Identification of Therapeutic Lag in Multiple Sclerosis

International audienceObjective: To develop a method that allows identification of the time to full clinically manifest effect of multiple sclerosis (MS) treatments (‘therapeutic lag’) on clinical disease activity.Background: In MS, treatment start or switch is prompted by evidence of disease activity, often presenting as relapses or disability progression. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear.Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included in the analysis. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start. This point represents the point of stabilisation of treatment effect, after the maximum treatment effect was observed. The method was developed using MSBase, and externally validated in OFSEP. A merged MSBase-OFSEP cohort was used for all subsequent analyses.Results: 11180 eligible treatment epochs were identified for analysis of relapses and 4088 treatment epochs for disability progression. There were no significant differences between the results of discovery and validation analyses. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12–30 weeks. The duration of therapeutic lag for disability progression was calculated for 7 therapies and ranged between 30–70 weeks.Conclusions: We have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies. This method will be applied in studies that will evaluate the effect of patient and disease characteristics on therapeutic lag

Determinants of Therapeutic Lag in Multiple Sclerosis

International audienceObjective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS<6 compared to the other represented groups.Conclusions: We have utilised a novel method for the quantification of therapeutic lag in different patient groups. Baseline EDSS and ARR are the most important determinants of therapeutic lag for both disability progression and relapses

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

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