Predicting the On-Study Relapse Rate for Multiple Sclerosis Patients in Clinical Trials

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p<0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate=-0.02) and previous relapse number (estimate=0.59 for 1, 0.91 for 2 and 1.45 for 3 or more relapses vs 0 relapse) remain. We were able to confirm these findings in a second, independent dataset. Conclusions: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course and gadolinium enhancement status, given the other covariates, have no significant influence on the on-study relapse rate

Multiple sclerosis, the measurement of disability and access to clinical trial data

Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Nevertheless, MS trials have been getting steadily shorter despite the lack of a consensus definition for the most important clinical outcome - unremitting progression of disability. Methods: We have examined widely used surrogate markers of disability progression in MS within a unique database of individual patient data from the placebo arms of 31 randomised clinical trials. Findings: Definitions of treatment failure used in secondary progressive MS trials include much change unrelated to the target of unremitting disability. In relapsing-remitting MS, disability progression by treatment failure definitions was no more likely than similarly defined improvement for these disability surrogates. Existing definitions of disease progression in relapsing-remitting trials encompass random variation, measurement error and remitting relapses and appear not to measure unremitting disability. Interpretation: Clinical surrogates of unremitting disability used in relapsing -remitting trials cannot be validated. Trials have been too short and/or degrees of disability change too small to evaluate unremitting disability outcomes. Important implications for trial design and reinterpretation of existing trial results have emerged long after regulatory approval and widespread use of therapies in MS, highlighting the necessity of having primary trial data in the public domain

Treating Systematic Errors in Multiple Sclerosis Data

Multiple sclerosis (MS) is characterized by high variability between patients and, more importantly here, within an individual over time. This makes categorization and prognosis difficult. Moreover, it is unclear to what degree this intra-individual variation reflects the long-term course of irreversible disability and what is attributable to short-term processes such as relapses, to interrater variability and to measurement error. Any investigation and prediction of the medium or long term evolution of irreversible disability in individual patients is therefore confronted with the problem of systematic error in addition to random fluctuations. The approach described in this article aims to assist in detecting relapses in disease curves and in identifying the underlying disease course. To this end neurological knowledge was transformed into simple rules which were then implemented into computer algorithms for pre-editing disease curves. Based on simulations it is shown that pre-editing time series of disability measured with the Expanded Disability Status Scale (EDSS) can lead to more robust and less biased estimates for important disease characteristics, such as baseline EDSS and time to reach certain EDSS levels or sustained progression

Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle

The mechanistic target of rapamycin (mTOR) is a central mediator of protein synthesis in skeletal muscle. We utilized immunofluorescence approaches to study mTOR cellular distribution and protein-protein co-localisation in human skeletal muscle in the basal state as well as immediately, 1 and 3 h after an acute bout of resistance exercise in a fed (FED; 20 g Protein/40 g carbohydrate/1 g fat) or energy-free control (CON) state. mTOR and the lysosomal protein LAMP2 were highly co-localised in basal samples. Resistance exercise resulted in rapid translocation of mTOR/LAMP2 towards the cell membrane. Concurrently, resistance exercise led to the dissociation of TSC2 from Rheb and increased in the co-localisation of mTOR and Rheb post exercise in both FED and CON. In addition, mTOR co-localised with Eukaryotic translation initiation factor 3 subunit F (eIF3F) at the cell membrane post-exercise in both groups, with the response significantly greater at 1 h of recovery in the FED compared to CON. Collectively our data demonstrate that cellular trafficking of mTOR occurs in human muscle in response to an anabolic stimulus, events that appear to be primarily influenced by muscle contraction. The translocation and association of mTOR with positive regulators (i.e. Rheb and eIF3F) is consistent with an enhanced mRNA translational capacity after resistance exercise

Incorporation of Omega-3 Fatty Acids Into Human Skeletal Muscle Sarcolemmal and Mitochondrial Membranes Following 12 Weeks of Fish Oil Supplementation

Fish oil (FO) supplementation in humans results in the incorporation of omega-3 fatty acids (FAs) eicosapentaenoic acid (EPA; C20:5) and docosahexaenoic acid (DHA; C20:6) into skeletal muscle membranes. However, despite the importance of membrane composition in structure–function relationships, a paucity of information exists regarding how different muscle membranes/organelles respond to FO supplementation. Therefore, the purpose of the present study was to determine the effects 12 weeks of FO supplementation (3g EPA/2g DHA daily) on the phospholipid composition of sarcolemmal and mitochondrial fractions, as well as whole muscle responses, in healthy young males. FO supplementation increased the total phospholipid content in whole muscle (57%; p &lt; 0.05) and the sarcolemma (38%; p = 0.05), but did not alter the content in mitochondria. The content of omega-3 FAs, EPA and DHA, were increased (+3-fold) in whole muscle, and mitochondrial membranes, and as a result the omega-6/omega-3 ratios were dramatically decreased (-3-fold), while conversely the unsaturation indexes were increased. Intriguingly, before supplementation the unsaturation index (UI) of sarcolemmal membranes was ∼3 times lower (p &lt; 0.001) than either whole muscle or mitochondrial membranes. While supplementation also increased DHA within sarcolemmal membranes, EPA was not altered, and as a result the omega-6/omega-3 ratio and UI of these membranes were not altered. All together, these data revealed that mitochondrial and sarcolemmal membranes display unique phospholipid compositions and responses to FO supplementation