Preferences and Perspectives of Specialist Multiple Sclerosis Nurses and Patients with Multiple Sclerosis Regarding the New RebiSmart® 3.0 Autoinjector versus Other Assistive Devices.

Purpose: RebiSmart® is an electromechanical multidose autoinjector developed for administering subcutaneous interferon beta-1a in patients with multiple sclerosis (pwMS). This online survey aimed to understand MS nurses' and pwMS preferences and perceptions regarding the features of an upgraded version of the RebiSmart device (RebiSmart 3.0) compared to other assistive devices used for multiple sclerosis (MS) therapy. Patients and Methods: Eligible MS nurses and pwMS from Germany, Italy, and the United Kingdom completed a double-blind, 30-minute online self-administered questionnaire, including a 10-minute video describing the features of RebiSmart 3.0 and its use in administering interferon beta-1a. Results: In total, 102 participants (MS nurses, n=52; patients, n=50) completed the survey. Overall, 70% respondents found the RebiSmart 3.0 device "very"/"extremely" appealing, 53% were "very"/"extremely" interested in learning more, and 71% stated they would be "very"/"extremely" comfortable using (pwMS) or educating (MS nurses) on it. Among current or recent RebiSmart 2.0 users (vs RebiSmart 2.0 nonusers), 67% (vs 52%) rated RebiSmart 3.0 "very" or "extremely" appealing, 52% (vs 43%) were "very" or "extremely" interested in learning more about the device, and 67% (vs 48%) stated they would be "very" or "extremely" comfortable using the RebiSmart 3.0 device. Respondents ranked customizable injection process (including injection speed, hold time, depth and rotation guide), self-injection process, and hidden needle as the most important self-assistive device features. RebiSmart 3.0 was rated higher than other self-injecting devices on all tested features. Overall, with respect to the top three features, 89% of the MS nurses and 73% of PwMS rated RebiSmart 3.0 "very good" or "excellent". After reviewing the video, 52% respondents had no questions, 67% nurses recommended providing more information on the customizable injection process feature of RebiSmart 3.0 to patients, and 88% nurses considered patient demonstration materials to be the most helpful type of information for them when initiating and educating pwMS on self-assistive devices. Conclusion: The overall reactions of MS nurses and pwMS to the RebiSmart 3.0 device features were positive. The incremental advances over previous versions of the device as well as in comparison with other currently available assistive devices were welcomed. The MS nurses identified key needs for patient education on the use of the device and the suitable approaches (training videos and educational leaflets) to support MS nurses and pwMS.

Evolution of the RebiSmart® Electromechanical Autoinjector to Improve Usability in Support of Adherence to Subcutaneous Interferon Beta-1a Therapy for People Living with Multiple Sclerosis.

Background: The RebiSmart® electromechanical autoinjector supports people living with relapsing multiple sclerosis (MS) with their adherence to treatment with subcutaneous interferon beta-1a (sc IFN ß-1a; Rebif®), a well-established and effective therapy. We report on the validation of the next-generation device, RebiSmart 3.0, tailored to meet patients' changing needs. Methods: To conclude a series of formative usability studies, a final formative study of an updated prototype version of the RebiSmart electromechanical autoinjector was conducted to identify the device's strengths, potential device-related use errors, opportunities for improvement, and to inform device safety. The findings were incorporated into the next-generation device, RebiSmart 3.0, which was then evaluated in a summative usability study involving 45 participants. The study consisted of evaluation activities - use scenarios and knowledge tasks - designed to validate mitigations to reduce the risks of not successfully completing critical tasks for successful administration of medication. During each evaluation activity, observations (including use errors, instances of moderator assistance, close calls, and difficulties) were recorded, focusing on the potential for serious harm arising from not completing critical tasks. Participants then provided their subjective assessment of RebiSmart 3.0 as part of a user needs survey that assessed device usability and design. Results: Regarding critical tasks, main findings were failure to inspect/dispose of the cartridge and not washing hands or disinfecting the injection site. These issues could be readily overcome by modifying future training. In the subjective assessment, 43 out of 45 participants considered the updated device safe to use as-is. In the user needs survey, overall, the participants rated the device positively. Conclusion: Findings validate the safety of use of the next-generation device, RebiSmart 3.0, through a comprehensive evaluation of use scenarios and knowledge tasks by the study participants, who provided positive ratings of the device in the user needs survey.

Assessment of adherence to, and persistence with, an electromechanical autoinjector for subcutaneous interferon beta-1a injections for multiple sclerosis treatment over 3 years.

BACKGROUND: Self-administration of subcutaneous interferon beta-1a (sc IFN ß-1a) can be achieved with the RebiSmart® electromechanical autoinjector. This study investigated adherence to, and duration of persistence with, the newest version of the device (v1.6) among 2644 people receiving sc IFN ß-1a for multiple sclerosis (MS). RESEARCH DESIGN AND METHODS: This retrospective, observational study utilized data from RebiSmart® devices, recorded on the MSdialog database, between January 2014 and November 2019. Adherence and persistence were evaluated over a 3-year period and assessed in relation to age, sex, injection type, and injection depth. RESULTS: The population of RebiSmart® users (N = 2644) comprised of 1826 (69.1%) females and mean age was 39 (range 16-83) years. Adherence to RebiSmart® use and data transfer to the MSdialog database was consistently high (mean 91.7%; range 86.8-92.6%), including across all variables (81.6-100%). Mean (±SD) persistence during the study period was 1.35 ± 1.06 years, with a maximum recorded persistence of 5.1 years. In multivariate analysis, the longest durations of persistence were observed among older individuals and males (p < 0.0001 and p = 0.0078, respectively). CONCLUSIONS: People living with MS were highly adherent to use of the RebiSmart® device, with higher persistence generally observed for older and/or male individuals.

It is important for people living with multiple sclerosis (MS) to take their medication regularly ­ and to keep doing so ­ in order to control their symptoms. Some people with MS receive a medication called interferon beta-1a (Rebif®) as a subcutaneous injection (given just under the skin), and the RebiSmart® electromechanical autoinjector was designed to help them to self-inject such medication. This study aimed to find out whether people were using the RebiSmart® device as often as they should be, and how long they continued to use it for. Information was taken from the MSdialog database, which recorded peoples' use of the RebiSmart® device between January 2014 and November 2019. Records for 2644 people using the device were analyzed. Results showed that the RebiSmart® device was used most of the time (around 91.7%). On average, people kept using the device for around a year and 4 months before stopping. This duration was generally longer for men compared with women, and longer for older people than younger people. These results increase our understanding of how people are using the RebiSmart® device to treat their MS symptoms.

The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study.

BACKGROUND: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear. METHODS: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5). RESULTS: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC. CONCLUSIONS: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity.

The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis.

BACKGROUND: White matter lesions and brain atrophy are both present early in multiple sclerosis. However, the spatio-temporal relationship between atrophy and lesion processes remains unclear. METHODS: Yearly magnetic resonance images were analyzed in 392 patients with clinically isolated syndrome from the 5-year REFLEX/REFLEXION studies. Patients received early treatment (from baseline; N = 262) or delayed treatment (from month-24; N = 130) with subcutaneous interferon beta-1a. Global and central atrophy were assessed using FSL-SIENA to provide yearly percentage volume change of brain and ventricles, respectively. Yearly total lesion volume change was calculated by subtracting the sum of the negative lesion volume change (disappearing + shrinking) from the positive lesion volume change (new + enlarging) for each yearly interval, as determined by an in-house developed semi-automated method. Using linear mixed models, during the period where patients had received ≥1 year of treatment, we investigated whether total lesion volume change was associated with percentage brain volume change or percentage ventricular volume change in the next year, and vice versa. RESULTS: Higher total lesion volume change was related to significantly faster global atrophy (percentage brain volume change) in the next year (B = - 0.113, SE = 0.022, p < 0.001). In patients receiving early treatment only, total lesion volume change was also associated with percentage ventricular volume change in the next year (B = 1.348, SE = 0.181, p < 0.001). Voxel-wise analyses showed that in patients receiving early treatment, higher total lesion volume change in years 2, 3, and 4 was related to faster atrophy in the next year, and in year 4 this relationship was stronger in patients receiving delayed treatment. Interestingly, faster atrophy was related to higher total lesion volume change in the next year (percentage brain volume change: B = - 0.136, SE = 0.062, p = 0.028; percentage ventricular volume change: B = 0.028, SE = 0.008, p < 0.001). CONCLUSIONS: Higher lesion volume changes were associated with faster atrophy in the next year. Interestingly, there was also an association between faster atrophy and higher lesion volume changes in the next year.

The effect of cladribine tablets in people with more active multiple sclerosis: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This article summarizes the findings from a previously published article in Current Medical Research and Opinion. Cladribine tablets are an oral treatment for relapsing multiple sclerosis (shortened to MS), that are given for 4 periods of 4 to 5 days over 2 years (for a total of 20 days). In this analysis, researchers looked at the effects of taking either cladribine tablets or placebo (dummy pills) in a group of people with MS who had more active MS inflammation and had participated in a clinical study (called the CLARITY study). Some of these participants had taken prior medicines for MS. WHAT WERE THE RESULTS?: Researchers found that in people with more active MS, treatment with cladribine tablets led to a lower risk of relapse and there were more people who had no relapses. People also had a lower chance of their MS worsening and had fewer new lesions in the brain. These benefits were seen regardless of whether the participants had prior treatment. WHAT DO THE RESULTS MEAN?: Researchers concluded that in these people with more active MS, treatment with cladribine tablets led to better outcomes over 2 years compared with treatment with placebo tablets, regardless of whether the participants had taken any prior MS treatments. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov).

Disease stability over five years in people with multiple sclerosis treated with cladribine tablets: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article originally published in the journal Advances in Therapy. Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS. HOW WAS THE ANALYSIS CARRIED OUT?: In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe. WHAT WERE THE RESULTS?: When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months. WHAT DO THE RESULTS MEAN?: Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration: NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration: NCT00641537 (ClinicalTrials.gov).

Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a.

BACKGROUND AND PURPOSE: In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon beta-1a (sc IFN ß-1a) versus placebo. This post hoc analysis evaluated the effect of sc IFN ß-1a on spatio-temporal evolution of disease activity, assessed by changes in T2 lesion distribution, in specific brain regions of such patients and its relationship with conversion to MS. METHODS: Post hoc analysis of baseline and 24-month magnetic resonance imaging data from FCDE patients who received sc IFN ß-1a 44 µg once or three times weekly, or placebo in the REFLEX trial. Patients were grouped according to McDonald MS status (converter/non-converter) or treatment (sc IFN ß-1a/placebo). For each patient group, a baseline lesion probability map (LPM) and longitudinal new/enlarging and shrinking/disappearing LPMs were created. Lesion location/frequency of lesion occurrence were assessed in the white matter. RESULTS: At Month 24, lesion frequency was significantly higher in the anterior thalamic radiation (ATR) and corticospinal tract (CST) of converters versus non-converters (p < 0.05). Additionally, the overall distribution of new/enlarging lesions across the brain at Month 24 was similar in placebo- and sc IFN ß-1a-treated patients (ratio: 0.95). Patients treated with sc IFN ß-1a versus placebo showed significantly lower new lesion frequency in specific brain regions (cluster corrected): ATR (p = 0.025), superior longitudinal fasciculus (p = 0.042), CST (p = 0.048), and inferior longitudinal fasciculus (p = 0.048). CONCLUSIONS: T2 lesion distribution in specific brain locations predict conversion to McDonald MS and show significantly reduced new lesion occurrence after treatment with sc IFN ß-1a in an FCDE population.

Family planning in people with multiple sclerosis: a plain language summary.

What is this summary about?: This is a plain language summary of an article originally published in the journal Frontiers in Neurology. People with multiple sclerosis (often shortened to MS) may have concerns about pregnancy and fertility. To understand more about these concerns, 332 people with MS in the USA, UK, France, Germany, Italy, and Spain took a survey with questions about how they made family planning decisions. What were the results?: Most of the survey participants (around 82%) were women. The survey found that people with MS were less likely to have children than people without MS. Over half (56%) of people with MS said the disease impacted their family planning decisions in some way, almost one quarter (22%) significantly changed their plans for the timing of their pregnancy or number of children, and 14% decided against having children. For almost 4 out of 5 (81%) people with MS the main source of family planning information was healthcare professionals. What do the results of the study mean?: Overall, MS significantly impacted patients' decisions about family planning.

Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment. This is the summary of a study that examined side effects from cladribine tablets treatment in the first 12 weeks of two clinical studies called CLARITY and ORACLE-MS. Overall, 34.7% of participants who took cladribine tablets experienced drug-related side effects compared to 23.2% of participants who took placebo. Most side effects were mild and were seen in 54.8% of participants taking cladribine tablets and 59.1% taking the placebo. A low number of participants discontinued treatment due to side effects (1.6% of participants who took cladribine tablets; 1.4% of participants who took placebo). The researchers concluded that cladribine tablets are well-tolerated and people with MS are likely to complete the full treatment course. ClinicalTrials.gov NCT numbers: CLARITY study - NCT00213135 and ORACLE-MS study - NCT00725985.

Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study.

BACKGROUND: No evidence of disease activity (NEDA-3) is a patient-centric outcome increasingly used as the goal of multiple sclerosis treatment. OBJECTIVE: Determine treatment durability of cladribine tablets beyond 2 years considering the variable bridging interval of 0.1-116.0 weeks between CLARITY and CLARITY Extension. METHODS: Between CLARITY and CLARITY Extension, patients transitioned from cladribine tablets 3.5 mg/kg to placebo (CP3.5 group, n = 98) or continued further treatment with cladribine tablets 3.5 mg/kg (CC7.0 group, n = 186). Treatment assignment was randomized and blinded in both CLARITY and CLARITY Extension. RESULTS: The 2-year NEDA-3 in CLARITY Extension (encompassing both years of CLARITY Extension) was 29.6% in the CP3.5 group and 32.8% in the CC7.0 group. There was no evidence that treatment effect differed with varying bridging intervals. For patients in the CP3.5 group with a bridging interval of ⩽48 weeks, 1 year NEDA-3 (the first year of CLARITY Extension) was 44.4% (28/63) compared with 31.4% (11/35) in patients with a bridging interval of >48 weeks. CONCLUSION: Treatment with cladribine tablets in CLARITY, followed by either placebo or cladribine tablets in CLARITY Extension, produced sustained benefits for NEDA-3 and its constituent elements for a follow up period up to 6 years from CLARITY baseline.

Outcomes of COVID-19 among patients treated with subcutaneous interferon beta-1a for multiple sclerosis.

BACKGROUND: In accordance with expert guidance, patients have typically continued to receive treatment with subcutaneous interferon beta-1a (sc IFN ß-1a) for relapsing multiple sclerosis (MS) during the COVID-19 pandemic. METHODS: We provide a summary of outcomes among sc IFN ß-1a-treated patients with adverse events related to confirmed or suspected COVID-19, as reported to the Merck Global Patient Safety Database (as of 2 February 2021). Serious COVID-19-related adverse events (as classified by the reporting clinician) included those leading to hospitalization, admission to intensive care, or death. Outcomes were classified per usual pharmacovigilance practice. RESULTS: The evaluable cohort comprised 603 patients of median age 43 (range, 13-84) years and 75.1% were female. COVID-19 was experienced at a median of 33.0 (range, 0-321.8) months after start of treatment with sc IFN ß-1a. A total of 136 (22.6%) patients experienced serious COVID-19 events, including 59 hospitalizations (4 patients admitted to intensive care) and 5 deaths (fatality rate, 0.8%). Regarding non-fatal outcomes, 47.8% of patients (289/603) with COVID-19 adverse events were recovered or recovering at time of analysis; similar findings were apparent for the serious and hospitalized cohorts. CONCLUSION: Findings of this analysis from the Merck Global Patient Safety Database suggest that, compared with available statistics for the general population and those with MS, patients receiving sc IFN ß-1a for treatment of relapsing MS have relatively low rates of serious disease and/or severe outcomes with COVID-19.

Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis.

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies.

INTRODUCTION: In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets. METHODS: Patients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated-patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences. RESULTS: The median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0-3.5) compared with 3.0 (2.5-3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0-3.0) compared with 2.5 (2.5-3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline. CONCLUSIONS: These findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose. TRIAL REGISTRATION: ClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension).

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

BACKGROUND: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. OBJECTIVE: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. METHODS: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. RESULTS: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). CONCLUSION: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

Family Planning Decision Making in People With Multiple Sclerosis.

Introduction: The majority of people diagnosed with MS are of childbearing or child fathering age, therefore family planning is an important issue for both women and men with MS. Fertility and the course of pregnancy are not affected by MS; however, people with MS (pwMS) may have concerns that there will be a greater risk of complications to the mother and/or adverse pregnancy outcomes either due to the disease or to ongoing medication. This survey aimed to understand family planning decision making in pwMS and related unmet educational needs. Methods: A total of 332 pwMS across the USA, UK, France, Germany, Italy, and Spain were recruited from a specialist patient panel agency to participate in a smartphone-enabled standing panel. The 80-question survey focussed on decision making and information sources for pwMS regarding family planning, as well as behavior during and after pregnancy. Male patients with MS did not respond to specific questions on pregnancy. Survey results were directly compared with the 2016 US and 2010 UN census data. Results: pwMS were more likely to have no children than the general population, particularly in the subgroup of patients aged 36-45 years. A total of 56% of pwMS reported that the disease affected, with different degrees of impact, their family planning decision making. Of these, 21% significantly changed their plans for timing of pregnancy and the number of children, and 14% decided against having children. Participants indicated that healthcare professionals were the primary source of information on family planning (81% of responses). The timing of planned pregnancy was not considered when selecting treatment by 78% of participants. Conclusion: MS was found to significantly impact family planning decision making, with pwMS significantly less likely to have children in comparison with the general population.

COVID-19 in patients with multiple sclerosis treated with cladribine tablets: An update.

BACKGROUND: We previously summarized outcomes for 46 cladribine tablets (CladT)-treated patients with multiple sclerosis (MS) and confirmed or suspected COVID-19, as reported to the Merck KGaA Global Patient Safety Database. This report updates on these findings, to 15 January 2021, for a total of 272 reported cases of COVID-19 among CladT recipients. METHODS: Case definitions: confirmed (COVID-19 diagnostic test was positive); suspected (no confirmatory test performed/reported). Cases fulfilling the criteria of hospitalized, medically significant, or fatal were designated as serious and outcomes were classified per usual pharmacovigilance practice. RESULTS: The evaluable cohort comprised 261 patients (confirmed COVID-19, n=160; suspected, n=101); an additional 11 patients had symptoms compatible with COVID-19 but were not evaluated further given their negative diagnostic tests. Median time to onset of COVID-19 from the most recent preceding CladT treatment course was 162 days (n=139). Outcomes were: recovered/recovering, n=133 (51%); not recovered/not resolved, n=19 (7%); died, n=1 (0.4%); and not reported/missing/pending, n=108 (41%). Of the total cohort, 40 (15%) experienced serious COVID-19. CONCLUSION: Our results suggest that CladT-treated patients with MS are generally not at greater risk of serious disease and/or a severe outcome with COVID-19 compared with the general population and other patients with MS who acquired COVID-19.

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

BACKGROUND: In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE). OBJECTIVE: To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI). METHODS: This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter. RESULTS: Compared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96 weeks. Similar results were observed with the 5.25 mg/kg dosage. CONCLUSION: In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation).

Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.

BACKGROUND/OBJECTIVE: Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS. METHODS: A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment. RESULTS: Mean age on starting cladribine was 47 years; mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years. CONCLUSION: These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings.

Efficacy of cladribine tablets in high disease activity patients with relapsing multiple sclerosis: post hoc analysis of subgroups with and without prior disease-modifying drug treatment.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine tablets 3.5 mg/kg in HDA patient subgroups that were either treated with disease-modifying drugs (DMDs) prior to study entry or were treatment naïve. METHODS: Post hoc analysis of the 96 week Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study compared cladribine tablets 3.5 mg/kg to placebo in subgroups of patients meeting the high relapse activity plus disease activity on treatment definition of HDA. Patients were categorized into either prior DMD treatment or DMD treatment-naïve subgroups. Endpoints included annualized relapse rate (ARR), time to first relapse, time to disability progression and magnetic resonance imaging (MRI) outcomes. No inferential statistical analyses were conducted between subgroups. RESULTS: The DMD-naïve cohort (n = 187) was larger than the prior-DMD cohort (n = 102). In both the DMD-naïve and prior-DMD cohorts, cladribine tablets were associated with a reduction in ARR (rate ratio [RR]: 0.26; 95% confidence interval [CI]: 0.16-0.42; p < .0001 and RR: 0.55; 95% CI: 0.32-0.95; p = .0324, respectively). In both subgroups, cladribine tablets increased the time to relapse versus placebo (hazard ratio [HR]: 0.36; 95% CI: 0.21-0.62; p = .0002 for DMD-naïve cohort and HR: 0.50; 95% CI: 0.24-1.02; p = .0557 for prior-DMD cohort). Significant differences were observed for all assessed disability and MRI outcomes independently of previous treatment. CONCLUSION: Post hoc evidence suggests consistent treatment benefits of cladribine tablets 3.5 mg/kg during the 96 week CLARITY study among HDA-RRMS patients who were either previously treated with DMDs or were treatment naïve.