Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis.
BACKGROUND
Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis (MS) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents. In this study, we evaluate the rate of cerebral atrophy in a 6-month period, investigate the predictive and explanatory value of other magnetic resonance imaging (MRI) measures in relation to cerebral atrophy, and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure.


METHODS
One hundred thirty-five relapsing-remitting multiple sclerosis patients underwent six monthly MRI scans from which the percentage brain volume change (PBVC) and the number and volume of gadolinium (Gd)-enhancing lesions, T2 lesions, and persistent black holes (PBH) were determined. By means of multiple linear regression analysis, the relationship between focal MRI variables and PBVC was assessed. Sample size calculations were performed for all patients and subgroups selected for enhancement or a high T2 lesion load at baseline.


RESULTS
A significant atrophy occurred over 6 months (PBVC = -0.33%, SE = 0.061, p < 0.0001). The number of baseline T2 lesions (p = 0.024), the on-study Gd-enhancing lesion volume (p = 0.044), and the number of on-study PBHs (p = 0.003) were associated with an increased rate of atrophy. For a 50% decrease in rate of atrophy, the sample size calculations showed that approximately 283 patients per arm are required in an unselected sampled population and 185 patients per arm are required in a selected population.


CONCLUSIONS
Within a 6-month period, significant atrophy can be detected and on-study associations of PBVC and PBHs emphasizes axonal loss to be a driving mechanism. Application as primary outcome measure in short-term clinical trials with feasible sample size requires a potent drug to obtain sufficient power.
van den Elskamp
I J
IJ
Department of Radiology, MS Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. i.vandenelskamp@vumc.nl
Boden
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Dattola
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Knol
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Filippi
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Kappos
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Fazekas
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Wagner
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Pohl
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Sandbrink
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Polman
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Uitdehaag
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Barkhof
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D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000328:Adult; D001284:Atrophy / Q000188:drug therapy / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D017063:Outcome Assessment, Health Care / Q000379:methods*; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D016899:Interferon-beta; D000068556:Interferon beta-1a