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Power Calculations and Estimates of Sample Size to Detect Treatment Effects

Nick C. Fox, MA, MRCP; Simon Cousens, DipMathStat; Rachael Scahill, MA; Richard J. Harvey, MD, MRCPsych; Martin N. Rossor, MD, FRCP

Arch Neurol. 2000;57:339-344.

Objective  To evaluate the rate of brain atrophy calculated from serial magnetic resonance imaging (MRI) registration as a surrogate marker of disease progression for use in clinical trials in Alzheimer disease (AD).

Methods  Eighteen patients with mild to moderate AD and 18 age-matched normal controls underwent 2 MRI brain scans separated by a 12-month interval. Each individual's later scan was registered to their first scan, and the volume of cerebral tissue loss calculated directly from the registered and subtracted MRI scan pairs. The mean and SD of the rate of brain volume changes were used to estimate the sample sizes that would be needed in a clinical trial with a drug anticipated to modify disease progression by varying degrees. Comparable sample size estimates were performed with data for other methods of monitoring rates of brain atrophy, extracted from published papers.

Results  The mean (SD) rate of brain atrophy for the patients with AD was 2.37% (1.11%) per year, while in the control group it was 0.41% (0.47%) per year. Based on these figures, to have 90% power to detect a drug effect equivalent to a 20% reduction in the rate of atrophy, 207 patients would be needed in each treatment arm. This assumes a 1-year placebo-controlled trial with a 10% patient dropout rate, and that 10% of scan pairs are unusable.

Conclusion  Registration of serial MRI volume images provides a powerful method of quantification of brain atrophy that can be used to monitor progression of AD in clinical trials.

From the Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, Queen Square (Drs Fox, Harvey, and Rossor and Ms Scahill), the Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (Mr Cousens), and the Imperial College School of Science, Technology and Medicine, St Mary's Campus (Dr Rossor), London, England.

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