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Objective: To investigate the reliability of clinical outcomes in secondary progressive multiple sclerosis (SPMS) trials, we compared the frequency of progression and improvement events on different clinical outcome measures in the placebo arms of 2 large randomized controlled trial (RCT) datasets., Methods: Using original trial data from the placebo arms of IMPACT (International MS Secondary Progressive Avonex Controlled Trial) and ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis), 2 large RCTs in SPMS, we compared disability progression and similarly defined improvement with and without 3- or 6-month confirmation on the outcome measures Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and their combinations., Results: In both datasets, the EDSS showed the highest rates of improvement over time, and the smallest difference between progression and improvement rates, followed by the T25FW and the 9HPT. For the T25FW and 9HPT, improvement rates were fairly stable over time and remained at below or around the 10% level. For the EDSS, improvement rates increased in parallel with disability progression rates., Conclusions: All investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the T25FW and 9HPT less so than the more established outcome EDSS. Our findings are relevant for the design and critical appraisal of trials in SPMS., (© 2020 American Academy of Neurology.)

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression., Methods: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models., Results: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline., Conclusion: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

Objective: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period., Methods: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria., Results: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets., Conclusions: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Although the natural history of multiple sclerosis has been charted extensively, it is still not known whether the trajectory of disability accumulation has changed in the era of disease-modifying therapies (DMTs)., Objective: The objective of this study was to examine trends in Multiple Sclerosis Severity Score (MSSS) with regard to calendar year of enrollment into the New York State MS Consortium (NYSMSC)., Methods: Distributions of MSSS were calculated for each year of enrollment, from 1996 to 2007. Quantile regression was used in a multivariable analysis to model for conditional distribution of MSSS quantiles as functions of potential confounders., Results: The cohort consisted of 6238 patients. Mean age at enrollment was 38 years (SD=10) and mean disease duration was 10.1 years (SD=7.3); 57% were on DMTs. The quantile regression model of trends in MSSS between 1996 and 2007 controlled for age, sex, ethnicity, diagnostic delay, and disease duration and demonstrated a robust trend toward lower MSSS with increasing year of enrollment. The model-predicted median MSSS at enrollment in 1996 was 5.04 (95% CI, 4.86-5.21), and in 2007 was 3.78 (95%CI, 3.36-4.20; p<0.001). The downward trend in MSSS during the enrollment period was confirmed by analysis of Expanded Disability Status Scale (EDSS) distributions, adjusted for disease duration, in successive years of enrollment., Conclusions: The recent enrollees into the NYSMSC had lower MSSSs compared to the earlier enrollees. The apparent slowing in disability accumulation is likely due to a complex combination of factors: advent of DMTs and improvements in MS care, as well as selection, migration, and recall biases.

Background: Quantitative measures derived from magnetic resonance imaging (MRI) have been widely investigated as non-invasive biomarkers in multiple sclerosis (MS). However, the correlation of single measures with Expanded Disability Status Scale (EDSS) is poor, especially for studies with large population samples., Objective: To explore the correlation of MRI-derived measures with EDSS through composite MRI scores., Methods: Magnetic resonance images of 126 patients with relapsing-remitting MS were segmented into white and gray matter, cerebrospinal fluid, T2-hyperintense lesions, gadolinium contrast-enhancing lesions, T1-hypointense lesions ('black holes': BH). The volumes and average T2 values for each of these tissues and lesions were calculated and converted to a z-score (in units of standard deviation from the mean). These z-scores were combined to construct composite z-scores, and evaluated against individual z-scores for correlation with EDSS., Results: Composite scores including relaxation times of different tissues and/or volumetric measures generally correlated more strongly with EDSS than individual measures. The maximum observed correlation of a composite with EDSS was r = 0.344 (p < 0.0001), which is an improvement over the highest-performing single MRI measure (BH; r = 0.298, p < 0.001)., Conclusion: Z-transformation permits construction of composite scores including volumetric and T2-relaxation measures. Inclusion of multiple MRI measures in the composite can provide a broader characterization of the disease process, resulting in more robust correlations with EDSS.

Background: Participants enrolled in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry report disability status using Performance Scales (PS), a self-report measure. The bladder/bowel subscale (PSB) of PS has not been validated. It is also unknown whether ethnic or socioeconomic disparities exist in bladder care., Objective: We aimed to validate the bladder/bowel subscale used by the NARCOMS registry and to describe urologic symptoms, investigations, and treatments received by registry participants., Methods: In the Fall 2005 update questionnaire, we collected the Bowel Control Scale (BWCS) and Urogenital Distress Inventory-6 (UDI-6) as criterion measures and urologic investigations and treatments. We measured associations between investigations, treatments, and symptoms with clinical and sociodemographic variables using chi(2) tests for categorical variables and Kruskal-Wallis tests for continuous variables, followed by multivariable logistic regression., Results: Nine thousand six hundred eighty-eight participants completed the survey. For the UDI-6, the median (interquartile range) score was 33.3 (16.7 to 50.0), for the BWCS 3 (1 to 6), and for the PSB 1 (1 to 3). The correlation between the PSB and the UDI-6 was r = 0.67 and between the PSB and the BWCS r = 0.53 (both p < 0.0001). Participants had increased odds of receiving medication for bladder symptoms if they had health insurance (odds ratio [OR] 1.90; 1.07 to 3.35). Participants who were white (OR 1.5; 1.16 to 1.94) and had health insurance (OR 2.0; 1.3 to 3.07) had increased odds of undergoing urologic investigations., Conclusion: The Performance Scales bladder question has adequate criterion and construct validity in multiple sclerosis (MS). There are ethnic and socioeconomic disparities in bladder management in MS.

The experience of pain has been documented in small studies of individuals with multiple sclerosis (MS). The present study examines the prevalence of persistent pain and uncomfortable sensations among participants in the large North American Research Committee on MS (NARCOMS) Patient Registry. Registrants (10,176) responded to a questionnaire on pain and 7579 reported experiencing some level of pain during the month prior to the survey. Among the respondents 49% reported mild to severe pain and 49% of those indicated severe pain. Increased pain intensity was positively associated with gender (more women), multiple pain sites (51% of the severe pain group reported four or more pain sites), and constancy of pain (44% among the group with severe pain). There was also a positive association with increased MS-related disability, relapsing-worsening type of MS, and depression. Respondents with severe pain made greater use of the healthcare system and of prescribed analgesics, but were less likely to be satisfied with their doctors' efforts to manage their pain. About one-third of the patients with moderate pain and 18% of those with severe pain reported no consultations for their pain. The effects of pain severity were fully evident in the respondents' daily life, their work, mood, recreational activities and enjoyment of life. Our results indicate that the high prevalence of MS-related severe pain, low satisfaction with management of intense pain, and the perceived interference with quality of life indicators necessitate greater attention by healthcare providers to the management of pain and uncomfortable sensations in the MS population.

Objective: To investigate differences in disability between African American and Caucasian patients with multiple sclerosis (MS) by comparing the relationship between current age and disability between races and by assessing the effect of adjustment for socioeconomic status (SES) on the associations., Methods: The authors selected US participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry with an age at symptom onset of 10 to 60 years, who reported their race as Caucasian or African American (n = 21,557). They classified participants as having mild, moderate, or severe disability in the domains of mobility, hand function, cognition, and vision using Patient Determined Disease Steps and Performance Scales and assessed the association of disability with race using polytomous logistic regression., Results: Disability increased more rapidly with increasing disease duration in older patients, but there was no interaction between race and age. African Americans had increased odds of severe vs mild disability in all four domains (odds ratio [OR] [95% CI]: hand 1.35 [1.10 to 1.64]; vision 1.75 [1.37 to 2.27]; cognition 1.32 [1.04 to 1.67]; mobility 1.32 [1.11 to 1.56]). Adjustment for all covariates, including SES, attenuated these associations (OR [95% CI]: hand 1.27 [1.00 to 1.61]; vision 1.59 [1.19 to 2.08]; cognition 0.98 [0.74 to 1.30]; mobility 1.37 [1.11 to 1.67]). Lack of adjustment for SES produced stronger associations. After enrollment in NARCOMS, disability progression did not differ between the groups., Conclusions: African Americans experience greater multiple sclerosis-associated disability than Caucasians. Failure to account for socioeconomic status leads to overestimation of these differences. Disease progression is similar in African Americans and Caucasians after diagnosis.

Objective: To prospectively characterize the relation between two-year changes in functional impairment as measured by the Multiple Sclerosis Functional Composite (MSFC) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS)., Methods: One hundred and eighty-eight patients with multiple sclerosis (MS) were recruited at our outpatient clinic. Impairment and disability were assessed using the MSFC and GNDS at baseline and follow-up. Longitudinal correlations were studied between changes in MSFC and GNDS and their corresponding components. We also studied changes in GNDS in relation to what can be classified as a reliable change in MSFC; for example, 20% change in each MSFC component or a change of 0.5 in total MSFC score. In addition, we studied the change in total number of GNDS subcategories with a score of 3 or higher in relation to the predefined MSFC changes, these subcategories being indicative of the requirement for help by another person., Results: Despite good cross-sectional correlations between MSFC and GNDS, no significant correlation was found between longitudinal changes in MSFC and GNDS. Analysing the change in GNDS in relation to the predefined MSFC changes shows that GNDS changes are nicely rank ordered when more stringent definitions of reliable change were applied. In addition, analysing the number of GNDS subcategories scored 3 or higher indicate that there is a profile of worsening on the MSFC being associated with increase in the amount of help required from others., Conclusion: Our longitudinal data suggest that a reliable change is associated with a likewise change in patient perceived disability, the smallest reliable change being identified by at least 20% change in each MSFC component.

Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.

With the advent and widespread use of partially effective disease modifying drug therapies for multiple sderosis (MS), future dinical trials will undoubtedly test experimental interventions against standard therapy, or will test combinations of drugs against standard therapy. In either case, incremental progress in slowing disability progression in future MS dinical trials will require much larger sample sizes, more sensitive outcome measures, or a combination of the two. Because improved dinical outcome methods would likely accelerate progress in MS therapeutics, the National Multiple Sclerosis Society (NMSS) convened an international task force in 1994 to recommend improved clinical outcome measures. As the result of a two-year process of discussion and data analysis, the task force recommended the Multiple Sderosis Functional Composite (MSFC) as a new clinical outcome measure for future MS trials. MSFC consists of timed tests of walking, arm function, and cognitive function, expressed as a single score along a continuous scale. The task force recommended that MSFC be induded in future MS trials, and recommended a series of validation studies. Subsequent studies have provided evidence that MSFC correlates moderately with Expanded Disability Status Scale (EDSS), and that correlation is driven by strong correlations with the ambulatory function component; arm function and cognitive function correlate at lower levels with EDSS. The MSFC correlates better than EDSS with magnetic resonance imaging (MRI) variables, including brain atrophy, and shows significant correlation with patient-reported disease-related quality of life (QOL). MSFC and short-term change in MSFC correlate with future clinical and MRI status, and the strength of the correlations compares favorably with well-known cardiovascular risk factors. The studies in aggregate indicate that MSFC and MSFC change are clinically meaningful, and that MSFC has substantial advantages over alternative clinical outcome measures for MS clinical trials.

Background: Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS., Methods: A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT])., Results: Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects., Conclusions: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNbeta-1a (Avonex) in relapsing- remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing--remitting MS.

The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.