Background

We have limited understanding of the risks and impact of COVID-19 in neuroinflammatory diseases (NID) of the central nervous system, particularly among patients receiving disease modifying therapies (DMTs).

Objectives

To report initial results of a planned multi-center year-long prospective study examining the risk and impact of COVID-19 among persons with NID.

Methods

In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of COVID-19 symptoms in persons with and without NID.

Results

Our cohort included 1,115 participants (630 NID, 98% MS; 485 reference) as of April 30, 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. Persons with NID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of persons with NID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (OR_adj=1.45, 1.17-1.84).

Conclusions

Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries that capture an excess of severe cases. Overall, persons with NID seem to have a risk of suspected COVID-19 similar to the reference population.

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

Background

Teriflunomide is a once-daily oral immunomodulator approved for treating relapsing multiple sclerosis (RMS) and relapsing-remitting MS, depending on the local label. Efficacy and safety of teriflunomide were established in the phase 2 (NCT01487096) and phase 3 trials of patients with RMS (TEMSO [NCT00134563], TOWER [NCT00751881], TENERE [NCT00883337]) and clinically isolated syndrome (TOPIC [NCT00622700]). In post hoc analysis of TEMSO patients stratified by age, structural image evaluation using normalization of atrophy (SIENA) revealed teriflunomide 14 mg significantly reduced the percentage of brain volume change in patients aged >25 to ≤35 years (48%; P=0.0217) and >45 to ≤55 years (35%; P=0.0092) versus placebo over 2 years.

Objectives

To analyze the effect of teriflunomide treatment on MRI lesion activity in TEMSO study patients with RMS stratified by age.

Methods

In TEMSO, patients were randomized 1:1:1 to receive either placebo or teriflunomide 7 mg or 14 mg for ≤108 weeks (Year 2). Through Year 2, MRI lesion activity (unique combined active lesions [UCAL], contrast-enhancing T1 weighted lesions [CEL], and T2 weighted [T2w] lesions) and safety were assessed in the SIENA analysis subgroup; patients were stratified by age at baseline: ≥18 to ≤25 years (n=97 [10%]); >25 to ≤35 years (n=283 [29%]); >35 to ≤45 years (n=388 [40%]); and >45 to ≤55 years (n=201 [21%]). P values between treatment groups were determined for MRI lesions using a Poisson model.

Results

Of 1086 patients in the TEMSO core study, 969 (89%) had scans appropriate for SIENA analysis. Compared with placebo, teriflunomide 14 mg significantly reduced the number of UCAL (0.31–1.44 vs 0.92–6.11 lesions; P≤0.0013) and CEL (0.10–0.46 vs 0.54–3.42 lesions; P≤0.0001) per scan across all age groups. In all age groups except the >45 to ≤55 years group, teriflunomide 14 mg significantly reduced the number of T2w lesions (0.50–0.93 vs 1.07–2.80 lesions; P≤0.001) per scan versus placebo. Similar effects on MRI lesion activity were seen with teriflunomide 7 mg versus placebo. Incidence of adverse events (AEs) generally increased with age, with no deaths reported through Year 2.

Conclusions

Over 2 years in TEMSO RMS patients, teriflunomide reduced the number of new MRI lesions versus placebo across age groups. Significant treatment effects were seen with teriflunomide 14 mg across all age groups for UCAL and CEL. Age-related increases in AEs were observed through Year 2.

STUDY SUPPORT: Sanofi.

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved in the United States for relapsing forms of multiple sclerosis (MS). DRF undergoes pre-systemic hydrolysis to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of MMF and are expected to have similar efficacy and safety profiles. In DMF-treated patients, annual rates of brain volume loss over 6 years ranged from -0.19 to -0.37, approaching rates observed in healthy adults (-0.1% to -0.3%).

Objectives

To report percent brain volume change (PBVC) and impact on disability in patients from EVOLVE-MS-1 who have received DRF treatment for up to 2 years.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, phase 3 study to assess the long-term safety, tolerability, and efficacy of DRF 462 mg over 96 weeks in adults with relapsing-remitting MS. Normalized brain volume was assessed at baseline and used to calculate PBVC at Weeks 48 and 96. Confirmed Disability progression (CDP) was measured using the Expanded Disability Status Scale (≥1.5-, ≥1.0-, or ≥0.5-point increase from a baseline score of 0, 1.0-5.5, or 6.0, respectively), with changes sustained for 12 weeks. Estimated proportion of patients with CDP was calculated by the Kaplan-Meier method. No evidence of disease activity (NEDA)-3 was defined as no relapses, no 12-week CDP, and no new/enlarging T2 or new gadolinium-enhancing lesions. This post hoc analysis was conducted in a subgroup of patients who had brain volume scan measurements at baseline, Week 48, and Week 96. The Week 48 and Week 96 visits occurred within an analysis window of ±12 weeks.

Results

As of 2 July 2019, a total of 1051 patients were enrolled in EVOLVE-MS-1 and 365 patients were included in this analysis. Median (range) exposure was 96 (75-100) weeks. Mean (SD) PBVC was -0.36 (0.60) from baseline to Week 48 and -0.35 (0.55) from Week 48 to Week 96. Estimated proportion of patients who were free of CDP was 94.3% at Week 48 and 90.7% at Week 96. The proportion of patients with NEDA-3 at Week 48 and Week 96 was 44.7% (163/365) and 25.2% (91/361), respectively.

Conclusions

Interim findings from the ongoing EVOLVE-MS-1 study demonstrate that yearly PBVC in DRF-treated patients approached the rate observed in healthy adults and was consistent with previous studies of DMF. Most patients remained free of CDP at 2 years.

Supported by: Biogen

Background

Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.

Objectives

To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.

Methods

We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).

Results

To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).

Conclusions

Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

Background

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

Background

The rapidly evolving therapeutic landscape of multiple sclerosis (MS) can make treatment decisions challenging. Novel tools using artificial intelligence (AI) can provide estimations of MS disease progression, which may aid MS therapeutic decisions. However, whether neurologists are willing to utilize information provided by AI-based models when making therapeutic decisions is unknown.

Objectives

To assess whether neurologists rely on clinical judgment (CJ) or quantitative/ qualitative estimations of disease progression provided by hypothetical AI-based models (assuming these models can reliably identify patients at high vs. low risk of disease progression) in simulated MS case scenarios.

Methods

Overall, 231 neurologists with expertise in MS from 20 countries were randomized to receive qualitative (high/low) or quantitative (85-90% vs. 15-20%) information regarding the likelihood of disease progression. Participants were presented with simulated MS case scenarios, and initially made 7 treatment decisions based on the clinical information using CJ. After randomization, participants made 10 treatment decisions using CJ and estimations of disease progression provided by AI models. We evaluated concordance and discordance of therapeutic decisions based on CJ and AI. The primary outcome was the proportion of “optimal” treatment decisions defined as treatment escalation when there was evidence of disease progression or continuing the same treatment when clinically stable. Mixed models were used to determine the effect of randomization group, case risk level, and CJ/AI. Clinicaltrials.gov #NCT04035720

Results

Of 300 neurologists invited to participate, 231 (77.0%) completed the study. Study participants had a mean age (SD) of 44 (±10) years. Of 2310 responses, 1702 (73.7%) were classified as optimal. Optimal decisions were more common for the high-risk vs. low-risk CJ group (84.5% vs 57.6%; p<0.001). There were no differences in the estimated odds of optimal responses between the quantitative vs. qualitative groups (OR 1.09; 95%CI 0.86, 1.39) after adjustment for pre-intervention responses. The estimated odds of optimal decisions for the high-risk vs low-risk CJ group was 2.96 (95%CI: 2.47, 3.56 ) after adjusting for group, pre-intervention responses, and AI-based estimations. For low-risk CJ cases, additional input by AI-based estimations was associated with a lower likelihood of optimal responses; being worse for high-risk vs. low-risk AI estimations (OR 0.235; 95%CI: 0.16, 0.340) adjusting for covariables.

Conclusions

Neurologists were more likely to make optimal treatment choices for high-risk simulated scenarios. The addition of hypothetical information provided by AI-based models- did not improve treatment decisions for low-risk cases. These results provide a framework for understanding therapeutic decision-making in MS neurologists, who are more reliant on their own CJ over AI-based tools.

Background

Cladribine tablets were recently approved for the treatment of RRMS based on evidence from Phase III trials. However, the real-world efficacy and safety of cladribine is unclear.

Objectives

To assess the early real-world safety, tolerability, and efficacy of cladribine tablets in relapsing-remitting multiple sclerosis (RRMS).

Methods

A retrospective chart review was performed to identify RRMS patients who initiated cladribine tablets prior to June 2019 at the MS Clinic in Toronto, Canada. Clinical features, reported side effects, lymphocyte nadir, and clinical/MRI disease activity after treatment initiation were collected.

Results

111 RRMS patients who initiated cladribine tablets were identified, of which 14%(n=16) completed the two annual treatment courses. The median follow-up time after cladribine initiation was 284 days (range 41-512). All patients were previously treated with DMTs with 51%, 25%, 24% on 1, 2, or >3 prior DMTs respectively. The most common reasons prompting the switch to cladribine were: persistent relapses or MRI activity (57%, n=63), intolerance to prior DMT/patient choice (19, n=21) or AE related to prior DMT (13%, n=14). At a mean of 2.3 months after cladribine initiation, 10% (n=11) had one or more relapse. 65% (n=72) of patients showed evidence of lymphopenia at any time point after cladribine initiation: 16%(n=18) were grade 3 and 2%(n=2) demonstrated grade 4 lymphopenia. The mean time to lymphocyte nadir was 3.6 months. The most commonly reported side effects within 3 months of cladribine initiation were: flu/cold-like symptoms (8%) and nausea (6%). Three cases of herpes zoster infection were reported. There have been no treatment discontinuations to date.

Conclusions

Our early real-world experience demonstrates that cladribine tablets are generally well-tolerated and safe, with observed adverse effects consistent with what was reported in clinical trials. Prospective follow-up of this cohort will enable an assessment of the on-going safety and efficacy of cladribine in the real-world.

Background

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

Background

Therapeutic inertia (TI) is a worldwide phenomenon affecting physicians who manage patients with chronic conditions. Previous studies in Multiple Sclerosis (MS) showed TI affects 60 to 90% of neurologists and up to 25% of daily treatment decisions.

Objectives

To determine the most important factors and levels of attributes associated with treatment escalation in an international sample of neurologists with expertise in the management of patients with MS.

Methods

We conducted an international study comprised of 300 neurologists with expertise in MS from 20 countries (Europe: 59.4%, Asia/Australia: 18.3%, America: 22.3%). Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Patient profiles included information on age, sex, previous MS history of relapses, MRI findings, desire for pregnancy, and other relevant details. We used disaggregated discrete choice experiments (a conjoint analysis), which is a standard technique used in economic research to estimate the weight of factors and attributes (e.g. categories) affecting physicians’ decisions when considering treatment selection by asking respondents to choose between pairs of options. In our study, participants were asked to select the ideal candidate (Patient A, B or neither) for treatment escalation (from first-line to second-line therapies- eg. Fingolimod, Cladribine, Monoclonal antibodies).

Results

Of 300 neurologists invited to participate, 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per week by each neurologist was 18 (±16).

The top 3 factors (relative importance) associated with treatment escalation were: previous relapses (20%), EDSS (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (<3%) in treatment escalation.

Participants were 13% less likely to escalate treatment for patients with EDSS >7.0 (compared to EDSS <6.0), whereas symptom severity during most recent relapse and higher number of MRI lesions at 1 year were each associated with 6% higher likelihood of treatment escalation.

We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-specialists and participants practicing in European vs. non-European countries.

Conclusions

This is the first study applying a conjoint design to assess factors associated with treatment escalation and therapeutic inertia in neurologists caring for people living with MS. Our results provide critical information on factors influencing neurologists’ treatment decisions and should be applied to continuing medical education strategies.

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

Background

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

Background

Cladribine tablets were approved in Canada in November 2017. All patients prescribed cladribine tablets in Canada are enrolled upon their consent in the adveva patient support program (PSP), which provides drug education, assistance with reimbursement and patient support services.

Objectives

To examine the demographics and treatment history of patients initiating cladribine tablets in Canada, assess the discontinuation rate over the two-year treatment and describe reported adverse events (AEs).

Methods

Analysis of data routinely collected by adveva nurses and all reported AEs from Dec2017 to Jan2020. Patients were included if they consented to enroll in the adveva PSP. They were contacted at enrollment and periodically therafter. Follow-up stopped when treatment was completed/discontinued.

Results

Overall, 1864 patients enrolled in the program; 1373 were female (74.4%) and mean age was 41.54 years (standard deviation [SD]: 10.34). None of the patients were treatment naïve; most (n=1191; 63.9%) had received only one prior disease modifying drug (DMD). The most recent prior DMDs were glatiramer acetate (23.1%), dimethyl fumarate (20.4%), teriflunomide (16.5%), fingolimod (10.9%), and subcutaneous interferon beta-1a (10.4%). Of 1864 enrolled, 1679 (90.1%) had completed pre-treatment evaluation. Of those, 1415 (84.3%) started year-1. Among those, 483 (34.1%) started year-2 and 394 (27.8%) completed it. Mean time to year-2 initiation was 12.75 (SD: 1.27) months. Among all patients who had started year-1 treatment, 38 (2.69%) reported discontinuation. Among those, 26.3% discontinued within <6 months, 52.6% between 6-12 months and 21.1% at ≥12 months. Main reported reasons were: 28.9% unknown, 21.1% AE other than flu-like syndrome and lymphopenia, 18.4% worsening disease, 10.5% patients decision, and 10.5% family planning/pregnant. A total of 843 patients (59.6%) reported at least one AE. Among the total AEs report (n= 3525)the most frequent were fatigue (8.0%), headache (5.4%), nausea (4.7%), and lymphocytopenia (2.5%).

Conclusions

The Canadian adveva program presented a high enrolment rate. Cladribine tablets were associated with a high continuation rate and most patients successfully self-adminstered the drug. Reported adverse events were not severe.

Background

Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited.

Objectives

We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.

Methods

We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS).

Results

As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow-up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%).

Conclusions

This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setting. First-line use was uncommon. ARR was low, consistent with clinical trial data, and early discontinuations were very rare.

Background

Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (PwMS). Currently, no treatments exist that substantially modify the course of clinical progression in MS, one of the greatest unmet needs in clinical practice. Characterizing the determinants of clinical progression is essential for the development of novel therapeutic agents and treatment approaches that target progression in PwMS.

Objectives

The overarching aim of CanProCo is to evaluate a wide spectrum of factors associated with the onset and rate of disease progression in MS, and to describe how these factors interact with one another to influence progression.

Methods

CanProCo is a prospective, observational cohort study aiming to recruit 1000 individuals with radiologically-isolated syndrome (RIS), relapsing-remitting MS (RRMS), and primary-progressive MS (PPMS) within 10-15 years of disease onset, and 50 healthy controls (HCs) from five large academic MS centers in Canada. Participants undergo detailed clinical evaluations annually. A subset of participants enrolled within 5-10 years of disease onset (n=500) also have blood, cerebrospinal fluid, and MRIs collected facilitating study of biological measures (e.g. single-cell RNA-sequencing[scRNASeq]), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and environmental factors as determinants contributing to the differential progression in MS.

Results

Recruitment commenced in April/May 2019 and n=536 patients have been recruited to date (RRMS=457, PPMS=35, RIS=25, HC=19). Baseline age, sex distribution, and Expanded Disability Status Scale (EDSS) scores (median, range) of each subgroup are: RRMS=38 years, 73% female, EDSS=1.5 (0-6.0); PPMS=52 years, 40% female, EDSS=4.0 (1.5-6.5); RIS=41 years, 68% female, EDSS=0 (0-3.0); HC=37 years, 63% female. Recruitment has surpassed the 50% target but has been paused due to the COVID-19 pandemic. scRNASeq on frozen blood samples has been validated.

Conclusions

Halting the progression of MS is a fundamental clinical need to improve the lives of PwMS. Achieving this requires leveraging transdisciplinary approaches to better characterize mechanisms underlying clinical progression. CanProCo is the first prospective cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Background

Evidence suggests that healthcare providers specializing in MS (HCP-MS) face an evolving treatment and clinical landscape, with a patient population who requires advanced care to manage the many facets of their condition. In this context, the gaps in knowledge, skill and confidence that may impact HCP-MS’ ability to make clinical decisions and optimize patient care need to be assessed.

Objectives

To assess HCP-MS’ clinical practice gaps and challenges, their associated causes, and impact on the care of people with MS.

Methods

In a mixed-methods study, 333 neurologists and 135 advanced practice nurses in Canada, France, Germany, Italy, Spain, the United Kingdom and the United States were interviewed or surveyed. Qualitative data were analysed thematically. Quantitative data were analysed using ANOVA and Chi-squares for comparison by country, years of experience, practice setting and MS certification status. Results were triangulated with data from the literature.

Results

Qualitative data indicate current guidelines are perceived as insufficient to manage the complex needs of people with MS. Tests of cognitive function are perceived as time-consuming, potentially inaccurate, and should preferably be administered by rehabilitation specialists or psychiatrists. Survey data indicate 42% of neurologists and 61% of nurses have no or only basic skills in administering such tests. A further 44% and 67%, respectively, have no/basic skills interpreting these tests. HCP-MS reported additional factors that may impede clinical decision-making for optimal personalized care. Thirty-nine percent of neurologists (higher in the UK, Canada and Italy, p<.05) and 44% of nurses report no/basic skills integrating patient goals into treatment recommendations. No/basic skills to make decisions about disease modifying treatment (DMT) sequencing was reported by 28% of neurologists and 62% of nurses. Some adverse events were considered challenging: HCP-MS reported no/basic skills identifying (51%) and managing (61%) infections, and no/basic skills identifying (47%) and managing (56%) cardiac issues.

Conclusions

HCP-MS face significant challenges trying to provide best care to people with MS. There appears to be a need to improve skills in cognitive testing, DMT decision-making, treatment monitoring, and patient communication. Professional development activities should focus on the heterogeneity of MS presentations and optimize different competencies required.

Disclosure: This project has been supported by educational funds from Merck KGaA, Darmstadt, Germany.

Abstract

The spinal cord and optic nerve are commonly involved structures in multiple sclerosis (MS) and imaging these regions can have clinical utility in people with MS (pwMS). Here, we discuss recent consensus recommendations regarding imaging the spinal cord and optic nerve in the diagnosis, prediction, and monitoring of pwMS. Standardized protocols are recommended to optimize lesion detection and acquisition time. A spinal cord MRI is routinely recommended for the diagnosis of pwMS. For disease monitoring in established MS, a spinal cord MRI is not routinely recommended, but can be useful in specific situations. Imaging the optic nerve is not routinely recommended for diagnosis or disease monitoring in pwMS. However, in specific situations, including pediatric cases and in patients presenting with atypical symptoms, imaging this region can have clinical utility. These recommendations are intended to provide practical guidance on the effective use of spinal cord and optic nerve MRI in MS clinical practice.

Background

Teriflunomide is a once-daily oral immunomodulator approved for treating relapsing multiple sclerosis (RMS) and relapsing-remitting MS, depending on the local label. Efficacy and safety of teriflunomide were established in the phase 2 (NCT01487096) and phase 3 trials of patients with RMS (TEMSO [NCT00134563], TOWER [NCT00751881], TENERE [NCT00883337]) and clinically isolated syndrome (TOPIC [NCT00622700]). In post hoc analysis of TEMSO patients stratified by age, structural image evaluation using normalization of atrophy (SIENA) revealed teriflunomide 14 mg significantly reduced the percentage of brain volume change in patients aged >25 to ≤35 years (48%; P=0.0217) and >45 to ≤55 years (35%; P=0.0092) versus placebo over 2 years.

Objectives

To analyze the effect of teriflunomide treatment on MRI lesion activity in TEMSO study patients with RMS stratified by age.

Methods

In TEMSO, patients were randomized 1:1:1 to receive either placebo or teriflunomide 7 mg or 14 mg for ≤108 weeks (Year 2). Through Year 2, MRI lesion activity (unique combined active lesions [UCAL], contrast-enhancing T1 weighted lesions [CEL], and T2 weighted [T2w] lesions) and safety were assessed in the SIENA analysis subgroup; patients were stratified by age at baseline: ≥18 to ≤25 years (n=97 [10%]); >25 to ≤35 years (n=283 [29%]); >35 to ≤45 years (n=388 [40%]); and >45 to ≤55 years (n=201 [21%]). P values between treatment groups were determined for MRI lesions using a Poisson model.

Results

Of 1086 patients in the TEMSO core study, 969 (89%) had scans appropriate for SIENA analysis. Compared with placebo, teriflunomide 14 mg significantly reduced the number of UCAL (0.31–1.44 vs 0.92–6.11 lesions; P≤0.0013) and CEL (0.10–0.46 vs 0.54–3.42 lesions; P≤0.0001) per scan across all age groups. In all age groups except the >45 to ≤55 years group, teriflunomide 14 mg significantly reduced the number of T2w lesions (0.50–0.93 vs 1.07–2.80 lesions; P≤0.001) per scan versus placebo. Similar effects on MRI lesion activity were seen with teriflunomide 7 mg versus placebo. Incidence of adverse events (AEs) generally increased with age, with no deaths reported through Year 2.

Conclusions

Over 2 years in TEMSO RMS patients, teriflunomide reduced the number of new MRI lesions versus placebo across age groups. Significant treatment effects were seen with teriflunomide 14 mg across all age groups for UCAL and CEL. Age-related increases in AEs were observed through Year 2.

STUDY SUPPORT: Sanofi.

Background

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

Background

Cladribine tablets were approved in Canada in November 2017. All patients prescribed cladribine tablets in Canada are enrolled upon their consent in the adveva patient support program (PSP), which provides drug education, assistance with reimbursement and patient support services.

Objectives

To examine the demographics and treatment history of patients initiating cladribine tablets in Canada, assess the discontinuation rate over the two-year treatment and describe reported adverse events (AEs).

Methods

Analysis of data routinely collected by adveva nurses and all reported AEs from Dec2017 to Jan2020. Patients were included if they consented to enroll in the adveva PSP. They were contacted at enrollment and periodically therafter. Follow-up stopped when treatment was completed/discontinued.

Results

Overall, 1864 patients enrolled in the program; 1373 were female (74.4%) and mean age was 41.54 years (standard deviation [SD]: 10.34). None of the patients were treatment naïve; most (n=1191; 63.9%) had received only one prior disease modifying drug (DMD). The most recent prior DMDs were glatiramer acetate (23.1%), dimethyl fumarate (20.4%), teriflunomide (16.5%), fingolimod (10.9%), and subcutaneous interferon beta-1a (10.4%). Of 1864 enrolled, 1679 (90.1%) had completed pre-treatment evaluation. Of those, 1415 (84.3%) started year-1. Among those, 483 (34.1%) started year-2 and 394 (27.8%) completed it. Mean time to year-2 initiation was 12.75 (SD: 1.27) months. Among all patients who had started year-1 treatment, 38 (2.69%) reported discontinuation. Among those, 26.3% discontinued within <6 months, 52.6% between 6-12 months and 21.1% at ≥12 months. Main reported reasons were: 28.9% unknown, 21.1% AE other than flu-like syndrome and lymphopenia, 18.4% worsening disease, 10.5% patients decision, and 10.5% family planning/pregnant. A total of 843 patients (59.6%) reported at least one AE. Among the total AEs report (n= 3525)the most frequent were fatigue (8.0%), headache (5.4%), nausea (4.7%), and lymphocytopenia (2.5%).

Conclusions

The Canadian adveva program presented a high enrolment rate. Cladribine tablets were associated with a high continuation rate and most patients successfully self-adminstered the drug. Reported adverse events were not severe.

Background

Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (PwMS). Currently, no treatments exist that substantially modify the course of clinical progression in MS, one of the greatest unmet needs in clinical practice. Characterizing the determinants of clinical progression is essential for the development of novel therapeutic agents and treatment approaches that target progression in PwMS.

Objectives

The overarching aim of CanProCo is to evaluate a wide spectrum of factors associated with the onset and rate of disease progression in MS, and to describe how these factors interact with one another to influence progression.

Methods

CanProCo is a prospective, observational cohort study aiming to recruit 1000 individuals with radiologically-isolated syndrome (RIS), relapsing-remitting MS (RRMS), and primary-progressive MS (PPMS) within 10-15 years of disease onset, and 50 healthy controls (HCs) from five large academic MS centers in Canada. Participants undergo detailed clinical evaluations annually. A subset of participants enrolled within 5-10 years of disease onset (n=500) also have blood, cerebrospinal fluid, and MRIs collected facilitating study of biological measures (e.g. single-cell RNA-sequencing[scRNASeq]), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and environmental factors as determinants contributing to the differential progression in MS.

Results

Recruitment commenced in April/May 2019 and n=536 patients have been recruited to date (RRMS=457, PPMS=35, RIS=25, HC=19). Baseline age, sex distribution, and Expanded Disability Status Scale (EDSS) scores (median, range) of each subgroup are: RRMS=38 years, 73% female, EDSS=1.5 (0-6.0); PPMS=52 years, 40% female, EDSS=4.0 (1.5-6.5); RIS=41 years, 68% female, EDSS=0 (0-3.0); HC=37 years, 63% female. Recruitment has surpassed the 50% target but has been paused due to the COVID-19 pandemic. scRNASeq on frozen blood samples has been validated.

Conclusions

Halting the progression of MS is a fundamental clinical need to improve the lives of PwMS. Achieving this requires leveraging transdisciplinary approaches to better characterize mechanisms underlying clinical progression. CanProCo is the first prospective cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Abstract

The spinal cord and optic nerve are commonly involved structures in multiple sclerosis (MS) and imaging these regions can have clinical utility in people with MS (pwMS). Here, we discuss recent consensus recommendations regarding imaging the spinal cord and optic nerve in the diagnosis, prediction, and monitoring of pwMS. Standardized protocols are recommended to optimize lesion detection and acquisition time. A spinal cord MRI is routinely recommended for the diagnosis of pwMS. For disease monitoring in established MS, a spinal cord MRI is not routinely recommended, but can be useful in specific situations. Imaging the optic nerve is not routinely recommended for diagnosis or disease monitoring in pwMS. However, in specific situations, including pediatric cases and in patients presenting with atypical symptoms, imaging this region can have clinical utility. These recommendations are intended to provide practical guidance on the effective use of spinal cord and optic nerve MRI in MS clinical practice.

Abstract

The spinal cord and optic nerve are commonly involved structures in multiple sclerosis (MS) and imaging these regions can have clinical utility in people with MS (pwMS). Here, we discuss recent consensus recommendations regarding imaging the spinal cord and optic nerve in the diagnosis, prediction, and monitoring of pwMS. Standardized protocols are recommended to optimize lesion detection and acquisition time. A spinal cord MRI is routinely recommended for the diagnosis of pwMS. For disease monitoring in established MS, a spinal cord MRI is not routinely recommended, but can be useful in specific situations. Imaging the optic nerve is not routinely recommended for diagnosis or disease monitoring in pwMS. However, in specific situations, including pediatric cases and in patients presenting with atypical symptoms, imaging this region can have clinical utility. These recommendations are intended to provide practical guidance on the effective use of spinal cord and optic nerve MRI in MS clinical practice.