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Persistent T1 hypointensity as an MRI marker for treatment efficacy in multiple sclerosis

Department of Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands, vandenelskamp{at}vume.nl

J Lembcke

Bayer-Schering Pharma, Berlin, Germany

V Dattola

Department of Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Neurosciences, Psychiatric and Anaesthesiological Sciences, University of Messina, Italy

K Beckmann

Bayer-Schering Pharma, Berlin, Germany

C Pohl

Bayer-Schering Pharma, Berlin, Germany; Department of Neurology, University Hospital of Bonn, Germany

W Hong

Bayer-Schering Pharma, Berlin, Germany

R Sandbrink

Bayer-Schering Pharma, Berlin, Germany

K Wagner

Bayer-Schering Pharma, Berlin, Germany

DL Knol

Department of Clinical Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

B Uitdehaag

Neurology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Neurology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

F Barkhof

Department of Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

Background

MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed.

Objective

To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS.

Methods

MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated.

Results

21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively.

Conclusion

To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power.

Key Words: MRI, persistent black hole, sample size, negative binomial distribution

Multiple Sclerosis, Vol. 14, No. 6, 764-769 (2008)
DOI: 10.1177/1352458507087842


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