Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis

Abstract

Background and Objectives

Clinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25-ft walk (T25FW) and 9-hole peg test (NHPT) may be more useful and patient relevant. The objective of this work was to compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset.

Methods

We used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening.

Results

CombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of <10% throughout the trial. We also found that Kaplan-Meier survival analysis, the standard presentation and analysis method in modern RRMS trials, yields exaggerated estimates of disability worsening. With the Kaplan-Meier method, the proportion of patients with worsening events steadily increases until it reaches several-fold the number of events seen with more conservative analysis methods. For 3-month confirmed disability worsening up to 36 months, the Kaplan-Meier method yields 2.6-fold higher estimates for the EDSS, 2.9-fold higher estimates for the T25FW, and 5.1-fold higher estimates for the NHPT compared to a more conservative presentation of the same data.

Discussion

Our analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.

An important goal of treatment in relapsing-remitting multiple sclerosis (RRMS) is to prevent the accumulation of irreversible disability. Typical randomized controlled trials (RCTs) in RRMS have a duration of 2 or 3 years. Relapses and the development of new lesions on cranial MRI scans occur frequently in RRMS trial cohorts, and it is therefore straightforward to compare relapse frequency and MRI outcomes between treatment arms in RCTs. The accumulation of irreversible disability in MS, however, is a process that evolves over decades; therefore, it is more difficult to show a treatment effect on disability outcomes.

RCTs usually use the Expanded Disability Status Scale (EDSS) as the primary disability outcome measure. Building on the Disability Status Scale published by Kurtzke¹ in 1955, the EDSS was published in 1983² and is an ordinal numerical rating scale ranging from 0 (normal neurologic exam) to 10 (death due to MS). Since the publication of the EDSS in 1983, newer outcome measures have been introduced in clinical trials, including the timed 25-ft walk (T25FW)^3,4 and 9-hole peg test (NHPT),⁵ which focus on walking ability and arm function.

Most RCTs in RRMS use confirmed EDSS worsening as the primary disability outcome. Confirmed disability worsening (CDW) means that a patient's disability is marked as worsened if the EDSS score increases by a full or half-point compared to the value at baseline and remains increased at a confirmation measurement at a later date (for example, 3-month CDW [3M CDW]). Phase 3 treatment trials from the last decade in both RRMS^6,7 and progressive MS^8-10 generally used the 3M CDW on the EDSS as their standard disability outcome measure.

It is unclear whether this definition of CDW is a good reflection of true and patient-relevant irreversible disability, as studies using placebo arms from RRMS RCTs have shown. One seminal article from 20 years ago attempted to get closer to capturing irreversible disability worsening by using the definition of sustained worsening.¹¹ Sustained disability worsening (SDW) means that a patient's disability is marked as worsened if the EDSS score increases by a full or half-point compared to the value at baseline, remains increased at a confirmation measurement at a later date, and remains increased at the last trial visit (for example, 3-month confirmed and sustained disability worsening). The study revealed significant differences between CDW and SDW: 3M CDW predicted 3M SDW in fewer than half of the cases (positive predictive value of confirmed for sustained 0.48 at 2 years). This suggests that 3M CDW, the most commonly used clinical outcome measure, may be a poor measure of irreversible disability worsening.

Another study using the placebo arms of several RRMS RCTs investigated a different aspect of the reliability of the EDSS by comparing rates of disability worsening with similarly defined disability improvement.¹² This study was based on the thought that if the EDSS truly could be used as a tool to measure irreversible disability in MS, the number of patients with EDSS worsening should always be substantially higher than the number of those with similarly defined EDSS improvement. Unexpectedly and somewhat worryingly, however, this investigation showed that placebo-treated trial participants were as likely to improve on the EDSS as they were to worsen throughout the duration of the trials, even when CDW or confirmed improvement was used as the outcome.

Last, current RCTs use the statistical technique of survival analysis to investigate the time to disability worsening and show Kaplan-Meier survival curves to document disability accumulation in trial publications. The choice to use this approach is debatable because Kaplan-Meier time to event analysis techniques count only the occurrence of a worsening event and regard this event as irreversible, so the proportion of patients with disability worsening can only increase over the course of the trial. While this approach may be appropriate to demonstrate a treatment effect, it clearly leads to inflated estimates of disability worsening at the end of the trial. An alternative to this Kaplan-Meier approach of counting worsening events is the cross-sectional approach whereby worsening events at each time point are compared to the baseline measurement only.

In a recent investigation in secondary progressive MS, we found that the EDSS is especially susceptible to measurement error, possibly due to its ordinal design.¹³ Quantitative measures such as the T25FW and NHPT are subject to similar effects, but the degree of measurement error may be lower relative to the disability signal. In this study, we investigate the EDSS as a disability outcome, including different ways that outcome data can be presented and statistically processed, and compare it to the alternative outcome measures T25FW and NHPT. We focus on 3 issues: (1) the difference between CDW and SDW, (2) the comparison of disability worsening vs similarly defined improvement, and (3) the impact of using a Kaplan-Meier vs a cross-sectional presentation of worsening events on overall worsening rates.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

The ethics approval for the original trial is described in the original publication.¹⁴ Ethics approval for this analysis was sought and granted by the University of Calgary Conjoint Health Research Ethics Board and the Institutional Review Board at the University of Alabama at Birmingham.

Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis Dataset

The Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) dataset is described in detail in the original publication of the trial.¹⁴ Briefly, CombiRx was a 3-arm, randomized, double-blind, placebo-controlled, multicenter phase 3 trial of interferon beta plus placebo (25%), glatiramer acetate plus placebo (25%), or the combination of the 2 active agents (50%) in RRMS. The inclusion criteria were age of 18 to 60 years inclusive, a diagnosis of RRMS according to the Poser et al.¹⁵ or 2001 McDonald¹⁶ criteria, an EDSS score of 0 to 5.5 inclusive, and at least 2 exacerbations in the 3 years before inclusion, of which 1 exacerbation could be an MRI change meeting the 2001 McDonald MRI criteria for dissemination in time. Exclusion criteria included any prior use of interferon beta or glatiramer acetate, an acute exacerbation within 30 days of screening, steroid use for acute exacerbations within 30 days of screening, long-term systemic steroid use, evidence of progressive MS, or any previous treatment with natalizumab, cladribine, alemtuzumab, daclizumab, rituximab, or total lymphoid irradiation. After enrollment, patient study visits occurred every 3 months for 36 months in the primary trial. Because all participants were followed up until the last participant completed the 36-month assessment, there are data for up to 7 years in the first participants recruited. At these visits, participants' disability was measured by a blinded physician observer assessing the EDSS and technicians assessing T25FW and NHPT. Additional visits took place at 39 (with measurements of the EDSS, T25FW, and NHPT) and 42 (with only the EDSS measured) months, which enables us to investigate 3M CDW up to month 36 for all outcomes and 6-month CDW (6M CDW) up to month 36 for the EDSS.

Analysis

Disability Worsening and Improvement Criteria

We determined the proportion of patients with significant disability change by comparing baseline and follow-up disability measures. For simplicity, participants missing the disability measure at baseline (EDSS n = 0, T25FW n = 8, NHPT n = 8), the time point of interest, or the corresponding confirmation assessments were excluded from the analysis, and no imputations were done. We defined significant disability change as a ≥20% change from baseline in the time for the T25FW and the NHPT. On the EDSS, we defined it as a change of 1 whole point if the baseline EDSS score was ≤5.0 and of 1 half-point if the baseline EDSS was ≥5.5.

CDW vs SDW

We investigated unconfirmed disability worsening (UDP), 3M CDW, and 6M CDW. For disability worsening to be labeled SDW, 3M CDW or 6M CDW had to be confirmed again at the 36-month visit, following the example of the Liu and Blumhardt¹¹ investigation. We calculated 3M SDW up to month 30 and 6M SDW up to month 27; the last measurements before the confirmation visit overlap with the 36-month visit.

Disability Worsening vs Disability Improvement

For each outcome of disability worsening, we defined a matching improvement outcome. Disability was labeled improved if there was a ≥20% decrease from baseline in the time for the T25FW and the average NHPT. On the EDSS, we defined it as a decrease of 1 whole point if the baseline EDSS score was ≤5.0 and of a half-point if the baseline EDSS score was ≥5.5.

Kaplan-Meier vs Cross-sectional Disability Worsening

To emulate the current standard method of event-driven trials used in RRMS RCTs, we calculated Kaplan-Meier survival curves and present cumulative percentages of progressed patients based on the Kaplan-Meier survival probability. Survival analysis takes each worsening event as irreversible, so that participants were labeled progressed at the first visit at which they fulfilled the worsening criteria or censored at their last study visit. For the cross-sectional presentation, patients were labeled as progressed only at the study visits at which they fulfilled the definition of significant worsening.

Data Availability

Access to the CombiRx dataset can be requested from the Coordinating Center or MS Center at the University of Alabama at Birmingham by completing a data use agreement that is reviewed by a committee overseeing the use of the data. Qualified researchers have or will obtain appropriate Institutional Review Board approval for the study request. Depending on the complexity of the request, researchers may need to cover the cost of producing the deidentified data.

Results

Dataset

The CombiRx dataset contained individual patient-level data on 1,008 patients. Table 1 shows the baseline characteristics of patients included in the dataset. The treatment groups were well balanced with a slightly older average age for the glatiramer acetate group. Given the lack of differences in progression by treatment, we combined the treatment groups and assessed the overall study in subsequent analyses.

Table 1.

Baseline Characteristics of the CombiRx Trial Participants

CDW vs SDW

Table 2 shows the proportion of patients with UDP, CDW, and SDW throughout the trial, thus cross-sectionally at the different time points. Figure 1 shows a comparison of the proportions of patients with confirmed and sustained worsening. Using the EDSS yielded the most worsening events, followed by the T25FW. Only very few trial participants, <5% throughout the trial, had significant worsening on the NHPT.

Table 2.

Percentages of Patients With CDW vs SDW Throughout the Trial

Figure 1. Confirmed vs Sustained Disability Worsening.

Difference between confirmed and sustained disability worsening. For both the Expanded Disability Status Scale (EDSS) (A) and timed 25-ft walk (T25FW) (B), confirmed disability worsening yields more worsening events that sustained disability worsening. There is only a little change in the 9-hole peg test (NHPT) (C), suggesting that it may not be a useful clinical outcome in relapsing-remitting multiple sclerosis trials. CDP = confirmed disability progression; SDP = sustained disability progression; 3M = 3-month.

Throughout the trial, there were substantially fewer sustained than confirmed worsening events, with a positive predictive value of 3M CDW for 3M SDW at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. Whether the confirmation took place at 3 or 6 months made little difference for all outcomes and throughout the trial.

Disability Worsening vs Disability Improvement

Table 3 and Figure 2 show the proportions of patients with worsening of disability compared to similarly defined improvement. The EDSS showed the highest rates of improvement over time. Throughout the 3 years of follow-up, the proportion of patients with worsening on the EDSS was remarkably similar to those with similarly defined improvement. Improvement rates increased in parallel with worsening rates throughout the trial. The T25FW measures showed relatively low proportions of improvement, generally fewer than a third of the worsening events, which remain roughly stable and <10% throughout the trial. There were so few worsening or improvement events in the NHPT measures that their interpretation is difficult. As expected, fewer participants had simultaneous significant worsening or improvement on the EDSS and the T25FW or NHPT than on either measure alone.

Table 3.

Comparison of Worsening vs Similarly Defined Improvement of Disability Throughout the Trial

Figure 2. Disability Worsening vs Similarly Defined Improvement.

Comparison of worsening with similarly defined improvement on the 3 outcome measures shows that the risk of worsening on the Expanded Disability Status Scale (EDSS) is similar to the risk of improvement throughout the trial (A). For the timed 25-ft walk (T25FW), there are meaningfully more worsening than improvement events, suggesting that the T25FW does reflect and measure disability accumulation (C). There is little difference between worsening and improvement on the 9-hole peg test (NHPT); however, this is difficult to interpret given the overall low number of events. 3MC = 3-month confirmed.

Kaplan-Meier vs Cross-sectional Disability Worsening

Table 4 shows the proportion of patients with worsening events based on the method of estimating the worsening at various points in time. Figure 3 shows a comparison between the conservative presentation of disability worsening 3M SDW and the most commonly used method of the cumulative 3M CDW from the Kaplan-Meier method. With the Kaplan-Meier method, the proportion of patients with worsening events steadily increases until it reaches several-fold the number of events seen with the cross-sectional method. For 3M CDW at 36 months, the Kaplan-Meier method yields 2.6-fold higher estimates for the EDSS, 2.9-fold higher estimates for the T25FW, and 5.1-fold higher estimates for the NHPT.

Table 4.

Comparison of Cumulative Disability Worsening (Kaplan-Meier) vs Cross-sectional Presentation of Disability Worsening Events Throughout the Trial

Figure 3. Comparison of Ways to Present Disability Worsening.

Black line shows the currently most commonly used presentation 3-month (3M) confirmed disability worsening based on the Kaplan-Meier curve; red bars show the most conservative 3-month sustained disability worsening presentation. There is a striking difference in worsening events between these 2 ways to present the same data. At 24 months, for example, estimates using the Kaplan-Meier presentation are 2- to 3-fold higher than those using the cross-sectional method for each outcome. EDSS = Expanded Disability Status Scale; NHPT = 9-hole peg test; T25FW = timed 25-ft walk.

Discussion

The measurement of disability worsening in RCTs is difficult, and while it is straightforward to reach consensus about MRI outcomes and a basic definition for a clinical relapse, the correct way of measuring disability worsening in RRMS is open for debate.

Current RCTs in RRMS only very rarely include placebo arms but rather use a comparator arm of participants treated with first-line immunomodulatory treatments such as interferon beta, glatiramer acetate, or teriflunomide. For this study, we were able to use the original trial dataset from CombiRx, a large phase 3 RCT comparing treatment with the first-line immunomodulatory treatments interferon beta (plus placebo), glatiramer acetate (plus placebo), and the combination of interferon beta and glatiramer acetate over 3 years of follow-up.¹⁴ It showed no significant difference between these 3 treatment arms with regard to disability worsening. Because the CombiRx participants were previously treatment naive and treated with first-line immunomodulatory drugs, the data are a good reflection of control arms of modern RRMS RCTs. In addition, CombiRx was a 3-year trial for the primary disability endpoints, providing a longer duration over which to make the comparisons of interest.

The EDSS is the most established outcome measure in all forms of MS. However, this distinction is based largely on history rather than its merits. For many years, the EDSS was the only available outcome measure that regulators would accept. Regulators today still prefer or even mandate the EDSS for registration trials. The availability of the CombiRx dataset made it possible to compare this established endpoint to the newer outcomes of T25FW and NHPT. Since the time of CombiRx, the Neurostatus training implementation and its regularization of the assessment of the EDSS have been widely adopted, which may be reducing some of the measurement error in the EDSS.¹⁷

Overall, our investigation shows that there is relatively little change in disability in treated patients with RRMS over a 3-year period, for example, compared to patients with secondary progressive MS.¹⁸ The established EDSS showed the greatest number of patients with significant worsening of disability for all outcomes, followed by the T25FW. The NHPT changes so little in this population of patients with early RRMS that it may not be a useful outcome measure in this patient group.

The most important long-term clinical goal of an RRMS treatment is to prevent irreversible disability. However, during the 2 or 3 years that a clinical trial continues, it is difficult to be certain that a measured worsening event is truly irreversible. The common practice of using 3M CDW mitigates some of the risk of overestimating the irreversibility of a worsening event. However, Liu and Blumhardt¹¹ showed in their seminal article on placebo arms from 2-year studies that even such a short-term confirmation predicts sustained worsening only in fewer than half of cases. Our investigation of patients treated with first-line agents for 3 years shows that this discrepancy between CDW and SDW remains, even if it is smaller in our study, with a positive predictive value of confirmed for sustained of 0.73 (EDSS 3M CDW for 3M SDW at 24 months). It may be that the higher positive predictive value in CombiRx compared to the Liu and Blumhardt study is due to the high retention rate of >85% and therefore less informative censoring. Given the differences between CDW and SDW, it may be useful to report sustained worsening rates in RRMS RCT publications because they more accurately reflect irreversible disability. However, SDW is likely not a good choice as a standard disability outcome because its reliability is affected by dropout throughout the trial and by the fact that it uses the last trial visit to judge the sustained status, so that the period for which an event is sustained decreases as the trial continues.

A more worrying result of our investigation is our confirmation of the Ebers et al.¹² findings regarding the surprising similarity of rates of disability worsening compared to similarly defined improvement on the EDSS. A useful measure of disability accumulation in MS should be sensitive to the steadily accumulating irreversible disability, and while treatments may indeed make individuals better, which could explain some of these findings, measurement error seems a more likely explanation. To accurately reflect the biological disease process of MS, an outcome measure would ideally show stability or worsening but not robustly defined improvement. Given the chronically progressive nature of the MS disease course, such improvement events must occur due to noise or measurement error. It is possible that our estimates of improvement include recovery from prior relapses appearing as disability worsening. However, if this were true, then treatment trials that show a treatment effect on CDW may only be reiterating the effects on relapses rather than truly assessing irreversible disability worsening. There is evidence that this could be the case because RRMS treatment trials often show nearly double the treatment effects on relapses than on CDW. If a meaningful proportion of the CDW events are due to relapses, then the recovery from these relapses would explain a large part of disability improvement. A recent investigation in 2 RRMS RCT datasets argues against this thought. That study found that most CDW events in the ocrelizumab in RRMS trial⁷ were not associated with protocol-defined relapses. The authors concluded that there was an underlying relapse-independent progression in RRMS, which even challenges the distinction between relapsing and progressive forms of MS.¹⁹ It should be kept in mind, however, that modern trials have a filtering process for relapses. In CombiRx, assessment of relapses included 3 types: protocol defined, non–protocol defined, and suspect. Each of the subsequent definitions of protocol-defined relapses roughly doubled the rate of relapses. This implies that in modern RRMS RCTs, at least some relapses escape the protocol definition for relapse but still exert their effect on CDW.

Our investigation in treated patients and the previous study in placebo arms^12,13 showed that the proportion of patients with improvement on the EDSS was quite similar to those with worsening and that the number of improvement events increased in parallel to the number of worsening events throughout the trial. This is problematic for an outcome aimed at representing the underlying MS disease process. The T25FW shows some similar noise, but improvement events occurred much less commonly, with worsening events outnumbering improvement events 2- to 3-fold (Table 3). Given these results, it would appear that the T25FW is the more robust outcome measure, even if using it yields fewer worsening events. It is possible that the lack of improvement events recorded in this dataset was due to the drugs studied or due to a floor effect for the T25FW in these participants with early RRMS. Nevertheless, the T25FW may be the more useful outcome measure in RRMS RCTs because it has shown similar treatment effects in most studies with effective treatments and is easier to implement, less costly to implement, and clinically meaningful.²⁰ Recent studies in trial datasets from progressive MS RCTs investigated the question of worsening vs similarly defined improvement. One study including 2 placebo arms from large trials in secondary progressive MS also found almost identical rates of worsening and improvement for the EDSS, which increased in parallel with each other throughout the trial, whereas on the T25FW and NHPT, improvement rates remained below or around the 10% level and were fairly stable over 2 years of follow-up.¹³ In contrast to these results in RRMS and secondary progressive MS, a study in a primary progressive trial dataset found improvement events to be much rarer than worsening events for all 3 outcome measures with little difference between them.²¹

The final part of our investigation deals with the analysis method and presentation of disability changes in trial publications. Disability worsening can be presented in a variety of different ways. Currently, EDSS 3M CDW is the most widely used disability outcome in trials. The statistical analysis method used in modern RRMS RCTs, for example, that of ocrelizumab in RRMS,⁷ is a time-to-event analysis. This method uses the time to a worsening event, and if a worsening event occurs, it is treated as irreversible. Consequently, the number of patients who are counted as worsened accumulates over time because it can only increase throughout the course of the trial.

In publications of RRMS RCTs, this Kaplan-Meier approach is presented in survival plots that show relatively high estimates for patients with disability worsening throughout the trial. This presentation may not reflect the clinical meaningfulness mandated by regulators. The reason is that overestimating disability worsening gives a false impression to clinicians and patients of what can be expected in a patient in clinical practice. In this investigation, we wanted to compare this now commonly used Kaplan-Meier approach with the straightforward cross-sectional approach in which we simply count how many patients have worsened disability at each time point, independently of previous measurements. Table 4 shows a comparison of the Kaplan-Meier and the cross-sectional method. In Figure 3, we went a step farther and contrasted the Kaplan-Meier presentation method with the most conservative estimate of 3M SDW. Our analyses show a large and meaningful difference between these methods of presenting the same data. The commonly used Kaplan-Meier approach yields much higher numbers of worsening events compared to 3M CDW or 3M SDW. Because 3M SDW is a closer approximation of irreversible disability, using the Kaplan-Meier approach may give a false and exaggerated impression of disability accumulation in RRMS. Given these considerations, it may be worthwhile to present cross-sectional disability measures alongside of Kaplan-Meier estimates and to use cross-sectional statistical analysis methods alongside time-to-event methods in RRMS RCTs. Recently, Signori et al.²² proposed another method of presenting disability change: rather than presenting disability change longitudinally, they propose reporting the prevalence of disability change in a given time period. This method uses a Kaplan-Meier estimate of the cumulative proportion who improve minus a Kaplan-Meier estimate of those who improved but then lose this improvement, thus yielding the net improvement prevalence at a particular time. While this technique was developed to describe disability improvement in a cohort of 121 patients with MS after autologous hematopoietic stem cell transplantation, it could also be used to describe disability worsening in clinical trials.

Our investigation shows that the current standard outcome measures in RRMS trials, 3M CDW on the EDSS, is more variable and more prone to noise and measurement error than the T25FW. In addition, the standard analysis method used in RRMS RCTs, Kaplan-Meier survival analysis, leads to exaggerated estimates for disability worsening in this patient population. It may be worthwhile to revise the design of RRMS trials to use the T25FW rather than the EDSS as the primary disability outcome measure and to use other methods beside Kaplan-Meier survival analysis to present disability outcome data in RRMS trials.

Glossary

CDW

confirmed disability worsening

CombiRx

Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis

EDSS

Expanded Disability Status Scale

NHPT

9-hole peg test

RCT

randomized controlled trial

RRMS

relapsing-remitting multiple sclerosis

SDW

sustained disability worsening

6M CDW

6-month CDW

3M CDW

3-month CDW

3M SDW

3-month SDW

T25FW

timed 25-ft walk

UDP

unconfirmed disability worsening

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

M.W. Koch received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme, and EMD Serono. J.P. Mostert reports no disclosures. J.S. Wolinsky received compensation for consulting, scientific advisory boards, or other activities from Acorda Therapeutics, Actelion, Alkermes, Avotres, Brainstorm Cell Therapeutics, EMD Serono, GeNeuro, GW Pharma, MedDay Pharmaceuticals, NervGen Pharma Corp, Novartis, Roche/Genentech, Sanofi Genzyme, University of Alabama, and University of Miami; royalties are received through UTHealth for out licensed monoclonal antibodies to Millipore (Chemicon International) Corp. F.D. Lublin received honoraria from consulting agreements and from serving on Scientific Advisory Boards, Data Safety and Monitoring Boards, and speakers’ bureaus for 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, National MS Society, NIH, and Brainstorm Cell Therapeutics. He holds stock options in Avotres. B. Uitdehaag received consultancy fees and/or research support from Biogen, Sanofi Genzyme, EMD Serono, Novartis, Roche, and Teva. G.R. Cutter served on Data and Safety Monitoring boards for AstraZeneca, 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, National Heart, Lung, and Blood Institute (Protocol Review Committee), and National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Units oversight committee), as well as Consulting or Advisory boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Inc, Medimmune, Medday, Neurogenesis Ltd, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, and TG Therapeutics. G.R. Cutter is employed by the University of Alabama at Birmingham and is president of Pythagoras, Inc, a private consulting company located in Birmingham AL. Go to Neurology.org/N for full disclosures.