Active Relapsing Multiple Sclerosis Research Articles

Cladribine effects on patient-reported outcomes and their clinical and biometric correlates in highly active relapsing multiple sclerosis at first switch: the observational, multicenter, prospective, phase IV CLADFIT-MS study.

Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients' lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient's experience and self-assessed impact of treatment on daily life.

Naujųjų anti-CD20 monokloninių antikūnų vaidmuo gydant itin aktyvią recidyvuojančiąją remituojančiąją išsėtinę sklerozę: ofatumumabo klinikinis efektyvumas ir saugumas

Multiple sclerosis is the most common chronic demyelinating neurodegenerative central nervous system disease among young adults. Considering its extent in a relatively young population, multiple sclerosis determines a significant socioeconomic burden to the society due to the cost of disease modifying treatment and a lower working capacity of patients and their caregivers. It is important to control neuroinflammation in the central nervous system caused by the pathologic activity of immune cells by considering a high efficacy treatment early in the disease course in order to prevent accumulation of neurological damage and to improve long term outcomes. According to the newest clinical studies, anti-CD20 therapies have proven their effectiveness and safety in active relapsing multiple sclerosis treatment: since 2018, ocrelizumab, and, since 2023, ofatumumab have both been available as treatment options in Lithuania. Because of its high potency and safety, as well as the specific mechanism of action, ofatumumab is effective in lower doses, and, after initial training at a health care facility, it can be self-administered through subcutaneous injection. This article reviews the efficacy, safety data and treatment indications of the latest available anti-CD20 monoclonal antibodies.

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study.

Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

Real-world use of cladribine tablets (completion rates and treatment persistence) in patients with multiple sclerosis in England: The CLARENCE study.

Treatment with cladribine tablets, a high-efficacy disease-modifying therapy (DMT), has been available in England since 2017 for patients with highly active relapsing multiple sclerosis (MS). Real-world data on treatment completion, persistence and switching in patients treated with cladribine tablets are beginning to emerge, but only small single and multicentre cohorts have reported so far. This longitudinal retrospective observational study (CLARENCE) evaluated a large cohort (>1900) of patients with highly active relapsing MS, receiving cladribine tablets across England, to determine rates of treatment completion, persistence and switching in the real world. Using data obtained from Blueteq® forms, a compulsory requirement for DMT reimbursement in England, we evaluated rates of treatment completion (defined as the proportion of patients who received the full 2-year course of cladribine tablets), treatment persistence (defined as the proportion of patients who did not switch and/or discontinue treatment before receiving the full 2-year course) and treatment switch (defined as the proportion of patients who switched treatment from cladribine tablets to another DMT at any point after their first course). The change in Expanded Disability Status Scale (EDSS) score between Years 1 and 2 of treatment was also determined. All data were analysed descriptively. Blueteq® forms were completed for 1934 MS patients treated with cladribine tablets; of these patients, 691 (36%) were treatment naïve. The median EDSS score (range) at treatment initiation with cladribine tablets was 2.5 (0, 8.5). At time of analysis (September 2021, last follow-up point), a total of 1020 (53%) patients had completed the full 2-year course of cladribine tablets. At the same time point, 1762 (91%) patients were considered as treatment persistent (i.e., the patient had completed either 1 course of tablets with <18months of follow-up data or the full 2-year course of cladribine tablets). Overall, 78 (4%) patients switched to another DMT at any point after their first course, which included 33 (1.7%) patients who switched after completing the full 2-year course. In terms of their disability, 469 (84%) patients had stable EDSS scores between Years 1 and 2 of treatment. In this large real-world study of patients receiving cladribine tablets across England, high rates of treatment persistence and low rates of switching were observed, with only 1.7% of patients receiving the full 2-year course and switching treatment. The majority (84%) of evaluable patients showed stable disability between Years 1 and 2 of treatment. These findings complement earlier data from clinical trials and real-world studies, confirming the effectiveness of cladribine tablets for patients with highly active relapsing MS.

Autologous hematopoietic stem cell transplantation is superior to alemtuzumab in patients with highly active relapsing multiple sclerosis and severe disability

ObjectiveTo assess the differences of treatment outcomes regarding disease activity in patients with highly active relapsing multiple sclerosis (RMS), treated with autologous hematopoietic stem cell transplantation (HSCT) or alemtuzumab (ATZ). MethodsOpen-label prospective single-center observational cohort study, enrolling patients with highly active RMS for treatment with ATZ or HSCT between 2014 and 2021. ResultsA total of 50 patients (31/50 (62 %) in HSCT vs 19/50 (38 %) in ATZ group) were included. There were no significant differences in relapse rate, MRI activity or disability worsening between the two study groups during the first two years after treatment onset. However, at 3 to 5 years follow-up, HSCT was superior to ATZ in all the aforementioned aspects. Kaplan-Meier analysis at 5 years post treatment revealed superiority of HSCT in relapse rate (69.6 % vs 95.7 %, p = 0.027), MRI activity (54.5 % vs 75.1 %, p = 0.038) and disability worsening (57.1 % vs 90.9 %, p = 0.031). ConclusionsATZ may halt disability progression early in the course of highly active RMS, but the disability starts accumulating later, while in HSCT patients disability improvement is consistent both 3 and 5 years after treatment onset.

Evaluation of Patient-Reported Outcomes in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets in the CLAWIR Study: 12-Month Interim Analysis.

Patient-reported outcomes (PROs) provide an insightful method of assessing the subjective impact of therapies for those affected by multiple sclerosis (MS), a chronic neurologic disease notable for symptoms of fatigue and reduced physical function. The ongoing CLAWIR study aims to assess the effect of cladribine tablets (3.5mg/kg cumulative dose over 2years) in patients with highly active relapsing MS focusing on PROs of fatigue, physical function, treatment satisfaction, and work productivity. Here, we report on a pre-planned analysis at 12 months after treatment initiation with cladribine tablets. CLAWIR is a 2-year, multicenter, prospective, observational study of patients with relapsing MS newly initiating cladribine tablets. The following PROs were analyzed: PRO Measurement Information System (PROMIS®) Fatigue MS (v1.0) and Physical Function MS (v2.1), Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4), and Work Productivity and Activity Impairment MS Questionnaire (WPAI-MS). Data were analyzed descriptively. In total, 128 patients were eligible for analysis: 95 females (74.2%); median (range) age 34.5(29, 44) years; 34 patients (26.6%) were treatment-naïve, and 89 (69.5%) were early switchers from platform therapies (the remaining 5 patients [3.9%] switched from a high-efficacy disease-modifying therapy). PROMIS® Fatigue MS mean (± standard deviation [SD]) T-scores decreased from 54.6 (± 9.59) at baseline to 51.8 (± 10.30) at 12 months, indicating an alleviation of fatigue, whereas PROMIS® Physical Function MS mean T-scores remained stable over time [baseline: 49.4 (± 10.69); 12months: 50.3 (± 10.88)]. TSQM v1.4 mean scores indicated an improvement over time, increasing from 52.2 (± 27.79) at baseline to 81.4 (± 17.06) at 12months for global satisfaction. WPAI-MS scores also showed an improvement across all four domains over 12 months. This real-world study demonstrates the effect of cladribine tablets over 12 months on PROs of fatigue, physical function, treatment satisfaction, and work productivity. The CLAWIR study is registered at the German Federal Institute for Drugs and Medical Devices with the internal NIS number 7469.

Early Onset of Action and Sustained Efficacy of MRI Outcomes During Cladribine Tablets Treatment in Highly Active Relapsing Multiple Sclerosis: Results of the 2-year MAGNIFY-MS Study (P6-3.018)

Early Onset of Action and Sustained Efficacy of MRI Outcomes During Cladribine Tablets Treatment in Highly Active Relapsing Multiple Sclerosis: Results of the 2-year MAGNIFY-MS Study (P6-3.018)

Blood Biomarker Dynamics in Highly Active Relapsing Multiple Sclerosis Patients Treated With Cladribine Tablets: Results of the 2-Year MAGNIFY-MS Study (S16.006)

Blood Biomarker Dynamics in Highly Active Relapsing Multiple Sclerosis Patients Treated With Cladribine Tablets: Results of the 2-Year MAGNIFY-MS Study (S16.006)

Interactive statistical monitoring to optimize review of potential clinical trial issues during study conduct

BackgroundStatistical monitoring involves the review of prospective study data collected in participating sites to detect intra/inter patients and sites inconsistencies. We report methods and results of statistical monitoring in a phase IV clinical trial. MethodPRO-MSACTIVE is a study evaluating ocrelizumab in active relapsing multiple sclerosis (RMS) patients in France. Specific statistical methods (volcano plots, mahalanobis distance, funnel plot …) have been applied to a SDTM database to detect potential issues. R-Shiny application was developed to generate an interactive web application in order to ease site and/or patients identification during statistical data review meetings. ResultsThe PRO-MSACTIVE study enrolled 422 patients in 46 centers between July 2018 and August 2019. Three data review meetings were held between April and October 2019 and 14 standard and planned tests were run on study data, with a total of 15 (32.6%) sites identified as needing review or investigation. Overall 36 findings were identified during the meetings: duplicate records, outliers, inconsistent delays between dates. ConclusionStatistical monitoring is useful to identify unusual or clustered data patterns that might be revealing issues that could impact the data integrity and/or may potentially impact patients’ safety. With anticipated and appropriate interactive data visualization, early signals can easily be identified or reviewed by the study team and appropriate actions be set up and assigned to the most appropriate function for a close follow-up and resolution. Interactive statistical monitoring is time consuming to initiate using R-Shiny, but is time saving after the 1st data review meeting (DRV).(ClinicalTrials.gov identifier: NCT03589105; EudraCT identifier: 2018-000780-91)

Early onset of Action and Sustained Efficacy of MRI Outcomes during Cladribine Tablets Treatment in Highly Active Relapsing Multiple Sclerosis: Results of the 2-Year MAGNIFY-MS Study

Early onset of Action and Sustained Efficacy of MRI Outcomes during Cladribine Tablets Treatment in Highly Active Relapsing Multiple Sclerosis: Results of the 2-Year MAGNIFY-MS Study

Improvements in Quality of Life Over 2 Years in Patients Treated with Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: Final Analysis of CLARIFY-MS

Improvements in Quality of Life Over 2 Years in Patients Treated with Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: Final Analysis of CLARIFY-MS

EE129 Cost-Effectiveness of Ofatumumab Versus Ocrelizumab in Patients With Active Relapsing Multiple Sclerosis in Portugal

Ofatumumab is an antibody against a protein called CD20, which is found on the surface of certain types of immune cells called B-cells, that was approved to treat relapsing Multiple Sclerosis (MS) in adults with active disease. Our objective was to estimate the cost effectiveness of ofatumumab versus ocrelizumab in adult patients with active disease, defined by clinical or imaging characteristics, without prior treatment (naïve patients, 1st line).

Real-Life Experience of the Effects of Cladribine Tablets on Lymphocyte Subsets and Serum Neurofilament Light Chain Levels in Relapsing Multiple Sclerosis Patients.

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. Starting from week 24, the B subsets recovered; however, at week 48, CD19+/CD38+ and CD19+/CD25+ reached values near the baseline, while the Bmem were significantly lower. The T cell subsets remained unchanged except for CD4+/CD25+, which increased compared to W0. The LS changes were not predictive of NEDA achievement. The sNfL levels were significantly lower at week 24 (p = 0.046) vs. baseline. These results could demonstrate how cladribine, by inflammatory activity depletion, can also reduce axonal damage, according to the sNfL levels.

Early Reduction of MRI Activity During 6 Months of Cladribine Tablet Treatment for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS.

Early Reduction of MRI Activity During 6 Months of Cladribine Tablet Treatment for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS.

Impact of autologous HSCT on the quality of life and fatigue in patients with relapsing multiple sclerosis

In this study, we aimed to assess the quality of life, fatigue, anxiety, and depression after Autologous haematopoietic stem cell transplantation (AHSCT) and to investigate its impact of on separate domains of health status and fatigue in patients with multiple sclerosis (MS). Overall, 18 patients with highly active relapsing MS (mean age 36.3 years, 83.3% female) underwent the AHSCT in Vilnius Multiple Sclerosis center, and we prospectively collected Short Form 36, Health Survey Questionnaire, Fatigue Descriptive Scale, and Hospital Anxiety and Depression Scale beforeand Month3, 12, and 24 after AHSCT. The median score of Expanded Disability Status Scale at Month3 after transplant improved in 14 patients (77.8%). A significant improvement in physical functioning, vitality, and pain was found at Month3 after AHSCT (p < 0.05), which was sustained until Month12 and 24. The improvement in fatigue score was found at Month12 after AHSCT, which was sustained until Month24. Decrease in EDSS score had a positive impact on the better HRQoL outcomes, especially physical and social outcomes. Thus, AHSCT improved quality of life and reduced symptoms of fatigue in patients with highly active relapsing MS. The improvement was determined earlier in the domains of QoL than in the fatigue.

Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS.

Background and ObjectivesThe onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an important parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS.MethodsMRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium-enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed.ResultsIncluded in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (−1.193 between month 1 and month 6, −1.500 between month 2 and month 6, and −1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (−0.857 at month 2, −1.355 at month 3, and −1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6.DiscussionFindings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time.Trial Registration InformationNCT03364036; Date registered: December 06, 2017.Classification of EvidenceUsing frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time.

Comparative Effectiveness of Cladribine versus Fingolimod in the Treatment of Highly Active Relapsing Multiple Sclerosis: The MERLYN (MavEnclad Real worLd comparative efficacY non-iNterventional) Study (P7-4.005)

Comparative Effectiveness of Cladribine versus Fingolimod in the Treatment of Highly Active Relapsing Multiple Sclerosis: The MERLYN (MavEnclad Real worLd comparative efficacY non-iNterventional) Study (P7-4.005)

Improvements in Quality of Life at 1 Year in Patients Treated with Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: An Interim Analysis of Clarify-MS

Background: Multiple sclerosis (MS) is a chronic disabling disease associated with negative effects on quality of life (QoL), including physical and mental health. The objective of this investigation was to evaluate the change in QoL for patients with highly active relapsing MS at 1 year after initiating treatment with cladribine tablets (CladT), by assessing changes in the physical and mental health composite scores of Multiple Sclerosis Quality of Life-54 (MSQoL-54).

POSB77 Comparing the Total Costs of Oral Disease Modifying Therapies for Patients with Active Relapsing Multiple Sclerosis in the US

There are currently several effective oral disease modifying therapies (DMTs) available for the treatment of active relapsing multiple sclerosis (RMS). This analysis aims to compare the lifetime costs of oral DMTs from a US societal perspective. This economic perspective may aid in decision making for patients for whom an oral therapy is the most appropriate or preferred option. A Markov model was constructed including 5 oral disease-modifying therapies. Health states were defined by Expanded Disability Status Scale (EDSS) scores with transitions allowed to secondary progressive MS (SPMS). Patients were assumed to transition to best supportive care after discontinuation of the first-line treatment. Direct costs related to treatment acquisition, administration, and monitoring, adverse events (AEs), disease management, and relapses as well as indirect disease costs (productivity loss, changes in working situation, and early retirement) were included. Data was sourced from published literature, cost databases, and a network meta-analysis. Treatment was assumed to impact the rate of progression to higher EDSS states (both RMS and SPMS) and the rate of relapses. All costs (2021 USD) were discounted at 3% annually. Total lifetime costs ranged from $1,728,582 (ponesimod) to $2,002,709 (fingolimod). First-line treatment costs (acquisition, administration, monitoring, and AEs) comprised between 28.7% of total costs ($495,627, ponesimod) and 38.2% ($764,173, fingolimod). Direct and indirect costs for disease management were also lowest for ponesimod ($379,847 and $853,107, respectively). Teriflunomide was estimated to have the highest disease management costs (direct and indirect: $385,611 and $862,425, respectively). For all comparators, indirect costs accounted for approximately 42 to 49% of the total cost of treatment. Among the currently available oral DMTs for RMS, ponesimod is likely to result in the lowest lifetime costs from both a societal and healthcare sector perspective.

Oral Cladribine in Patients who Change From First-Line Disease Modifying Treatments for Multiple Sclerosis: Protocol of a Prospective Effectiveness and Safety Study (CLAD CROSS).

BackgroundRecently, the number of available disease modifying therapies for multiple sclerosis (MS) has increased. However, a proportion of patients treated with these agents continue to experience relapses and disease progression. Cladribine tablets, approved in 2017 for highly active relapsing MS, comprise a sparsely administered oral treatment which exerts its therapeutic effect through a reduction and subsequent repletion of the lymphocyte population.Purpose/Study SampleHere we describe the design of CLAD CROSS, a prospective, non-interventional, multicenter, Phase IV study in patients with a confirmed diagnosis of RRMS who switch from first-line disease modifying drugs (DMDs) to treatment with cladribine tablets in routine clinical practice. 242 adult patients will be recruited in 61 sites (6 countries) over 30 months and will be followed up for 2 years following prescription of cladribine tablets per the decision of the treating physicians.Research DesignThe primary endpoint is the change in annualized relapse rate (ARR) between the 12-month pre-baseline period and over the 12-month period before end of study. Secondary endpoints are the percentage of patients with 6-month disability progression or improvement at the end of the study, measured by the Expanded Disability Status Scale, Timed 25 Foot Walk and 9-Hole Peg Test scales and quality of life, treatment satisfaction, and healthcare resource utilization, measured through the MSIS-29, TSQM 1.4, and EQ-5D-3L scales, respectively. MRI lesions will be compared in the exploratory setting between the 12-month pre-baseline period, baseline, and at years 1 and 2. Adverse events will be monitored throughout the study. Interim analyses are pre-planned when 30% and 60% of patients will complete the 12-month follow-up visit.ConclusionsCLAD CROSS will provide efficacy data on cladribine tablets, used as a follow-up treatment to first-line DMDs in the real-world setting, will further establish its safety profile and will collect information to support pharmacoeconomic studies.