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While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Koch received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme, and EMD Serono. Dr. Camara-Lemarroy received consulting/speaker fees from EMD Serono, Novartis, Biogen, and Horizon Therapeutics. Dr. Leavitt received honoraria as consultant on advisory boards for Biogen, and as a reviewer for the National Institutes of Health and the United States Department of Defense. Dr. Repovic received consulting and/or speaking honoraria from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech/Roche, Horizon/Amgen, Novartis, and TG therapeutics. Dr. Bowen received honoraria from serving on the scientific advisory board and speaker’s bureau of Biogen, Celgene, EMD Serono, Genentech and Novartis. He has received research support from AbbVie Inc, Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis, and TG Therapeutics. Dr. Comtois received consulting honoraria from Novartis and travel support from EDM Serono. Prof. Uitdehaag received consultancy fees and/or research support from Biogen, Sanofi Genzyme, EMD Serono, Novartis, Roche, Teva, and Immunic Therapeutics. Prof. Cutter served on Data and Safety Monitoring Boards: Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). Consulting or Advisory Boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Dr. Strijbis and Dr. Mostert report no disclosures.

Background: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery., Objective: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS)., Methods: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery., Results: CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery., Conclusion: Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr M.W.H. received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme, and EMD Serono. Dr E.M. received honoraria as consultant in advisory boards, and as chairperson or lecturer in meetings, or travel support from Actelion, Almirall, Bayer, Biogen Idec, Bristol Myers Squibb, Merck Serono, Teva, Novartis, Roche, and Sanofi Genzyme. Dr L.B. received honoraria from serving as a speaker and as a consultant in advisory boards from Bayer, Teva, Celgene, Biogen, Sanofi, Merck Serono, Novartis, Roche, Almirall, Bristol Myers Squibb, and Janssen. Dr J.M. reports no disclosures. Dr E.M.M.S. reports no disclosures. Dr J.C. reports no disclosures. Dr P.R. received consulting and speaking honoraria from Alexion, Banner, Biogen, Bristol Myers Squibb, Genentech, Genzyme, Horizon, and TG Therapeutics. Dr J.D.B. received honoraria from serving on the scientific advisory board and speaker’s bureau of Biogen, Celgene, EMD Serono, Genentech, and Novartis. He has received research support from AbbVie Inc., Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis, and TG Therapeutics. Dr J.S.W. received compensation for consulting, scientific advisory boards, or other activities with Avotres, Brainstorm Cell Therapeutics, Cleveland Clinic Foundation, EMD Serono, Inmagine, Novartis/Sandoz, Roche/Genentech; royalties are received through UTHealth for out-licensed monoclonal antibodies to Millipore (Chemicon International) Corporation. Dr F.D.L. received honoraria from consulting agreements and from serving on scientific advisory boards and data safety and monitoring boards and speaker’s bureau of Biogen, EMD Serono, Novartis, Teva, Actelion/Janssen, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune/Viela Bio, Receptos/Celgene/BMS, TG Therapeutics, MedDay, Atara Biotherapeutics, Mapi Pharma, Innate Immunotherapeutics, Apitope, Orion Biotechnology, Brainstorm Cell Therapeutics, Jazz Pharmaceuticals, GW Pharma, Mylan, Immunic, Population Council, Avotres, and Neurogene. He received research funding from Novartis, Actelion, Biogen, Sanofi, NMSS, NIH, Brainstorm Cell Therapeutics. He holds stock options of Avotres. Prof G.C. served on Data and Safety Monitoring Boards: Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Orphazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, Viela Bio Inc., Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). Consulting or Advisory Boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, MedImmune, MedDay, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr G.C. is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc., a private consulting company located in Birmingham AL.

Background: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD)., Objective: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum., Methods: Adults ( n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed., Results: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks., Conclusion: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Background: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures., Objective: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS)., Methods: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening., Results: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW., Conclusions: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.

Background: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability., Objective: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS., Methods: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C., Results: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model., Conclusion: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Objective: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS., Methods: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial., Results: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) ( r  = 0.21, p  = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) ( r  = 0.516, p  < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R., Conclusion: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.

Background: Patient-reported outcome measures (PROMs) are often used in clinical research, but little is known about their performance as longitudinal outcomes., Methods: We used data from ASCEND, a large SPMS trial ( n  = 889), to investigate changes on the Short Form Health Survey 36 (SF-36 v2) and the Multiple Sclerosis Impact Scale (MSIS-29) over 2 years of follow-up., Results: PROM scores changed little over the 2 years of follow-up. In contrast to physical disability measures, there was no consistent trend in PROM change: significant worsening occurred about as often as improvement. Using a 6-month confirmation reduced the number of both worsening and improvement events without altering their relative balance. There was no clear difference in worsening events in groups based on population characteristics, nor was there a noticeable effect using different thresholds for clinically significant change., Conclusion: We found little consistent change in MSIS-29 and SF-36 over 2 years of follow-up in people with SPMS. Our findings show a disconnect between disability worsening and PROM change in this population. Our findings raise caution about the use of these PROMs as primary outcome measures in SPMS trials and call for a critical reappraisal of the longitudinal use of these measures in SPMS trials.

Background: Health-related quality of life (HRQOL) outcomes are often included as secondary outcomes in clinical trials in secondary progressive MS (SPMS), but little is known about the longitudinal association of HRQOL and clinical and imaging outcome measures in SPMS., Objective: To assess the association of change in clinical and imaging outcomes with HRQOL in people with SPMS., Methods: We used data from ASCEND, a large randomized controlled trial ( n  = 889), to investigate the association of significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and change in lesional and volumetric imaging outcomes with significant worsening on the 36-Item Short Form Health Survey (SF-36) and the Multiple Sclerosis Impact Scale (MSIS-29) during 2 years of follow-up using logistic regression models., Results: HRQOL measures were most associated with EDSS and T25FW, less so with NHPT and SDMT, and not associated with lesional and volumetric imaging outcomes., Discussion: Worsening of the EDSS and T25FW was associated with two commonly used HRQOL measures. These outcomes therefore appear to be more patient relevant than either the NHPT or SDMT in the context of a 2-year clinical trial.

Background: Magnetic resonance imaging (MRI) of brain volume measures are widely used outcomes in secondary progressive multiple sclerosis (SPMS), but it is unclear whether they are associated with physical and cognitive disability., Objective: To investigate the association between MRI outcomes and physical and cognitive disability worsening in people with SPMS., Methods: We used data from ASCEND, a large randomized controlled trial ( n = 889). We investigated the association of change in whole brain and gray matter volume, contrast enhancing lesions, and T2 lesions with significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT) with logistic regression models., Results: We found no association between MRI measures and EDSS or SDMT worsening. T25FW worsening at 48 and 96 weeks, and NHPT worsening at 96 weeks were associated with cumulative new or newly enlarging T2 lesions at 96 weeks. NHPT worsening at 48 and 96 weeks was associated with normalized brain volume loss at 48 weeks, but not with other MRI outcomes., Conclusion: The association of standard MRI outcomes and disability was noticeably weak and inconsistent over 2 years of follow-up. These MRI outcomes may not be useful surrogates of disability measures in SPMS.

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT)., Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs., Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions., Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population ( n  = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials., Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.

Background: The timed 25-foot walk (T25FW) is a key clinical outcome measure in multiple sclerosis patient management and clinical research., Objectives: To evaluate T25FW performance and factors associated with its change in the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo Database ( n  = 2465)., Methods: We created confirmed disability progression (CDP) variables for T25FW and Expanded Disability Status Scale (EDSS) outcomes. We used intraclass correlation coefficients (ICCs) and Bland Altman plots to evaluate reliability. We evaluated T25FW changes and predictive validity using a mixed-effects model, survival analysis, and nested case-control analysis., Results: The mean baseline score for the T25FW in this study population was 9.2 seconds, median = 6.1 (standard deviation = 11.0, interquartile range (IQR) = 4.8, 9.0). The T25FW measure demonstrated excellent test-retest reliability (ICC = 0.98). Walk times increased with age, disability, disease type, and disease duration; relapses were not associated with an increase. Patients with T25FW progression had a faster time to EDSS-CDP compared to those without (hazards ratio (HR): 2.6; confidence interval (CI): 2.2, 3.1). Changes in the T25FW were more likely to precede changes in EDSS., Conclusion: This research confirms the association of the T25FW with disability and provides some evidence of predictive validity. Our findings support the continued use of the T25FW in clinical practice and clinical trials.

Background: Multiple sclerosis (MS) is an autoimmune disease leading to physical, emotional and cognitive disability. High body mass index (BMI) may impact cognitive function and brain volume in MS. Yet, there is paucity of evidence addressing the impact of BMI on cognitive function and brain volume in MS., Objectives: The purpose of this study was to examine the effects of BMI on normal appearing brain volume and cognitive function in patients with relapsing-remitting MS., Methods: A secondary data analysis of the NIH CombiRx study was conducted. Multivariate regression and mixed model analyses were executed to analyze the effect of BMI on brain volume and cognitive function., Results: The mean baseline age of the 768 participants was 38.2(SD = 9.4) years. 73% were female and 88.8% were Caucasian. The mean BMI was 28.8 kg/m 2 (SD = 6.7). The multivariate regression and mixed model analyses failed to show a clinical effect of BMI on brain volume and cognitive function., Conclusion: BMI did not show an effect on cognitive function and brain volume among MS patients. Although there is increased interest in the effects of modifiable factors on the course of MS, the effects of BMI on brain volume and cognitive function are debatable and warrant further research.ClinicalTrials.gov NCT00211887., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: We recently compared clinical outcomes in secondary progressive MS (SPMS) clinical trials and found an association of timed 25 foot walk (T25FW) worsening events and baseline disability scores. It is unclear whether disability worsening in clinical trials is comparable to that seen in clinical practice., Objective: The objective of this study is to compare disability worsening between the IMPACT and ASCEND data sets and data from the Calgary MS clinic and to characterize the association of baseline T25FW and expanded disability status scale (EDSS) scores with disability worsening., Methods: We combined the three data sets and investigated the impact of baseline characteristics on disability worsening with a logistic regression model. We calculated T25FW, EDSS, and 'EDSS or T25FW' worsening events as a function of ascending cut-off baseline disability scores., Results: Data source was not associated with T25FW worsening at 12 months. There was a strong association of baseline T25FW and EDSS cut-off scores with T25FW worsening. No such association was present for the EDSS and 'EDSS or T25FW'., Conclusion: Our results suggest that it is possible to 'enrich' a trial cohort for expected T25FW worsening events using specific baseline T25FW and EDSS cut-off scores. These analyses inform the selection of inclusion criteria for clinical trials in SPMS.

Background: The expanded disability status scale (EDSS) is the standard clinical outcome measure in primary progressive multiple sclerosis (PPMS), even though the timed 25-foot walk (T25FW), nine-hole peg test (NHPT) or combinations of these measures may be more useful. The paced auditory serial addition test (PASAT) is a widely used cognitive measure in MS, but little is known about change in PASAT scores over time in PPMS., Objective: The objective of this study is to compare clinical outcome measures in a large PPMS trial data set., Methods: We determined significant worsening events on the EDSS, T25FW and NHPT, and PASAT scores over the course of this 3-year trial. We compared unconfirmed, confirmed and sustained disability worsening and contrasted disability worsening with similarly defined improvement. We examined the association of baseline characteristics with the risk of disability worsening at 12, 24 and 36 months with logistic regression models., Results: The EDSS and T25FW showed most worsening events, while only few patients worsened on the NHPT. Adding the NHPT to a combined outcome added only few further worsening events. PASAT scores slightly increased over time, possibly due to a practice effect., Conclusion: Both the EDSS and T25FW, but not NHPT or PASAT, appear to be useful outcome measures in PPMS.

Background: Disability outcome measures in multiple sclerosis (MS) focus heavily on ambulation; however, limitations in performing everyday activities encompass another type of disability., Objectives: The aim of this study was to examine the ability of instrumental activities of daily living (IADL) scale to discriminate between different levels of disability and to predict disability progression., Methods: The North American Research Committee on Multiple Sclerosis (NARCOMS) registry fall 2006 semi-annual survey asked participants to complete the RAND-12, Performance Scales, Patient Determined Disease Steps (PDDS), and IADL questionnaires. We modeled the trajectory of disability change, using the PDDS, over 12 years. Analyses used linear and repeated measures regression methods., Results: Of respondents ( n  = 9931), 9559 (96%) completed the PDDS and IADL scale. Respondents were mostly female (76%), Caucasian (92%), and 52.3 (10.5) years old with moderate disability (median PDDS 4 (early cane)). Mean (SD) IADL total score was 20.5 (3.7). Discriminant ability of the IADL scale was higher than other measures considered at higher levels of disability. Adjusted longitudinal models showed that needing greater assistance on IADLs was independently predictive of trajectories of greater disability change., Conclusion: IADL scale had a greater ability to discriminate between higher disability levels than RAND-12 domains. The IADL scale may provide a useful and clinically relevant tool to measure disability in progressive MS populations.

Background: Still too little is known about the natural history of clinical outcome measures beyond the Expanded Disability Status Scale (EDSS), such as the timed 25-foot walk (T25FW) and nine-hole peg test (9HPT) in secondary progressive multiple sclerosis (SPMS)., Objective: To describe progression on the EDSS, T25FW, 9HPT, and their combinations. To investigate the association of the baseline characteristics age, sex, EDSS, T25FW, gadolinium-enhancing lesions, and relapse activity with EDSS and T25FW progression., Methods: Using original trial data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, we describe disability progression (with and without 3- or 6-month confirmation). We investigated the association of selected baseline characteristics with EDSS and T25FW progression over 2 years using binary logistic regression., Results: T25FW was the single outcome measure with the largest proportion of patients progressing, followed by EDSS and 9HPT. EDSS and T25FW at baseline were associated with EDSS and T25FW progression in both data sets. Age and relapse activity were only mild and inconsistent predictors, while sex and gadolinium enhancement at baseline did not predict disability progression in either data set., Conclusion: Our analyses inform the selection of primary outcome measures as well as inclusion criteria for clinical trials in SPMS.

Background: Metabolic comorbidity is overrepresented in people with multiple sclerosis (MS) and is associated with adverse MS outcomes. Excess visceral adiposity, approximated using waist circumference (WC), is a risk factor for metabolic comorbidity and predicts poorer outcomes in other neurologic diseases., Objective: To evaluate the association between WC and clinical and disease characteristics in people with MS., Methods: North American Research Committee on MS (NARCOMS) registry participants reported height and weight (used to calculate body mass index (BMI)) and were mailed a tape measure with instructions to measure WC. We considered WC continuously and used cut-points derived from the abdominal obesity criteria for the metabolic syndrome (men: WC ⩾ 40 in; women: WC ⩾ 35 in). We assessed the association between WC and disability (Patient-Determined Disease Steps) and symptom severity (validated scales) using multivariable-adjusted multinomial models., Results: Of 6367 responders with MS, we included 5832 (92%). Of these, 3181 (55%) reported WC meeting criteria for the abdominal obesity component of metabolic syndrome. In multivariable models adjusting for overall obesity status, WC was associated with 47% increased odds of severe versus mild disability (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.22-1.78)., Conclusions: Increased WC is associated with more severe disability, even after adjusting for overall obesity in this large cross-sectional survey.

Background: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS)., Objective: To examine the predictive validity of different NEDA definitions., Methods: Predictive validity for negative disability outcomes (NDOs) at 16 years and survival at 21 years post-randomization were assessed. NEDA in the first 2 years was defined as follows: clinical NEDA: no relapses or Expanded Disability Status Scale (EDSS) progression from baseline to Year 2; NEDA-3a: no relapses, no confirmed ⩾1-point EDSS progression, and no new T2-active lesions; NEDA-3b: no relapses, no EDSS progression, and no increase in T2 burden of disease (T2-BOD); and NEDA-4: no relapses, no EDSS progression, and no increase in T2-BOD or atrophy. NDOs were defined as death, need for wheelchair, EDSS ⩾6, or progressive MS., Results: A total of 245 and 371 patients were evaluated at 16 and 21 years, respectively. Clinical NEDA predicted NDOs ( p = 0.0029), as did baseline EDSS ( p < 0.0001), baseline T2-BOD ( p < 0.0001), and change in T2-BOD ( p = 0.0033). IFNB-1b treatment ( p = 0.0251), relapse rate in the 2 years before study start ( p = 0.0260), T2-BOD at baseline ( p = 0.0014), and change in T2-BOD ( p = 0.0129) predicted survival at 21 years., Conclusion: Clinical NEDA predicted long-term disability outcome. By contrast, definitions of NEDA that included on-therapy changes in magnetic resonance imaging variables did not increase the predictive validity.

The design of clinical trials is a key aspect to maximizing the possibility to detect a treatment effect. This fact is particularly challenging in progressive multiple sclerosis (PMS) studies due to the uncertainty about the right target and/or outcome in phase-2 studies. The aim of this review is to evaluate the current challenges facing the design of clinical trials for PMS. The selection of patients, the instrumental and clinical outcomes that can be used in PMS trials, and issues in their design will be covered in this report.

Background: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported., Objective: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity., Methods: We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design., Results: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide., Conclusion: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path., (© The Author(s), 2015.)

Background: Studies of cancer incidence and prevalence in multiple sclerosis (MS) have produced conflicting results., Objective: To estimate the incidence and prevalence of cancer in persons with MS and review the quality of included studies., Methods: We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I (2) statistic, and conducted meta-analyses for population-based studies., Results: We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected., Conclusion: The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed., (© The Author(s), 2014.)

Background: Findings regarding the prevalence of vascular comorbidities in multiple sclerosis (MS) are conflicting., Objective: The objective of this review is to estimate the incidence and prevalence of vascular comorbidities and predisposing comorbidities in persons with MS and to assess the quality of the included studies., Methods: The PubMed, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched. One reviewer abstracted data using a standardized data collection form, while the second reviewer verified the abstraction. Included studies were assessed qualitatively. Quantitatively, we assessed studies using the I² statistic, and conducted meta-analyses for population-based studies only., Results: The prevalence of hypertension and hyperlipidemia exceeded 10% in the MS population and increased with age. While the prevalence of ischemic heart disease, congestive heart failure, and stroke were less than 5% overall, the prevalence of these conditions exceeded expectations when compared to the general population. Cardiac valvular disease, however, affected the MS population less often than expected. Problems with study quality were common., Conclusion: Despite the relatively high prevalence of some vascular comorbidities in the MS population, important gaps exist in our understanding of their epidemiology. Most of our knowledge is based on studies conducted in a small number of regions., (© The Author(s), 2015.)

Background: As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS)., Objective: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS., Methods: The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies., Results: Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid., Conclusion: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide., (© The Author(s), 2015.)

Background: Psychiatric comorbidity is associated with lower quality of life, more fatigue, and reduced adherence to disease-modifying therapy in multiple sclerosis (MS)., Objectives: The objectives of this review are to estimate the incidence and prevalence of selected comorbid psychiatric disorders in MS and evaluate the quality of included studies., Methods: We searched the PubMed, PsychInfo, SCOPUS, and Web of Knowledge databases and reference lists of retrieved articles. Abstracts were screened for relevance by two independent reviewers, followed by full-text review. Data were abstracted by one reviewer, and verified by a second reviewer. Study quality was evaluated using a standardized tool. For population-based studies we assessed heterogeneity quantitatively using the I² statistic, and conducted meta-analyses., Results: We included 118 studies in this review. Among population-based studies, the prevalence of anxiety was 21.9% (95% CI: 8.76%-35.0%), while it was 14.8% for alcohol abuse, 5.83% for bipolar disorder, 23.7% (95% CI: 17.4%-30.0%) for depression, 2.5% for substance abuse, and 4.3% (95% CI: 0%-10.3%) for psychosis., Conclusion: This review confirms that psychiatric comorbidity, particularly depression and anxiety, is common in MS. However, the incidence of psychiatric comorbidity remains understudied. Future comparisons across studies would be enhanced by developing a consistent approach to measuring psychiatric comorbidity, and reporting of age-, sex-, and ethnicity-specific estimates., (© The Author(s), 2015.)

Background: Several studies have suggested that comorbid neurologic disorders are more common than expected in multiple sclerosis (MS)., Objective: To estimate the incidence and prevalence of comorbid seizure disorders and sleep disorders in persons with MS and to evaluate the quality of studies included., Methods: The PUBMED, EMBASE, Web of Knowledge, and SCOPUS databases, conference proceedings, and reference lists of retrieved articles were searched. Two reviewers independently screened abstracts to identify relevant articles, followed by full-text review of selected articles. We assessed included studies qualitatively and quantitatively (I² statistic), and conducted meta-analyses among population-based studies., Results: We reviewed 32 studies regarding seizure disorders. Among population-based studies the incidence of seizure disorders was 2.28% (95% CI: 1.11-3.44%), while the prevalence was 3.09% (95% CI: 2.01-4.16%). For sleep disorders we evaluated 18 studies; none were population-based. The prevalence ranged from 0-1.6% for narcolepsy, 14.4-57.5% for restless legs syndrome, 2.22-3.2% for REM behavior disorder, and 7.14-58.1% for obstructive sleep apnea., Conclusion: This review suggests that seizure disorders and sleep disorders are common in MS, but highlights gaps in the epidemiological knowledge of these conditions in MS worldwide. Other than central-western Europe and North America, most regions are understudied., (© The Author(s), 2015.)

Background: The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials., Objective: This study evaluated composite disability end points as alternatives to EDSS alone., Methods: SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D)., Results: Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials., Conclusion: Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials., (© The Author(s) 2014.)

Background: Sexual dysfunction is common in multiple sclerosis (MS) but reliable and valid measurement in this population is needed., Objective: The objective of this research is to re-validate the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 in a large US sample., Methods: A total of 6300 MS patients from the NARCOMS registry completed the MSISQ-19. Unforced principal component analysis utilizing oblique rotation with Kaiser Normalization validated its construct validity., Results: The scree plot supported a three-component solution, with 63% of total variance explained. The components mirrored the original validation study measuring primary, secondary, and tertiary sexual dysfunction. PCA suggested the scale could be shortened to 15 items, which were found to apply equally well to males and females (with one primary item specific for each sex). The components were moderately intercorrelated (Pearson rs ranged from 0.5 to 0.67). The secondary subscale correlated most highly with self-reported disability (r (6081) = 0.44, p < 0.001), whereas the tertiary subscale correlated most highly with psychological distress (r (5992) = -.37, p < 0.001). Cronbach's alpha for the total scale (0.92) and the subscales (primary, 0.87; secondary, 0.82; tertiary, 0.91) demonstrated good reliability., Conclusion: The revised 15-item MSISQ is a reliable and valid measure of sexual dysfunction in men and women with MS.

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.

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation., Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation., Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade., Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation., Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.

Background: Visual comorbidities are common in multiple sclerosis (MS) but the impact of visual comorbidities on visual disability is unknown., Objective: We assessed the impact of visual and vascular comorbidities on severity of visual disability in MS., Methods: In 2006, we queried participants of the North American Research Committee on Multiple Sclerosis (NARCOMS) about cataracts, glaucoma, uveitis, hypertension, hypercholesterolemia, heart disease, diabetes and peripheral vascular disease. We assessed visual disability using the Vision subscale of Performance Scales. Using Cox regression, we investigated whether visual or vascular comorbidities affected the time between MS symptom onset and the development of mild, moderate and severe visual disability., Results: Of 8983 respondents, 1415 (15.9%) reported a visual comorbidity while 4745 (52.8%) reported a vascular comorbidity. The median (interquartile range) visual score was 1 (0-2). In a multivariable Cox model the risk of mild visual disability was higher among participants with vascular (hazard ratio [HR] 1.45; 95% confidence interval [CI]: 1.39-1.51) and visual comorbidities (HR 1.47; 95% CI: 1.37-1.59). Vascular and visual comorbidities were similarly associated with increased risks of moderate and severe visual disability., Conclusions: Visual and vascular comorbidities are associated with progression of visual disability in MS. Clinicians hearing reports of worsening visual symptoms in MS patients should consider visual comorbidities as contributing factors. Further study of these issues using objective, systematic neuro-ophthalmologic evaluations is warranted.

Background: Accurate classification of multiple sclerosis (MS) lesions in the brain cortex may be important in understanding their impact on cognitive impairment (CI). Improved accuracy in identification/classification of cortical lesions was demonstrated in a study combining two magnetic resonance imaging (MRI) sequences: double inversion recovery (DIR) and T1-weighted phase-sensitive inversion recovery (PSIR)., Objective: To evaluate the role of intracortical lesions (IC) in MS-related CI and compare it with the role of mixed (MX), juxtacortical (JX), the sum of IC + MX and with total lesions as detected on DIR/PSIR images. Correlations between CI and brain atrophy, disease severity and disease duration were also sought., Methods: A total of 39 patients underwent extensive neuropsychological testing and were classified into normal and impaired groups. Images were obtained on a 3T scanner and cortical lesions were assessed blind to the cognitive status of the subjects., Results: Some 238 cortical lesions were identified (130 IC, 108 MX) in 82% of the patients; 39 JX lesions were also identified. Correlations between CI and MX lesions alone (p = 0.010) and with the sum of IC + MX lesions (p = 0.030) were found. A correlation between severity of CI and Expanded Disability Status Scale was also seen (p = 0.009)., Conclusion: Cortical lesions play an important role in CI. However, our results suggest that lesions that remain contained within the cortical ribbon do not play a more important role than ones extending into the adjacent white matter; furthermore, the size of the cortical lesion, and not the tissue-specific location, may better explain their correlation with CI.