Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): Single-center evidence from 6,779 sessions
INTRODUCTION/BACKGROUND:The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS. OBJECTIVE:To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials. METHODS:We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18-78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs). RESULTS:No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity. CONCLUSIONS:At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.
Risk of COVID-19 infection and severe disease in MS patients on different disease-modifying therapies
BACKGROUND:The risk of SARS-CoV-2 infection and severity with disease modifying therapies (DMTs) in multiple sclerosis (MS) remains unclear, with some studies demonstrating increased risks of infection with B-cell-depleting (anti-CD20) therapies and severity, while others fail to observe an association. Most existing studies are limited by a reliance on 'numerator' data (i.e., COVID-19 cases) only. OBJECTIVE:To assess the risks of COVID-19 by DMT, this study aimed to assess both 'numerator' (patients with SARS-CoV-2 infection) and 'denominator' data (all patients treated with DMTs of interest) to determine if any DMTs impart an increased risk of SARS-CoV-2 infection or disease severity. METHODS:We systematically reviewed charts and queried patients during clinic encounters in the NYU MS Comprehensive Care Center (MSCCC) for evidence of COVID-19 in all patients who were on the most commonly used DMTs in our clinic (sphingosine-1-phosphate receptor (S1P) modulators (fingolimod/siponimod), rituximab, ocrelizumab, fumarates (dimethyl fumarate/diroximel fumarate), and natalizumab). COVID-19 status was determined by clinical symptoms (CDC case definition) and laboratory testing where available (SARS-CoV-2 PCR, SARS-CoV-2 IgG). Multivariable analyses were conducted to determine predictors of infection and severe disease (hospitalization or death) using SARS-CoV-2 infected individuals per DMT group and all individuals on a given DMT as denominator. RESULTS:We identified 1,439 MS patients on DMTs of interest, of which 230 had lab-confirmed (nâ€¯=â€¯173; 75.2%) or suspected (nâ€¯=â€¯57; 24.8%) COVID-19. Infection was most frequent in those on rituximab (35/138; 25.4%), followed by fumarates (39/217; 18.0%), S1P modulators (43/250; 17.2%), natalizumab (36/245; 14.7%), and ocrelizumab (77/589; 13.1%). There were 14 hospitalizations and 2 deaths. No DMT was found to be significantly associated with increased risk of SARS-CoV-2 infection. Rituximab was a predictor of severe SARS-CoV-2 infection among patients with SARS-CoV-2 infection (OR 6.7; 95% CI 1.1-41.7) but did not reach statistical significance when the entire patient population on DMT was used (OR 2.8; 95% CI 0.6-12.2). No other DMT was associated with an increased risk of severe COVID-19. CONCLUSIONS:Analysis of COVID-19 risk among all patients on the commonly used DMTs did not demonstrate increased risk of infection with any DMT. Rituximab was associated with increased risk for severe disease.
A novel disease specific scale to characterize the symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis: A real-world study
BACKGROUND:Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE:To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS:This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS:300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): meanÂ±SD symptom score of 54.6Â Â±Â 17.8 vs. 67.0Â Â±Â 19.7, p<Â 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean Â± SD symptom score of 62.8Â Â±Â 16.9 vs. 52.1Â Â±Â 19.3, p<Â 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2Â Â±Â 19.2 vs. 55.9Â Â±Â 18.6; p<Â 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION/CONCLUSIONS:Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.
Association Between Time Spent Outdoors and Risk of Multiple Sclerosis
OBJECTIVE:This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of paediatric-onset multiple sclerosis (MS). METHODS:Children with MS and controls recruited from multiple centres in the USA were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year prior to birth and the year prior to diagnosis, with MS risk, adjusting for sex, age, race, birth season, child's skin colour, mother's education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection. RESULTS:, 95%CI 0.62-0.94, p=0.01). CONCLUSIONS:If this is a causal association, spending more time in the sun during summer may be strongly protective against developing paediatric MS, as well as residing in a sunnier location.
No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS
BACKGROUND:Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS:Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EIDÂ +Â SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS:The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; pÂ =Â 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; pÂ =Â 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; pÂ =Â 0.566) and -0.11% (-0.25%, -0.10%; pÂ =Â 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p<0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p<0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; pÂ =Â 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p<0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS:The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.
Effect of fingolimod on health-related quality of life in paediatric patients with multiple sclerosis: results from the phase 3 PARADIGMS Study
Background/UNASSIGNED:. Methods/UNASSIGNED:Patients with PoMS (N=215; aged 10-<18 years) were randomised to once-daily oral fingolimod (N=107) or once-weekly intramuscular IFN Î²-1a (N=108). HRQoL outcomes were assessed using the 23-item Pediatric Quality of Life (PedsQL) scale that comprises Physical and Psychosocial Health Summary Scores (including Emotional, Social and School Functioning). A post hoc inferential analysis evaluated changes in self-reported or parent-reported PedsQL scores from baseline up to 2 years between treatment groups using an analysis of covariance model. Results/UNASSIGNED:Treatment with fingolimod showed improvements versus IFN Î²-1a on the PedsQL scale in both the self-reported and parent-reported Total Scale Scores (4.66 vs -1.16, pâ‰¤0.001â€‰and 2.71 vs -1.02, pâ‰¤0.05, respectively). The proportion of patients achieving a clinically meaningful improvement in the PedsQL Total Scale Score was two times higher with fingolimod versus IFN Î²-1a per the self-reported scores (47.5% vs 24.2%, p=0.001), and fingolimod was favoured versus IFN Î²-1a per the parent-reported scores (37.8% vs 24.7%, p=non-significant). Group differences in self-reported Total Scale Scores in favour of fingolimod were most pronounced among patients who had â‰¥2 relapses in the year prior to study entry or who showed improving or stable Expanded Disability Status Scale scores during the study. Conclusion/UNASSIGNED:Fingolimod improved HRQoL compared with IFN Î²-1a in patients with PoMS as evidenced by the self-reported and parent-reported PedsQL scores.
Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age
BACKGROUND:Multiple sclerosis (MS) patients with stable disease course might view continued treatment as unnecessary. However, guidelines regarding treatment discontinuation are currently lacking. OBJECTIVE:To assess the clinical course after treatment discontinuation in MS patients with long disease duration. METHODS:Patients who discontinued disease-modifying treatments (DMTs) and not resume treatment (nÂ =Â 216) were extracted from New York State MS Consortium (NYSMSC) and followed across three time points (average 4.6 years). Stable course was defined as no change in Expanded Disability Status Scale (EDSS) scores (<1.0 increase if EDSS<6.0 or <0.5-point increase if EDSSâ‰¥6.0) from baseline (time 1) to DMT discontinuation (time 2). Both stable and worsening MS patients were later assessed again after the DMT discontinuation (time 3). Additional analyses were performed based on disease subtype, type of medication, age cut-off of 55 and EDSS of 6.0. RESULTS:From the cohort of 216 MS patients who discontinued DMT, 161 (72.5%) were classified as stable before DMT discontinuation. After DMT discontinuation, 53 previously stable MS patients (32.9%) experienced disability worsening/progression (DWP). 29.2 and 40% of previously stable RRMS and SPMS respectively had DWP after DMT discontinuation. Over two years after DMT discontinuation, the rate of DWP was similar between patients younger or older than 55 years (31.1% vs 25.9%, respectively). MS patients with EDSSâ‰¥6.0 had greater DWP when compared to less disabled patients while remaining on therapy as well as after discontinuation (40.7% vs 15.4%, pÂ <Â 0.001 and 39.6% vs 15.2%, pÂ <Â 0.001, respectively). CONCLUSION/CONCLUSIONS:MS patients with stable disease course experience DWP after treatment discontinuation, with no clear relation to age and disease subtype. Patients with EDSSâ‰¥6.0 are at higher risk for DWP.
Telehealth transcranial direct current stimulation for recovery from Post-Acute Sequelae of SARS-CoV-2 (PASC) [Letter]
Demographic features and clinical course of pediatriconset MS patients on newer disease-modifying treatments [Meeting Abstract]
Introduction: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Data regarding the demographic features and clinical outcomes of POMS patients treated with these DMTs could help guide future treatment algorithms in this population. Objective/Aims: To describe the demographic features and clinical and radiologic course of POMS patients on the commonly used newer DMTs within the US Network of Pediatric MS Centers.
Method(s): This is an analysis of prospectively collected data from patients seen at 11 regional pediatric MS referral centers participating in the US Network of Pediatric MS Centers. POMS patients who initiated treatment between 10- & lt;18 years with dimethyl fumarate, fingolimod, natalizumab, rituximab or ocrelizumab were included and analyzed as individual cohorts.
Result(s): 168 patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2-16.5 years (median EDSS from 1.0-2.0), with 96-100% of patients at or above Tanner Stage 2. Disease duration at time of initiation of index DMT ranged from 1.1-1.6 years, while treatment duration with the index DMT ranged from 1.1-2.2 years. Mean number of relapses in the year prior to initiating index DMT ranged from 0.4-1.0. Mean number of relapses while on index DMT ranged from 0.1-0.4. New T2 and enhancing lesions occurred in 77-88% and 55-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 7-52% and 11-35% patients, respectively.
Conclusion(s): Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit in a large number of POMS patients, which can be used to guide future studies in this population
Innovative phase 3 NEOS study design evaluating efficacy and safety of ofatumumab and siponimod versus fingolimod in paediatric multiple sclerosis [Meeting Abstract]
Introduction: Patients (pts) with paediatric multiple sclerosis (PedMS) have higher relapse rates and radiological activity, accumulating disability at a younger age vs adult-onset MS. There are challenges in conducting clinical trials for PedMS due to the low number of available pts and competing trials. Moreover, testing a new drug vs placebo or low efficacy control poses ethical concerns due to the high disease activity. Few Phase 3 studies have assessed the efficacy/safety of disease-modifying therapies (DMTs) in PedMS; PARADIGMS demonstrated a significant reduction in annualised relapse rate (ARR) for fingolimod vs interferon (IFN)beta-1a in PedMS. A large unmet need for new studied treatment options for PedMS remains.
Objective(s): To present the innovative Bayesian design of the Phase 3 NEOS study aimed to assess the efficacy and safety of ofatumumab and siponimod in PedMS.
Method(s): NEOS is a 2-year, randomised, 3-arm, double-blind, triple-dummy, parallel-group, multicentre, active-comparator, controlled global study comparing ofatumumab and siponimod vs fingolimod in the core part, followed by 2-5 years of an openlabel extension part. Eligibility criteria include pts aged 10 to <18 years, with Expanded Disability Status Scale score 0-5.5 who had experienced >=1 relapse in the last year or >=2 relapses in last 2 years or evidence of >=1 gadolinium-enhancing lesions on MRI within 12 months before randomisation. The primary objective is to demonstrate the non-inferiority (NI) of ofatumumab and siponimod vs fingolimod, assessed by ARR up to 2 years, and will be analysed using a Bayesian negative binomial regression model. This model incorporates information from historical studies on all 3 treatments to reduce the required sample size. The key secondary objective is to demonstrate superiority of ofatumumab and siponimod vs historical IFNbeta-1a data, assessed by ARR. Other endpoints include number of new/newly enlarging T2 lesions on MRI per year, serum neurofilament light chain and safety/tolerability. Randomisation of ~180 pts (n=60 per arm) will provide >80% power for the demonstration of NI (margin of 2.0) for each test treatment vs fingolimod.
Result(s): Study design will be presented at the congress.
Conclusion(s): The innovative NEOS study design does not include placebo or low efficacy controls and thus offers PedMS pts a DMT already shown to be highly effective in adults. NEOS has the potential to bring 2 new future treatment options-ofatumumab and siponimod for PedMS