@article {dong_further_2014, title = {Further investigation of safety monitoring guidelines based on magnetic resonance imaging lesion activity in multiple sclerosis clinical trials}, journal = {Multiple Sclerosis Journal}, volume = {21}, year = {2015}, pages = {101-104}, abstract = {

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1{\textendash}2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures.

}, keywords = {Clinical trials methodology, contrast-enhancing lesions, magnetic resonance imaging, multiple sclerosis, patient safety}, doi = {10.1177/1352458514533846}, url = {http://msj.sagepub.com/content/early/2014/05/20/1352458514533846}, author = {Dong, J and Zhao, Y and Petkau, A.John and Li, DKB and Riddehough, A and Traboulsee, A} } @article {altman_mri-based_2012, title = {MRI-based clinical trials in relapsing-remitting multiple sclerosis: new sample size calculations based on a longitudinal model}, journal = {Multiple Sclerosis Journal}, volume = {18}, number = {11}, year = {2012}, pages = {1600{\textendash}1608}, abstract = {

BACKGROUND: Sample sizes for magnetic resonance imaging (MRI)-based clinical trials in multiple sclerosis (MS) generally assume that lesion counts are reasonably described by the negative binomial (NB) model. OBJECTIVE: This study aimed to assess the appropriateness of the NB model for lesion count data and to provide sample sizes for placebo-controlled, MRI-based clinical trials in relapsing-remitting MS using a more realistic model. METHODS: The fit of the NB model in each arm of five MS clinical trials was assessed using Pearson{\textquoteright}s chi-squared statistic. Required sample sizes associated with various tests of treatment effect were estimated by simulating data from a new, longitudinal model for repeated lesion count data on individual patients. RESULTS: Evidence (p \< 0.05) against the NB model was found in at least one arm of four of the five trials. If a trial is designed using this model but the resulting clinical data do not follow its assumptions then this trial can be seriously under-powered for assessing differences in mean lesion counts. CONCLUSION: Sample sizes based on the longitudinal model are more realistic and often smaller than those previously reported using the NB model.

}, keywords = {Brain, Chi-Square Distribution, Computer Simulation, Controlled Clinical Trials as Topic, Endpoint Determination, Humans, Longitudinal Studies, magnetic resonance imaging, Models, multiple sclerosis, Predictive Value of Tests, Relapsing-Remitting, Sample Size, Statistical, Time Factors, Treatment Outcome}, doi = {10.1177/1352458512444326}, author = {Altman, RM and Petkau, A.John and Vrecko, D and Smith, A} } @article {petkau_magnetic_2008, title = {Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses}, journal = {Multiple Sclerosis}, volume = {14}, year = {2008}, pages = {770-778}, abstract = {

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

}, keywords = {correlations, gadolinium enhanced lesions, magnetic resonance imaging, multiple sclerosis, prognosis, surrogacy}, doi = {10.1177/1352458507088104}, url = {http://msj.sagepub.com/content/early/2008/06/05/1352458507088104}, author = {Petkau, J. and Reingold, S. C. and Held, U. and Cutter, G. R. and Fleming, T. R. and Hughes, M. D. and Miller, D. H. and McFarland, H. F. and Wolinsky, J. S.} }