Molyneux, PD; (1999) The developing role of magnetic resonance imaging in Phase III multiple sclerosis treatment trials: Technical considerations and results of a large multicentre study. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Magnetic resonance imaging (MRI) provides a powerful tool for both monitoring disease evolution in multiple sclerosis (MS) and assessing the efficacy of therapeutic intervention. A monthly MRI protocol is now routinely used to screen potential MS therapies, with the effect of treatment on MR activity providing the primary outcome measure. Phase III definitive MS treatment trials also generally incorporate an MR protocol. However, in view of the uncertain relationship between MR measures and clinical outcome, the primary endpoints of phase III studies are currently based on clinical indices. The first chapter of this thesis provides a critical review of the available MRI tools for monitoring disease progression. The limited extent of the relationship between clinical outcome and standard MR measures is stressed, and potential factors contributing to this dissociation are reviewed. The thesis is then presented in three parts, the first of which looks at recent developments in MRI acquisition and analysis methodology. In particular, the utility of three established techniques for measuring brain lesion volume (global thresholding, manual outlining and contouring) is examined. Work is presented that suggests a limited role for global thresholding-based lesion segmentation in serial MS studies. A comparison of a semi-automated local thresholding algorithm (contouring) with the currently recognised gold standard segmentation method (manual outlining) is presented, highlighting the advantages in terms of precision and reliability with the contour technique. The effect of slice thickness on MS lesion detection and brain lesion volume is examined, in order to define an optimal slice thickness for MS treatment trials. The second part examines the relationship between different MRI parameters and assesses the strength of clinical/MRI correlations in a substantial cohort of patients. The extent to which change in annual T2 lesion volume is dictated by ongoing inflammatory activity (assessed with monthly gadolinium enhanced imaging) is investigated using this cohort. Furthermore, the relationship between standard clinical indices of disease activity and progression on the one hand, and MR activity on monthly and annual imaging on the other, is defined. Using an extension of this database, power calculations are presented based on an annual imaging protocol where the change in T2 lesion volume provides the outcome measure. The aim is to guide efficient trial design by providing sample sizes for a typical multicentre parallel group placebo-controlled design. The results suggest that annual T2 lesion volume quantification provides a powerful and robust tool for monitoring the effect of treatment, and demonstrate that the current practice of including several hundred patients in an MR protocol produces substantial overpowering. Part Three describes the MRI results of a phase III trial using interferon beta-1b in patients with secondary progressive MS. The relationships between clinical and MR indices are also presented, and their implications for future trial design are discussed.

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