepartment of Biostatistics, cMR Centre for Multiple Sclerosis Research, Free University Hospital, Postbus 7057, 1007 MB, Amsterdam, The Netherlands
- Professor DH Miller, NMR Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Telephone 0044 171 837 3611; fax 0044 171 278 5616.
- Received 3 April 1997
- Revised 23 July 1997
- Accepted 5 August 1997
Abstract
OBJECTIVES Serial brain MRI is widely used in pilot studies of new agents to monitor treatment efficacy in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS). For pilot trials, sample size calculations for the RR subgroup are based on the data from small numbers of patients and separate calculations for the SP subgroup have not been performed. The present study considers these issues.
METHODS The sample size calculations were based on data from six months of monthly T2 weighted and gadolinium enhanced MRI in 31 RR and 28 SP untreated patients undergoing natural history studies or in the placebo arm of a therapeutic trial. The calculations were for a placebo controlled, parallel groups design lasting six months. The sample sizes were based on bootstrap analysis with an 80% likelihood of showing a given treatment effect.
RESULTS With a single pretreatment scan, demonstration of a 70% reduction in newly active lesions required 2×30 RR and 2×50 SP patients. With an extra run-in scan one month before treatment, the sample sizes were 2×20 for RR and 2×30 for SP patients.
CONCLUSIONS The sample sizes required for RR patients were comparable with previous smaller studies. Larger sample sizes were needed for the SP group, but the extra run in scan resulted in a reduction in both groups. The larger sample sizes in the SPMS group were probably due to the combination of a higher proportion of patients with low MRI activity (≤2 active MRI lesions in 50% of SP and 32% RR patients), as well as a few patients who displayed extremely high activity, thus increasing interpatient variability. These data should be considered in planning pilot MRI outcome trials.
