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Regression of new gadolinium enhancing lesion activity in relapsing-remitting multiple sclerosis

From the Department of Medicine, Division of Neurology (Y.Z., A.T.), Department of Statistics (A.J.P.), and Department of Radiology (D.L.), University of British Columbia, Vancouver, Canada.

Address correspondence and reprint requests to Dr. Yinshan Zhao, Faculty of Medicine (Neurology), Rm S195, 2211 Wesbrook Mall, University of British Columbia, Vancouver, BC, Canada V6T 2B5 yinshan{at}interchange.ubc.ca

Background: Contrast enhancing lesions (CEL) is a common endpoint in multiple sclerosis (MS) clinical trials. To minimize sample size or placebo exposure, a crossover design without a concurrent control group is attractive. Natural regression may confound this strategy. We assessed the degree of regression in monthly new gadolinium activity in relapsing-remitting (RR) placebo patients.

Methods: A post hoc analysis was performed on 65 RRMS placebo patients in the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial. Patients were originally selected for relapses but not preselected for MRI activity. Eleven MRI scans were taken at screening, baseline, and months 1 through 9. Monthly new CEL rates were examined using a random effects Poisson model. Patients were analyzed as a single group and by screening CEL count level subgroups: no, low, and high (0, 1 to 3, >3 CEL).

Results: A total of 32, 19, and 14 patients had no, low, and high CEL counts at screening. The monthly new CEL rates (95% CI) of all patients at baseline, months 1 to 3, 4 to 6, and 7 to 9 were 2.0 (1.3, 2.9), 1.8 (1.3, 2.5), 1.4 (1.0, 2.0), and 1.2 (0.8, 1.7). Compared to baseline, the rate decreased by 10%, 27%, and 39%. The monthly rate of the no subgroup remained stable. The rates for both the low and high subgroups decreased by 4%, 29%, and 48% at months 1 to 3, 4 to 6, and 7 to 9 compared to baseline.

Conclusions: Placebo relapsing-remitting multiple sclerosis patients experience a decline of new gadolinium activity over 9 months. A crossover design without a concurrent comparison group may overestimate the treatment effect.

GLOSSARY: CEL = contrast enhancing lesions; MS = multiple sclerosis; PRISMS = Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis; RR = relapsing-remitting.

e-Pub ahead of print on November 14, 2007, at www.neurology.org.

Supported by the MS/MRI Research Group at University of British Columbia.

Disclosure: This study is conducted independently by the MS/MRI Research Group at University of British Columbia. The authors report no conflicts of interest.

Received May 28, 2007. Accepted in final form July 20, 2007.