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Published online before print November 12, 2008, doi:10.1212/01.wnl.0000335765.55346.fc)
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NEUROLOGY 2009;72:595-601
© 2009 American Academy of Neurology

Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis

D. R. Altmann, DPhil, B. Jasperse, MD, F. Barkhof, PhD, K. Beckmann, MSc, M. Filippi, MD, L. D. Kappos, MD, P. Molyneux, MD, C. H. Polman, PhD, C. Pozzilli, MD, A. J. Thompson, FRCP, K. Wagner, MD, T. A. Yousry, FRCR and D. H. Miller, FRCP

From the Medical Statistics Unit (D.R.A.), London School of Hygiene and Tropical Medicine, UK; Nuclear Magnetic Resonance Research Unit (D.R.A., D.H.M.), Department of Neuroinflammation, Institute of Neurology, University College London, UK; Multiple Sclerosis Centre Amsterdam and Image Analysis Centre (B.J., F.B., C.H.P.), VU University Medical Centre, The Netherlands; Bayer Schering Pharma AG (K.B., K.W.), Berlin, Germany; Neuroimaging Research Unit (M.F.), Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy; Neurology and Department of Biomedicine (L.D.K.), University Hospital, Basel, Switzerland; Addenbrookes Hospital (P.M.), Cambridge, UK; Department of Neurological Science (C.P.), University of Rome "La Sapienza," Italy; and Department of Brain Repair and Rehabilitation (A.J.T., T.A.Y.), Institute of Neurology, University College London, UK.

Address correspondence and reprint requests to Dr. Dan R. Altmann, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK daniel.altmann{at}lshtm.ac.uk

Background: Progressive brain atrophy in multiple sclerosis (MS) may reflect neuroaxonal and myelin loss and MRI measures of brain tissue loss are used as outcome measures in MS treatment trials. This study investigated sample sizes required to demonstrate reduction of brain atrophy using three outcome measures in a parallel group, placebo-controlled trial for secondary progressive MS (SPMS).

Methods: Data were taken from a cohort of 43 patients with SPMS who had been followed up with 6-monthly T1-weighted MRI for up to 3 years within the placebo arm of a therapeutic trial. Central cerebral volumes (CCVs) were measured using a semiautomated segmentation approach, and brain volume normalized for skull size (NBV) was measured using automated segmentation (SIENAX). Change in CCV and NBV was measured by subtraction of baseline from serial CCV and SIENAX images; in addition, percentage brain volume change relative to baseline was measured directly using a registration-based method (SIENA). Sample sizes for given treatment effects and power were calculated for standard analyses using parameters estimated from the sample.

Results: For a 2-year trial duration, minimum sample sizes per arm required to detect a 50% treatment effect at 80% power were 32 for SIENA, 69 for CCV, and 273 for SIENAX. Two-year minimum sample sizes were smaller than 1-year by 71% for SIENAX, 55% for CCV, and 44% for SIENA.

Conclusion: SIENA and central cerebral volume are feasible outcome measures for inclusion in placebo-controlled trials in secondary progressive multiple sclerosis.

Abbreviations: ANCOVA = analysis of covariance; CCV = central cerebral volume; FSL = FMRIB Software Library; MNI = Montreal Neurological Institute; MS = multiple sclerosis; NBV = normalized brain volume; PBVC = percent brain volume change; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.

Supplemental data at www.neurology.org

Editorial, page 586

e-Pub ahead of print on November 12, 2008, at www.neurology.org.

The Nuclear Magnetic Resonance Research Unit is partly supported by The Multiple Sclerosis Society of Great Britain and Northern Ireland. The Multiple Sclerosis Centre Amsterdam is supported by the Dutch Foundation for MS Research (grant 05-538c).

Disclosure: Bayer Schering Pharma AG supported the data collection for this study. F.B., M.F., P.M., C.H.P., and D.H.M. have received honoraria from Bayer Schering Pharma AG (less than $10,000). K.W. and K.B. are current employees of Bayer Schering Pharma AG.

Received May 19, 2008. Accepted in final form August 20, 2008.


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