Management of multiple sclerosis fatigue in the digital age: from assessment to treatment.

Fatigue is one of the most disabling symptoms of Multiple Sclerosis (MS), affecting more than 80% of patients over the disease course. Nevertheless, it has a multi-faceted and complex nature, making its diagnosis, evaluation, and treatment extremely challenging in clinical practice. In the last years, digital supporting tools have emerged to support the care of people with MS. These include not only smartphone or table-based apps, but also wearable devices or novel techniques such as virtual reality. Furthermore, an additional effective and cost-efficient tool for the therapeutic management of people with fatigue is becoming increasingly available. Virtual reality and e-Health are viable and modern tools to both assess and treat fatigue, with a variety of applications and adaptability to patient needs and disability levels. Most importantly, they can be employed in the patient's home setting and can not only bridge clinic visits but also be complementary to the monitoring and treatment means for those MS patients who live far away from healthcare structures. In this narrative review, we discuss the current knowledge and future perspectives in the digital management of fatigue in MS. These may also serve as sources for research of novel digital biomarkers in the identification of disease activity and progression.

Ella versus Simoa Serum Neurofilament Assessment to Monitor Treatment Response in Highly Active Multiple Sclerosis Patients.

The measurement of serum neurofilament light chain (sNfL) is of growing importance in the field of neurology. In the management of multiple sclerosis, it can serve as a useful marker to assess disease activity and treatment response. This paper compares two available methods, namely the Single Molecule Array (Simoa) and the Ella microfluid platform, to measure longitudinal sNfL levels of 42 highly active multiple sclerosis patients treated with alemtuzumab over a period of 36 months. In order to assess the methods agreement, Bland-Altman plots and Passing-Bablok regression were analyzed. Here, we show that despite the fact that Ella measures around 24% higher values than Simoa, both are equally suitable for longitudinal sNfL monitoring.

Comparing the long-term clinical and economic impact of ofatumumab versus dimethyl fumarate and glatiramer acetate in patients with relapsing multiple sclerosis: A cost-consequence analysis from a societal perspective in Germany.

Background: Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective: A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods: An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results: The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0-3 (Δ - 7.5% DMF; Δ - 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ - 4.0% DMF; Δ - 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion: Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.

[The Multiple Sclerosis Health Resource Utilization Survey]. / Der Multiple Sclerosis Health Resource Utilization Survey.

BACKGROUND: In health economic studies, valid and reliable cost data are essential to reach meaningful conclusions. In the case of multiple sclerosis (MS), such studies are often based on primary data for which the underlying survey instruments have not been published. In addition, heterogeneous methods make the comparability and interpretation of such study results difficult. To standardize health economic studies in MS, the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS) was developed, validated and published in a freely accessible format. RESEARCH QUESTION: This review focuses on the MS-HRS. We report on the methodological background of studies on the assessment of cost of illness as well as MS-HRS-based results on the costs of disease dynamics in people with MS. METHODS: This article is based on a selective literature review on the MS-HRS as well as on health economic aspects of cost assessment. RESULTS: The MS-HRS provides a holistic assessment of direct medical, direct non-medical and indirect resource utilization. Within indirect costs, we considered absenteeism, either short term (sick leave) or long term (disability pension), but also presenteeism, which refers to impaired performance during work. Resources were valued at the societal opportunity cost or the best possible approximation. First analyses based on MS-HRS showed that, in addition to inpatient disease severity and clinical course, disease dynamics in form of relapses and progression have enormous socioeconomic implications. CONCLUSION: Valid cost data bring transparency to the economic consequences of diseases. In addition to clinical data, cost data can be used to determine cost-effectiveness and thus reveal opportunities for more efficient patient care. For the case of MS, a freely accessible tool is available for cost assessments.

Real-world patient characteristics, treatment patterns and costs in relapsing multiple sclerosis patients treated with glatiramer acetate, dimethyl fumarate or teriflunomide in Germany.

Aim: To evaluate adherence, healthcare resource utilization (HRU) and costs for glatiramer acetate (GA; injectable), dimethyl fumarate (oral) and teriflunomide (oral) in relapsing multiple sclerosis. Patients & methods: Retrospective analyses of a claims database. Results: Teriflunomide patients were older with more co-morbidities and fewer relapses versus GA and dimethyl fumarate. GA patients were mostly disease-modifying therapies (DMTs)-treatment naive. Treatment adherence was 61-70%. All DMTs reduced HRU versus pre-index. Costs were comparable across cohorts. High adherence reduced hospitalizations and several costs versus low adherers. Conclusion: Adherence rates were high and comparable with all DMTs. Similar (and high) reductions in HRU and costs occurred with all DMTs. High adherence improved economic outcomes versus low adherence. Thus, investing in adherence improvement is beneficial to improve outcomes in relapsing multiple sclerosis.

Drugs used for relapsing multiple sclerosis (RMS) include, among others, glatiramer acetate (injection), dimethyl fumarate (tablet) and teriflunomide (tablet). We compared treatment adherence (based on drug claims), healthcare use and costs for these drugs. Treatment adherence and healthcare use was similar for these three drugs. The need to be in hospital was lower with these drugs compared with not using them. No differences in treatment costs were seen between these drugs. Adherence reduced the need for hospital stays and lowered some costs compared with patients who were classified as adherent. RMS patients should be encouraged to take their RMS medication as prescribed. Improving treatment adherence will have a positive effect on RMS, and a good impact on healthcare use and costs.

Cost of illness in multiple sclerosis by disease characteristics - A review of reviews.

INTRODUCTION: In light of the increasing number of economic burden studies and heterogeneity in methodology and reporting standards, there is a need for robust evidence synthesis on an umbrella review level. AREAS COVERED: We performed the first review of reviews of cost-of-illness studies in multiple sclerosis. Focusing on disaggregated costs by disease characteristics (disability level, relapse, disease course), we also characterized the underlying methodological evidence base of individual (primary) studies. EXPERT COMMENTARY: We identified 17 reviews encompassing 111 unique primary studies, and a high degree of overlap across reviews. Costs were substantial, rising with disability level, relapse episodes, and disease progression. Disability was the key cost driver. Compared to mild disability, total costs for moderate disability were 1.4-2.3-fold higher and 1.8-2.9-fold higher for severe disability. With escalating disability, the share of costs outside the health system (indirect costs, informal care) increasingly outweighed the share of direct medical costs. Of all 111 primary studies, 72% gathered resource use/loss data by patient self-report. Associated costs were mostly reported by disability level (75%), followed by relapse (48%) and disease course (21%). In conclusion, although heterogeneity can make in-depth comparisons of costs across studies impossible, important patterns are broadly apparent.

Improving Digital Patient Care: Lessons Learned from Patient-Reported and Expert-Reported Experience Measures for the Clinical Practice of Multidimensional Walking Assessment.

BACKGROUND: Walking assessment (WA) enables meaningful patient mobility assessment. In this context, patient satisfaction with WA can influence assessment compliance and indirectly affect outcomes. One opportunity to assess patient satisfaction is patient-reported and expert-reported experience measures (PREM). Research on PREMs and WA in daily clinical multiple sclerosis (MS) practice does not exist yet. METHODS: We surveyed people with MS about their experience and assessed healthcare professionals' experience via an interview after patients completed WA. RESULTS: Gait parameters were related to perceived difficulty and strain during performance. Less impaired patients perceived the WA to be less difficult and exhausting but were less likely to use WA results for themselves. Men and patients with higher impairment would perform WA more frequently. A good workflow, a fully performed WA with standardized testing, fully functional measurement systems, support and safeguarding by staff in case of falls, direct feedback after the testing, and patients' motivation are identified by the experts as necessary factors for a successful WA. CONCLUSIONS: As patients' experience has an impact on patients' outcomes, long-term monitoring of PREMs should become an integral part of the healthcare service to identify and avoid problems early.

The Dresden Protocol for Multidimensional Walking Assessment (DMWA) in Clinical Practice.

Walking impairments represent one of the most debilitating symptom areas for people with multiple sclerosis (MS). It is important to detect even slightest walking impairments in order to start and optimize necessary interventions in time to counteract further progression of the disability. For this reason, a regular monitoring through gait analysis is highly necessary. At advanced stages of MS with significant walking impairment, this assessment is also necessary to optimize symptomatic treatment, choose the most suitable walking aid and plan individualized rehabilitation. In clinical practice, walking impairment is only assessed at higher levels of the disease using e.g., the Expanded Disability Status Scale (EDSS). In contrast to the EDSS, standardized functional tests such as walking speed, walking endurance and balance as well as walking quality and gait-related patient-reported outcomes allow a more holistic and sensitive assessment of walking impairment. In recent years, the MS Center Dresden has established a standardized monitoring procedure for the routine multidimensional assessment of gait and balance disorders. In the following protocol, we present the techniques and procedures for the analysis of gait and balance of people with MS at the MS Center Dresden. Patients are assessed with a multidimensional gait analysis at least once a year. This enables long-term monitoring of walking impairment, which allows early active intervention regarding further progression of disease and improves the current standard clinical practice.

Gender disparities in health resource utilization in patients with relapsing-remitting multiple sclerosis: a prospective longitudinal real-world study with more than 2000 patients.

BACKGROUND: For the case of multiple sclerosis, research on gender differences from a health economics perspective has not received much attention. However, cost-of-illness analyses can provide valuable information about the diverse impact of the disease and thus help decision-makers to allocate scarce resources. The aim of this study was to describe healthcare resource use and associated societal costs from a gender perspective. In particular, we aimed to identify how resource utilization potentially differs in certain cost components between men and women. METHODS: Clinical and economic data were extracted from two prospective, multicentre, non-interventional, observational studies in Germany. Information on health resource use was obtained from all patients on a quarterly basis using a validated questionnaire.Cost analyses were conducted from the societal perspective including all direct (healthcare-related) and indirect (work-related) costs, regardless of who bears them. Gender-related differences were analysed by a multivariable generalized linear model with a negative binomial distribution and log link function due to the right-skewed distribution pattern of cost data. In addition, costs for men and women were descriptively analysed within subgroups of two-year disease activity. RESULTS: In total, 2095 patients (women-to-men ratio of 2.7:1) presented a mean age of 41.85 years and a median Expanded Disability Status Scale of 2 (interquartile range 1-3.5) (p > 0.30 for gender-related differences). Women and men did not statistically differ in total quarterly costs (€2329 ± €2570 versus €2361 ± €2612). For both, costs were higher with advancing disease severity and indirect costs were the main societal cost driver. Regarding healthcare-related resources, women incurred higher costs for ambulant consultations [incidence rate ratio (IRR) 1.16, confidence interval (CI) 1.04-1.31], complementary medicine (IRR 2.41, CI 1.14-5.06), medical consumables (IRR 2.53, CI 1.69-3.79) and informal care (IRR 2.79, CI 1.56-5.01). Among indirect costs, we found higher costs for men for presenteeism (IRR 0.62; CI 0.53-0.72) and higher costs for women for disability pension (IRR 1.62; CI 1.23-2.13). CONCLUSIONS: Multiple sclerosis poses a significant economic burden on patients, families and society. While the total economic burden did not differ between male and female patients, we found gender differences in specific cost items that are similar to those in the wider non-MS population.

Why Cognitive-Cognitive Dual-Task Testing Assessment Should Be Implemented in Studies on Multiple Sclerosis and in Regular Clinical Practice.

Cognitive impairment is prevalent and disabling in multiple sclerosis (MS) and is severely impacting quality of life (QoL). Aside its routine assessment in clinical care, it should more often be implemented as endpoint/outcome measure in clinical trials. However, a fundamental aspect-often neglected in clinical practice and clinical trials-is the assessment of multi-tasking and dual-tasking abilities. In this perspective article, we outline why, given the nature of MS, particularly the assessment of "cognitive-cognitive dual-tasking" is relevant in MS. We delineate how knowledge from basic cognitive science can inform the assessment of this important cognitive impairment in MS. Finally, we outline how the assessment of "cognitive-cognitive dual-tasking" can be implemented in computer-based screening tools (e-health devices) that can be used not only in clinical diagnostics but also in clinical trials.

Correction to: Real-World Evidence on the Patterns of Increased Societal Economic Relapse Costs in Patients with Multiple Sclerosis.

In the original version of this article, the title of the article has been published incorrectly.

Real-World Evidence on the Societal Economic Relapse Costs in Patients with Multiple Sclerosis.

BACKGROUND: Relapses are the hallmark of multiple sclerosis (MS). Analyses have shown that the cost of MS increases during periods of relapse. However, results are inconsistent between studies, possibly due to different study designs and the different implications of relapses with respect to patient characteristics. OBJECTIVES: The aims were to estimate and describe direct and indirect relapse costs and to determine differences in costs with respect to patient characteristics. Furthermore, we describe the pharmacoeconomic impact during the relapse follow-up. METHODS: Data were extracted from two German, multicenter, observational studies applying a validated resource costs instrument. Relapse costs were calculated as the difference in quarterly costs between propensity score (PS)-matched patients with and without relapses (1:1 ratio). For relapse active patients, we additionally calculated the difference between quarterly costs prior to and during relapse and determined costs in the post-relapse quarter. RESULTS: Of 1882 patients, 607 (32%) presented at least one relapse. After PS-matching, 597 relapse active and relapse inactive patients were retained. Relapse costs (in 2019 values) ranged between €791 (age 50 + years) and €1910 (disease duration < 5 years). In mildly disabled and recently diagnosed patients, indirect relapse costs (range €1073-€1207) constantly outweighed direct costs (range €591-€703). The increase from prior quarter to relapse quarter was strongest for inpatient stays (+ 366%, €432; p < 0.001), day admissions (+ 228%, €57; p < 0.001), and absenteeism (127%, €463; p < 0.001). In the post-relapse quarter, direct costs and costs of absenteeism remained elevated for patients with relapse-associated worsening. CONCLUSION: A recent diagnosis and mild disability lead to high relapse costs. The results suggest the necessity to incorporate patient characteristics when assessing relapse costs.

The Multiple Sclerosis Health Resource Utilization Survey (MS-HRS): Development and Validation Study.

BACKGROUND: Survey-based studies are frequently used to describe the economic impact of multiple sclerosis (MS). However, there is no validated health resource survey available, preventing comparison of study results and meaningful conclusions regarding the efficiency of long-term treatments. OBJECTIVE: The aim of this study was to develop and validate a tablet- and paper-based MS health resource utilization survey. METHODS: We developed and validated the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS), consisting of 24 cost items for paper and tablet users. Data for validation came from two large German observational studies. Survey practicability was assessed according to the response rate. Reliability was described using test-retest reliability as well as Guttman lambda. Construct validity was assessed as convergent and discriminant validity via correlations with associated patient-reported outcomes and known-group analyses. RESULTS: In total, 2207 out of 2388 (response rate: 92.4%) patients completed the survey and were included to determine psychometric properties. The test-retest reliability had an intraclass correlation coefficient of 0.828 over a course of 3 months. Convergent validity analyses showed that total costs correlated positively with increased disability (r=0.411, P<.001). For discriminant validity, correlations of total costs with the Treatment Satisfaction Questionnaire for Medication ranged from -0.006 (convenience) to -0.216 (effectiveness). The mean annual cost was €28,203 (SD €14,808) (US $39,203; SD US $20,583) with disease-modifying therapies. CONCLUSIONS: The MS-HRS is a multilingual, reliable, valid, electronically available, and easy-to-administer questionnaire providing a holistic cross-sectional and longitudinal assessment of resource utilization in patients with MS.

Balance Testing in Multiple Sclerosis-Improving Neurological Assessment With Static Posturography?

Background: Balance problems can severely limit the quality of life for people with Multiple Sclerosis (pwMS) already in the early stages of the disease. PwMS are usually assessed with the Expanded Disability Status Scale (EDSS), which includes a Romberg test for assessing balance. As the EDSS assessments are subjective to the examining neurologist, the postural stability of pwMS could be objectively quantified by implementing static posturography to detect balance problems and address preventive medical care. Methods: In this cross-sectional study, we added static posturography to the neurological EDSS examination in pwMS and healthy subjects to determine how this technique could supply additional information during the evaluation of the cerebellar functional system of the neurostatus EDSS as clinical outcome already in early disease stages. Static posturography was performed with subjects standing on a force platform while outcome variables such as delineated area, average speed and average sway were obtained. Unpaired t-test as well as (Welch's) analysis of variance (ANOVA) with pairwise post-hoc comparisons according to Games-Howell were used. Spearman rank correlations were implemented to study associations of balance outcomes with EDSS-associated outcomes. Results: A total of 99 pwMS (mean age: 35.01 years; EDSS median: 2.0, 68.69% females) and 30 healthy subjects (mean age: 34.03 years; 70% females) were enrolled. PwMS had worse performances in the three evaluated balance parameters than the healthy group (all p < 0.001). Even patients without postural instability as documented in the Romberg test score of the EDSS assessment showed significantly worse outcome regarding the delineated area [+1.97 cm2, 95%-CI (0.61-3.34); p = 0.002] vs. healthy controls. Similar results were observed for the comparison between pwMS with normal cerebellar function EDSS-systems and healthy subjects. There were significant correlations with the EDSS, cerebellar function score and Romberg test for the delineated area and average speed (r's ranging from 0.330 to 0.537, p < 0.001). Conclusions: Static posturography can complement neurological assessment of EDSS as an objective and quantitative test, especially for MS patients in early stages of the disease.

Correction to: Differentiating societal costs of disability worsening in multiple sclerosis.

The original version of this article unfortunately contained a mistake. The captions of Fig. 2 and Fig. 3 are mismatched.

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management.

BACKGROUND: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. OBJECTIVE: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. METHODS: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. RESULTS: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. CONCLUSION: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Differentiating societal costs of disability worsening in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). However, the economic effect of PIRA and RAW on societal economic costs in patients with MS is not well understood. OBJECTIVE: To determine societal economic costs of patients achieving disease activity free status (DAF) and compare them with those having PIRA and RAW events. METHODS: We used a roving EDSS score analysis to detect PIRA and RAW events with confirmation after at least 6 months. We estimated the age-, gender-, EDSS-adjusted effects of PIRA and RAW on total, direct medical, direct non-medical and indirect societal economic costs. Patients achieving DAF were assigned to as reference. RESULTS: Overall, 1959 patients were analyzed. Total mean quarterly societal economic costs including disease-modifying therapies (DMTs) were 6929€ (SD: 2886€) per patient averaged over a period of 2 years. Excluding DMTs, patients achieving DAF had total mean quarterly costs of 1703€ (SD: 2489€). PIRA caused 29% (IRR: 1.29; CI 1.06-1.50, p < 0.05) higher total costs compared to DAF. On the contrary, RAW increased total costs by factor 1.56 (CI 1.30-1.87, p < 0.001). The effect of PIRA and RAW was striking for direct medical costs which increased by factor 1.48 (95% CI 1.13-1.95, p < 0.01) and 2.25 (95% CI 1.72-2.94, p < 0.001), respectively. CONCLUSION: Disease progression increases societal economic costs significantly. Thus, delaying or even preventing disease progression in MS may reduce the societal economic burden of MS.

Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS.

Objective: To evaluate individual neurofilament light chain (NfL) variation over the time of disease course and the potential of NfL measurement to predict treatment response in patients with MS. Methods: We investigated 15 patients with MS after immune reconstitution treatment with alemtuzumab (ATZ). Monthly serum NfL (sNFL) measurements were correlated with Expanded Disability Status Scale (EDSS), MRI, and relapse activity over an observational period of up to 102 months. Results: Before ATZ, sNfL was significantly increased in correlation with previous relapse/MRI activity. After ATZ, sNfL decreased quickly within the first 6 months. In patients classified as NEDA-3, sNfL declined and persisted at an individual low steady-state level of <8 pg/mL. During follow-up, 34 sNfL peaks with a >20 fold increase could be detected, which were associated with clinical or MRI disease activity. Even patient-reported relapse-suspicious symptoms, which have not been confirmed because relapses were accompanied by sNfL, increase, proposing sNfL assessment as a marker for relapse activity. sNfL started to increase earliest 5 months before, peaked at clinical onset, and recovered within 4-5 months. sNfL presented at higher levels in active patients requiring ATZ retreatment compared with responder patients. During 2 documented pregnancies, sNfL was at a low level, whereas a postpartum transient sNfL increase was seen without any signs of activity. Conclusions: This study applied a long-term high-frequency sNfL assessment in an ATZ-treated cohort, allowing a holistic profiling on the individual level and highlighted that sNfL can eminently complement the individual clinical and MRI monitoring in clinical practice.

Assessment of Clinically Meaningful Improvements in Self-Reported Walking Ability in Participants with Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III ENHANCE Trial of Prolonged-Release Fampridine.

BACKGROUND: Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. OBJECTIVE: The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. METHODS: ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18-70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0-7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5-7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. RESULTS: In total, 636 participants with MS were randomized (PR-fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-fampridine, n = 315; placebo, n = 318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0-7.0] and 5.5 [4.0-7.0], mean [range] MSWS-12 scores were 63.6 [0-100] and 65.4 [0-100], and mean [range] TUG speed was 0.38 [0.0-1.0] and 0.38 [0.0-1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15-2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p < 0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (difference ≥ 3%) by Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term were urinary tract infection and insomnia. There were no seizures reported. CONCLUSIONS: PR-fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in self-reported walking and functional ability in walking-disabled participants with MS. CLINICALTRIALS. GOV IDENTIFIER: NCT02219932.

Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential.

BACKGROUND: Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies. OBJECTIVE: MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants. METHODS: This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24. RESULTS: A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was - 17.57 and - 31.41 nanovolts (nV) in placebo but only - 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV (p = 0.050) and 33.33 nV (p < 0.01), respectively]. CONCLUSION: Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment. REGISTRATION: ClinicalTrials.gov identifier NCT01721161.