Multiple Sclerosis and Related Disorders 57 (2022) 103385 Contents lists available at ScienceDirect Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard Treatment satisfaction, safety, and tolerability of cladribine tablets in patients with highly active relapsing multiple sclerosis: CLARIFY-MS study 6-month interim analysis Bruno Brochet a, *, Raymond Hupperts b, Dawn Langdon c, Alessandra Solari d, Fredrik Piehl e, Jeannette Lechner-Scott f, g, Xavier Montalban h, Krzysztof Selmaj i, Martin Valis j, Konrad Rejdak k, Eva K. Havrdova l, Francesco Patti m, Nektaria Alexandri n, Axel Nolting n, Birgit Keller n a INSERM U 1215, University of Bordeaux, Bordeaux, France b Zuyderland Medisch Centrum Sittard, Maastricht University Medical Center, Maastricht, the Netherlands c Department of Psychology, Royal Holloway, University of London, Egham, United Kingdom d Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy e Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden f University of Newcastle, Newcastle, NSW, Australia g Division of Neurology, John Hunter Hospital, Newcastle, NSW, Australia h Department of Neurology-Neuroimmunology Centre of Multiple Sclerosis of Catalonia (Cemcat), University Hospital Vall d’Hebron, Barcelona, Spain i Center for Neurology, Lodz, Poland j Charles University and University Hospital, Hradec Králové, Czech Republic k Medical University of Lublin, Lublin, Poland l Charles University, First Medical Faculty, Prague, Czech Republic m Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, University of Catania, and Azienda Ospedaliero Universitaria Policlinico “G Rodolico”- San Marco, University of Catania, Catania, Italy n Merck Healthcare KGaA, Darmstadt, Germany A R T I C L E I N F O A B S T R A C T Keywords: Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on Cladribine tablets health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets Treatment satisfaction 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with Relapsing multiple sclerosis highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease- modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard devi­ ation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness * Corresponding author. E-mail address: bruno.brochet@u-bordeaux.fr (B. Brochet). https://doi.org/10.1016/j.msard.2021.103385 Received 25 June 2021; Received in revised form 24 September 2021; Accepted 5 November 2021 Available online 9 November 2021 2211-0348/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). B. Brochet et al. Multiple Sclerosis and Related Disorders 57 (2022) 103385 was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS. 1. Introduction prospective, multicenter, phase IV study. Eligible patients with highly active RMS receive open-label cladribine tablets 3.5 mg/kg body weight Multiple sclerosis (MS) is a chronic disabling disease that is associ­ over 2 years, administered as one treatment course of 1.75 mg/kg body ated with negative effects on health-related quality of life (HRQoL) due weight per year with each treatment course consisting of 2 weeks of to reduced physical and psychosocial functioning (Jongen, 2017; Ore­ active treatment (week 1 and week 5 of each year). The study visits and ja-Guevara, 2015; Orme et al., 2007; Pashazadeh Kan et al., 2020; Epub assessments at each visit are captured in Fig. 1. ahead of print). Cladribine tablets 10 mg (3.5 mg/kg cumulative dose The primary objective of CLARIFY-MS is to assess HRQoL through over 2 years) have been approved for the treatment of adult patients the MS QoL 54-item questionnaire (MSQoL-54) in highly active RMS with highly active relapsing multiple sclerosis (RMS). Treatment is patients treated with cladribine tablets for 2 years. To assess this administered as two annual courses, each of 2 weeks and administered 1 objective, the primary endpoint is the change in MSQoL-54 (physical month apart; no additional treatment is required in years 3 and 4 (EMD and mental health composite scores) at 24 months compared to baseline. Serono, 2019; Merck Europe B.V., 2021). The secondary objective is to examine treatment satisfaction of cla­ In the CLARITY study, treatment with cladribine tablets was asso­ dribine tablets, assessed through the Treatment Satisfaction Question­ ciated with a decreased need for medical and societal support and naire for Medication (TSQM, v1.4) at 6 months of treatment. This improved HRQoL (Afolabi et al., 2018; Ali et al., 2012). However, effects endpoint was the main focus of a pre-planned interim analysis (reported on HRQoL, cognition, employment status, and treatment satisfaction here), conducted when all patients had completed the 6-month assess­ need to be further explored. Indeed, higher treatment satisfaction is ment. The TSQM is a simple, non-MS specific, and widely used treatment generally associated with fewer relapses and lower disability scores satisfaction questionnaire in studies of patients with MS (Atkinson et al., (Haase et al., 2016). As such, it is important to investigate 2004), which has good psychometric properties (Vermersch et al., patient-reported responses to assess treatment satisfaction and supple­ 2017). Global satisfaction is assessed based on confidence in benefits, a ment clinical trial data. balance between good and bad effects, and overall satisfaction with a The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: score from 0 to 100 (higher numbers indicate higher satisfaction) 2017–002632–17) aims to assess the effect of cladribine tablets 3.5 mg/ (Supplementary Figure 1). Tertiary objectives of CLARIFY-MS include: kg on HRQoL in patients with highly active RMS. In this paper, we report assessment of: safety and tolerability of cladribine tablets; the effect of on the design of the CLARIFY-MS study and baseline patient charac­ treatment on the progression of disability, cognition, and brain atrophy; teristics, and summarize the results of a pre-planned interim analysis and to establish correlations between clinical outcomes and HRQoL with focusing on treatment satisfaction, safety, and tolerability that includes treatment satisfaction. The full list of tertiary endpoints is provided in all data reported till 6 months after start of treatment. the supplementary material. In order for patients to be included in CLARIFY-MS they were 2. Methods required to meet all of the following criteria: adults aged ≥18 years with highly active RMS (defined as one relapse in the previous year and a 2.1. Study design and patients total lesion count of ≥1 T1 Gd+ lesion or ≥9 T2 lesions while on therapy with another disease-modifying therapy [DMT] or ≥2 relapses in the The CLARIFY-MS study is a 2-year, open-label, single-arm, previous year regardless of prior DMT) and an Expanded Disability Fig. 1. CLARIFY-MS study design 9-HPT, 9-hole peg test; B, baseline; BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; EDSS, Expanded Disability Status Scale; FSS, Fatigue Severity Scale; HADS, Hospital Anxiety and Depression Scale; HRQoL, health-related quality of life; MRI, magnetic resonance imaging; MSQoL-54, Multiple Sclerosis Quality of Life-54; SmPC, Summary of Product Characteristics; T25FW, timed 25-foot walking test; TSQM, Treatment Satisfaction Questionnaire for Medication. 2 B. Brochet et al. Multiple Sclerosis and Related Disorders 57 (2022) 103385 Status Scale (EDSS) score of ≤5.0. The following three criteria were to be 3.1. Baseline characteristics and prior disease-modifying therapy met for establishing a relapse: 1) Neurological abnormality, either newly appearing or re-appearing. The abnormality must be separated by at Patients had a mean age of 37.4 years and most were female (70.1%); least 30 days from onset of a preceding clinical event, and last for at least a total of 345 patients (71.6%) were prior DMT users (Table 1). Among 24 h. 2) Absence of fever (>37.5 ◦ C / 99.5◦ F) or known infection. 3) patients who had received DMT in the 6 months before cladribine Objective neurological impairment, correlating with the subject’s re­ treatment, patients mainly switched from interferons (28.9%) and ported symptoms, defined as either an increase in at least one of the dimethyl fumarate (22.2%). Other common preceding treatments functional system scores of the EDSS, or an increase of the total EDSS included glatiramer acetate (14.4%), teriflunomide (13.7%), and fin­ score. Females were required to not be pregnant or breast-feeding, and golimod (13.4%) (Table 1). all patients were required to use contraception. Screening MRIs were Baseline demographics were generally comparable among patients performed for all patients. For patients switching to cladribine tablets who were treatment naïve and the subgroup who had received prior from any DMT historically linked to progressive multifocal leukoence­ DMT; as expected, patients with prior DMT use tended to have a longer phalopathy (PML) as an adverse event, the absence of PML on their disease duration than those who were treatment naïve. Mean time since screening MRI was required (and confirmed by independent central onset of MS was 46.1 months versus 120.1 months, and mean time since viewers). first relapse was 21.3 months versus 85.5 months, in the treatment naïve Patients were excluded if they had one or more of the following: any and prior DMT subgroups, respectively. signs of PML or major central nervous system disease other than MS; positive test for human immunodeficiency virus (HIV), hepatitis C, 3.2. Treatment satisfaction hepatitis B, and tuberculosis; and immunocompromised clinical status (including patients receiving immunosuppressive or myelosuppressive The mean global satisfaction score was 70.4 (standard deviation, ± therapy). The full inclusion and exclusion criteria are listed in the 18.5) for the total study cohort, 69.5 (± 18.7) for treatment naïve pa­ supplementary material. tients, and 70.8 (± 18.4) for those with prior DMT use. After adjustment The study was performed according to principles in the Declaration for age and EDSS at Baseline, the mean global satisfaction score was 70.0 of Helsinki and International Council for Harmonisation Guidelines for Good Clinical Practice (ICH GCP). Written informed consent was Table 1 required from study participants before any trial-related activities were Baseline characteristics and prior disease-modifying therapy of patients in carried out. A patient information sheet was prepared in accordance CLARIFY-MS (full analysis set). with ICH GCP for the purpose of obtaining informed consent. Treatment Prior Total study naïve DMT cohort 2.2. Interim analysis n = 137 n = 345 n = 482 Age, mean ± SD, years 35.4 ± 11.46 38.2 ± 37.4 ± A pre-planned interim analysis was conducted after all patients had 9.83 10.39 completed the 6-month assessment, before reaching a full dose of cla­ Female, n (%) 91 (66.4) 247 338 (70.1) dribine tablets. The interim analysis is considered to be supportive of the (71.6) final 2-year analysis. Due to the exploratory nature of the study, no Time since onset of MS, mean ± SD, 46.1 ± 70.5 120.1 ± 99.1 ± 89.8 months 88.0 alpha spending functions were planned to control for overall type I error Time since the first clinical episode, 21.3 ± 41.1 85.5 ± 67.5 ± 78.1 inflation. The cut-off date was defined for each patient individually, mean ± SD, months 81.6 either at the Month 6 visit date, or 180 days after the start of cladribine Relapses in prior 12 months, n (%) tablets if the visit date was missing. The full analysis set for efficacy 0 0 7 (2.0) 7 (1.5) consisted of all patients who were classified as eligible and treated with 1 40 (29.2) 233 273 (56.6) 2 87 (63.5) (67.5) 181 (37.6) at least one dose of cladribine tablets. The safety analysis set consisted of >2 10 (7.3) 94 (27.2) 21 (4.4) all patients who were treated with at least one dose of cladribine tablets. 11 (3.2) Subgroup analysis split patients into treatment naïve and prior DMT EDSS, median (range) 2.0 (0–5.0) 2.5 2.5 (0–5.0) users (previous treatment with DMTs any time before initiating cla­ (0–5.0) a DMT use in prior 6 months, n (%) 284 dribine tablets). (82.3) Results for the TSQM global satisfaction score are presented. The Last DMT within 6 months of start of analysis used a mixed-effects linear model to estimate the TSQM global study medication, n (%)b satisfaction score at 6 months, after adjusting for age, EDSS at baseline, Interferons 82 (28.9) and within-country correlation (Scandinavian countries were pooled). Interferon beta-1a 53 (18.7) Interferon beta-1b 15 (5.3) Treatment effectiveness, side effects, and convenience, as assessed by Peginterferon beta-1a 11 (3.9) TSQM, are also summarized using descriptive statistics. Occurrence of Interferon 1 (0.4) relapses, adverse events, and lymphocyte counts are summarized Interferon beta 1 (0.4) descriptively. Lymphocyte counts were categorized using NCI-CTCAE Peginterferon 1 (0.4) Dimethyl fumarate 63 (22.2) version 5.0 (grade 2, <0.8–0.5 × 109/L; grade 3, <0.5–0.2 × 109/L; Glatiramer acetate 41 (14.4) grade 4, <0.2 × 109/L), and summarized by worst grade per patient. Teriflunomide 39 (13.7) Fingolimod 38 (13.4) 3. Results Natalizumab 7 (2.5) Investigational drug 5 (1.8) Daclizumab 4 (1.4) This ongoing study has enrolled 554 patients, who provided Diroximel fumarate 3 (1.1) informed consent, at a total of 85 sites in 18 European countries between Methotrexate 1 (0.4) June 2018 and April 2019. There were 485 eligible patients; three pa­ Ozanimod 1 (0.4) tients did not receive treatment, and therefore the full analysis set for a At least one DMT within 6 months prior to cladribine tablets treatment. this interim analysis comprised 482 patients (CONSORT diagram shown b Percentages are of the total patients (n = 284) who received at least one DMT in Supplementary Figure 2). within 6 months prior to cladribine tablets treatment. DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; SD, standard deviation. 3 B. Brochet et al. Multiple Sclerosis and Related Disorders 57 (2022) 103385 (95% confidence interval, 66.7–73.5) for the total study cohort, 68.7 Table 2 (62.1–75.4) for treatment naïve patients, and 70.2 (66.4–74.0) for prior TSQM scores at 6 months (full analysis set). DMT users (Fig. 2). Scores for treatment effectiveness, side effects, and TSQM scores Treatment naïve n Prior DMT n Total study cohort n convenience were similar between the treatment naïve and prior DMT = 137 = 345 = 482 subgroups (Table 2). The median side effects score was the maximum Global 100 for both subgroups and the total population. satisfaction Mean ± SD 69.5 ± 18.71 70.8 ± 18.40 70.4 ± 18.48 Median 71.4 71.4 71.4 3.3. Occurrence of relapses Side effects Mean ± SD 92.7 ± 17.85 91.5 ± 17.63 91.9 ± 17.68 The overall number of patients with at least one relapse at 6 months Median 100 100 100 was 42 (8.7%; including 12 [8.8%] treatment naïve patients and 30 Convenience [8.7%] prior DMT users). Mean ± SD 88.0 ± 13.71 86.1 ± 13.51 86.6 ± 13.57 Median 94.4 88.9 88.9 Effectiveness 3.4. Safety and tolerability Mean ± SD 65.1 ± 20.99 66.1 ± 21.23 65.8 ± 21.14 Median 66.7 66.7 66.7 A total of 275 patients (57.1%) reported at least one treatment- DMT, disease-modifying therapy; SD, standard deviation; TSQM, Treatment emergent adverse event (TEAE, any adverse event reported after drug Satisfaction Questionnaire for Medication. administration) (Table 3). The proportion of patients with a mild or moderate treatment-related TEAE was 18.7% and 9.1%, respectively; SAEs, four were considered related to study treatment all of which were few patients (0.6%, n = 3) experienced severe treatment-related TEAEs. overdoses. No change in medication dosage was required. The remain­ There were seven cases (1.5%) of herpes zoster recorded in total, ing SAEs deemed unrelated to study treatment included a medication including two (1.5%) treatment naïve patients and five (1.4%) prior error, panic disorder, ovarian cyst, and aortic aneurysm. There were no DMT users. Three patients (0.6%) had a TEAE that led to a temporary deaths reported in the study. discontinuation of treatment, and one patient (0.2%) had a TEAE that The majority of potentially drug-induced lymphopenia cases were of led to permanent treatment discontinuation (advanced ovarian carci­ grade 1 or 2; 33 patients (6.8%) of the total study cohort had grade 3 noma [as per biopsy], 5 months after starting treatment with cladribine lymphopenia, and no grade 4 lymphopenia was reported. Lymphopenia tablets). was more commonly reported in prior DMT users compared with the Nine patients (1.9%) had a serious adverse event (SAE). Of these Fig. 2. Global satisfaction score at 6 months (using TSQM v1.4) CI, confidence interval; DMT, disease-modifying therapy; TSQM, Treatment Satisfaction Questionnaire for Medication. 4 B. Brochet et al. Multiple Sclerosis and Related Disorders 57 (2022) 103385 Table 3 In the total study cohort, a mean global satisfaction score of 70.4 ± Summary of treatment-emergent adverse events (safety analysis set). 18.5 was recorded. In other studies investigating DMT for patients with Number of patients with: Treatment Prior Total study MS, those who received glatiramer acetate reported a global satisfaction naïve DMT cohort score of 68.7 ± 17.8. In the same study, patients treated with interferon n = 137 n= n = 482 β− 1a had a global satisfaction score of 72.4 ± 20.3 (Fernández et al., 345 2017). A 2019 study found that patients reported a global satisfaction Any TEAE, n (%) 82 (59.9) 193 275 (57.1) score of 65.1 for teriflunomide in the phase IV Teri-PRO study (Coyle (55.9) et al., 2019). ≥1 study-treatment related TEAE, n (%) 38 (27.7) 99 137 (28.4) (28.7) Safety results obtained from this population of patients with highly Any TEAE by severity,a n (%) active RMS, including no reports of serious infections, were consistent Mild 27 (19.7) 63 90 (18.7) with the known safety profile of cladribine tablets (Cook et al., 2011, Moderate 9 (6.6) (18.3) 44 (9.1) 2019) and provide a good indication of early safety events. Of the four Severe 2 (1.5) 35 3 (0.6) overdose SAEs, two patients from the same site received cladribine (10.1) 2 (0.3) tablets in 2 consecutive weeks instead of consecutive months, due to an Any serious TEAE, n (%) 3 (2.2) 6 (1.7) 9 (1.9) error in translation of the patient diary. Another patient took the whole Any TEAE leading to death, n (%) 0 0 0 of Year 1 treatment in the first week due to a dispensing error, while the Any TEAE leading to temporary 0 3 (0.9) 3 (0.6) remaining patient took an additional tablet during Week 1 of treatment discontinuation of study treatment, n (%) for Year 1 (a dose adjustment was therefore made for Week 2). These Any TEAE leading to permanent 0 1 (0.3) 1 (0.2) overdose events occurred without sequelae. Most observed cases of discontinuation of study treatment, n lymphopenia were of grade 1 or 2. Only 6.8% of the total study cohort (%) had grade 3 lymphopenia and no grade 4 cases were observed. Prior TEAEs observed in ≥2% of total patients, treatment status did not appear to greatly influence safety results, with n (%) Headache 21 (15.3) 42 63 (13.1) 59.9% of treatment naïve patients and 55.9% of prior DMT users (12.2) reporting at least one TEAE. However, the majority of lymphopenia Lymphopenia 5 (3.6) 35 40 (8.3) cases were reported in the prior DMT subgroup. (10.1) Of note, this is the first study of cladribine tablets to report on use of Nasopharyngitis 14 (10.2) 16 (4.6) 30 (6.2) TSQM v1.4, a simple and validated method of measuring treatment Upper respiratory tract infection 9 (6.6) 11 (3.2) 20 (4.1) Back pain 6 (4.4) 11 (3.2) 17 (3.5) satisfaction (Vermersch et al., 2017). The data obtained from Urinary tract infection 1 (0.7) 15 (4.3) 16 (3.3) patient-reported outcomes of cladribine tablets treatment through the Nausea 4 (2.9) 11 (3.2) 15 (3.1) TSQM v1.4 can therefore supplement the wealth of clinical trial results Fatigue 9 (6.6) 5 (1.4) 14 (2.9) already reported. However, there are some limitations including the Alopecia 3 (2.2) 10 (2.9) 13 (2.7) Influenza 5 (3.6) 7 (2.0) 12 (2.5) time of the interim analysis – where all patients are 6 months from their Bronchitis 2 (1.5) 9 (2.6) 11 (2.3) first dose of cladribine tablets, and only half of the recommended cu­ Oral herpes 4 (2.9) 7 (2.0) 11 (2.3) mulative dose over 2 years had therefore been administered. This re­ Lymphocyte count decreased 1 (0.7) 9 (2.6) 10 (2.1) stricts the interpretation of the TSQM effectiveness score and the overall Pain in extremity 4 (2.9) 6 (1.7) 10 (2.1) combined score. Nevertheless, it provides evidence of good treatment DMT, disease-modifying therapy; TSQM, Treatment Satisfaction Questionnaire satisfaction already in the first phase of the treatment cycle. Safety for Medication. outcomes are also restricted in their interpretation, where adverse a Worst severity per patient is reported. events such as severe lymphopenia may become more common following the full recommended cumulative dose. At the close of the treatment naïve subgroup (Table 4). CLARIFY-MS trial, TSQM v1.4 results will have been collected at Months 12 and 24 of the study. This will allow for a more accurate interpretation 4. Discussion of treatment satisfaction, effectiveness and safety after the full dose of cladribine tablets has been received. The ongoing CLARIFY-MS study aims to assess the effect of cla­ dribine tablets 3.5 mg/kg on HRQoL in patients with highly active RMS, 5. Conclusion with an interim analysis to evaluate treatment satisfaction, safety, and tolerability. Overall, the results of this pre-planned interim analysis In summary, patients reported high satisfaction (TSQM) with cla­ demonstrate that patients reported high treatment satisfaction over 6 dribine tablets treatment in this pre-planned interim analysis at 6 months following initiation of treatment (as determined by TSQM), and months. Adverse events reported were consistent with those reported in few SAEs were reported. These findings suggest that cladribine tablets cladribine tablets pivotal trials, and few SAEs were reported. Most have good treatment efficacy that develops early during Year 1 of lymphopenia cases were of grade 1 or 2, and there were no instances of administration. grade 4 lymphopenia. The majority of lymphopenia cases were reported in the prior DMT subgroup. These data therefore provide evidence of Table 4 good tolerability and treatment satisfaction with cladribine tablets both Lymphopenia experienced at any time during the first 6 months (safety analysis in treatment naïve and DMT-experienced patients during the first phase set). of the treatment cycle. Data from longer follow-up times will be avail­ Patients, n (%)a Treatment naïve Prior DMT Total study cohort able at the end of the study to track these outcomes over the full treat­ n = 137 n = 345 n = 482 ment cycle. Grade ≥2 27 (19.7) 133 (38.6) 160 (33.2) Grade ≥3 3 (2.2) 30 (8.7) 33 (6.8) Author contributions Grade 4 0 0 0 Missing 0 3 (0.9) 3 (0.6) All authors contributed to the concept, design, and critical re­ a Patients were categorized using NCI-CTCAE version 5.0 (grade 2, <0.8–0.5 view of the manuscript, and approved the final version for × 109/L; grade 3, <0.5–0.2 × 109/L; grade 4, <0.2 × 109/L), and summarized submission by worst grade. 5 B. Brochet et al. Multiple Sclerosis and Related Disorders 57 (2022) 103385 Data availability program PROGRES Q27/LF1. FP has served on scientific advisory boards for Almirall, Bayer, Biogen, Celgene (BMS), Merck Healthcare Any requests for data by qualified scientific and medical researchers KGaA, Darmstadt, Germany, Novartis, Roche, Sanofi-Genzyme, and for legitimate research purposes will be subject to Merck Healthcare Teva; he also received speaker honoraria from the same companies and KGaA’s Data Sharing Policy. All requests should be submitted in writing non-personal research grants for his department from Biogen, Merck to Merck Healthcare KGaA’s data sharing portal https://www. Healthcare KGaA, Darmstadt, Germany, Novartis, and Sanofi-Genzyme. merckgroup.com/en/research/our-approach-to-research-and- NA, AN, and BK are employees of Merck Healthcare KGaA, Darmstadt, development/healthcare/clinical-trials/commitment-responsible-data- Germany. sharing.html. When Merck Healthcare KGaA has a co-research, co- development, or co-marketing or co-promotion agreement, or when the Acknowledgments product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circum­ The authors would like to thank patients and their families, in­ stances, Merck Healthcare KGaA will endeavor to gain agreement to vestigators, co-investigators, and the study teams at each of the share data in response to requests. participating centers and at Merck Healthcare KGaA, Darmstadt, Ger­ many. Medical writing assistance was provided by Joseph Ward and Declaration of Competing Interest Elizabeth Strickland of inScience Communications, Springer Healthcare Ltd (UK and USA, respectively), and was funded by Merck Healthcare BB has received consultancy fees, speaker fees, research grants (non- KGaA, Darmstadt, Germany. personal), or honoraria from Actelion (Janssen/J&J), Bayer, Biogen, Celgene (BMS), MedDay, Merck Healthcare KGaA, Darmstadt, Germany, Role of the funding source Novartis, Roche, Sanofi-Genzyme, and Teva. RH has received institu­ tional research grants and fees for lectures and advisory boards from This study was sponsored by Merck Healthcare KGaA, Darmstadt, Biogen, Merck Healthcare KGaA, Darmstadt, Germany, and Sanofi- Germany (CrossRef Funder ID: 10.13039/100009945). Genzyme. DL has participated in speaker bureau for Almirall, Bayer, Biogen, Merck Healthcare KGaA, Darmstadt, Germany, Novartis, Roche, Sanofi-Genzyme, and Teva; has received consultancy fees from Bayer, References Biogen, Merck Healthcare KGaA, Darmstadt, Germany, Novartis, and Afolabi, D., Albor, C., Zalewski, L., Altmann, D.R., Baker, D., Schmierer, K., 2018. Teva; and has received research grants from Bayer, Biogen, Merck Positive impact of cladribine on quality of life in people with relapsing multiple Healthcare KGaA Darmstadt, Germany, and Novartis. AS has served on sclerosis. Mult. Scler. 24, 1461–1468. the advisory boards for Merck Healthcare KGaA, Darmstadt, Germany, Ali, S., Paracha, N., Cook, S., Giovannoni, G., Comi, G., Rammohan, K., Rieckmann, P., Sorensen, P.S., Vermersch, P., Greenberg, S., Scott, D.A., Joyeux, A., Group, C.S., Novartis, and Sanofi-Genzyme, and has been invited to speak on behalf 2012. Reduction in healthcare and societal resource utilization associated with of Almirall, Biogen, Excemed, Merck Healthcare KGaA, Darmstadt, cladribine tablets in patients with relapsing-remitting multiple sclerosis: analysis of Germany, and Teva. FP has received research grants from Genzyme, economic data from the CLARITY Study. Clin. Drug Investig. 32, 15–27. Atkinson, M.J., Sinha, A., Hass, S.L., Colman, S.S., Kumar, R.N., Brod, M., Rowland, C.R., Merck Healthcare KGaA, Darmstadt, Germany, and Novartis, and fees 2004. Validation of a general measure of treatment satisfaction, the Treatment for serving as Chair of DMC in clinical trials with Parexel. JL-S has Satisfaction Questionnaire for Medication (TSQM), using a national panel study of accepted travel compensation from Biogen, Merck Healthcare KGaA, chronic disease. Health Qual. Life Outcomes 2, 12. Cook, S., Leist, T., Comi, G., Montalban, X., Giovannoni, G., Nolting, A., Hicking, C., Darmstadt, Germany, and Novartis. Her institution receives the hono­ Galazka, A., Sylvester, E., 2019. Safety of cladribine tablets in the treatment of raria for talks and advisory board commitment as well as research grants patients with multiple sclerosis: an integrated analysis. Mult. Scler. Relat. Disord. 29, from Biogen, Celgene (BMS), Merck Healthcare KGaA, Darmstadt, Ger­ 157–167. Cook, S., Vermersch, P., Comi, G., Giovannoni, G., Rammohan, K., Rieckmann, P., many, Novartis, Roche, Sanofi-Genzyme, and Teva. XM has received Sorensen, P.S., Hamlett, A., Miret, M., Weiner, J., Viglietta, V., Musch, B., speaking honoraria and travel expenses for participation in scientific Greenberg, S.J., Group, C.S., 2011. Safety and tolerability of cladribine tablets in meetings, has been a steering committee member of clinical trials or multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. Mult. Scler. 17, 578–593. participated in advisory boards of clinical trials in the past years with Coyle, P.K., Khatri, B., Edwards, K.R., Meca-Lallana, J.E., Cavalier, S., Rufi, P., Actelion, Alexion, Bayer, Biogen, Celgene (BMS), EMD Serono, Gen­ Benamor, M., Poole, E.M., Robinson, M., Gold, R., 2019. Teriflunomide real-world zyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Med­ evidence: global differences in the phase 4 Teri-PRO study. Mult. Scler. Relat. Disord. day, Merck Healthcare KGaA, Darmstadt, Germany, Mylan, Nervgen, 31, 157–164. EMD Serono, I., 2019. MAVENCLAD Prescribing Information. Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeu­ Fernández, O., Duran, E., Ayuso, T., Hernández, L., Bonaventura, I., Forner, M., 2017. tics, Excemed, MSIF and NMSS. KS has received honoraria for speaking, Treatment satisfaction with injectable disease-modifying therapies in patients with consulting and serving for advisory boards for Biogen, Celgene (BMS), relapsing-remitting multiple sclerosis (the STICK study). PLoS ONE 12 (10), e0185766. Merck Healthcare KGaA, Darmstadt, Germany, Novartis, Roche, and TG Haase, R., Kullmann, J.S., Ziemssen, T., 2016. Therapy satisfaction and adherence in Therapeutics. MV has received speaking honoraria and travel expenses patients with relapsing–remitting multiple sclerosis: the THEPA-MS survey. Ther. for participation in scientific meetings, or participated in advisory Adv. Neurol. Disord. 9 (4), 250–263. Jongen, P.J., 2017. Health-related quality of life in patients with multiple sclerosis: boards in the past years with Biogen, Merck Healthcare KGaA, Darm­ impact of disease-modifying drugs. CNS Drugs 31, 585–602. stadt, Germany, Novartis, Roche, Sanofi-Genzyme, and Teva Pharma­ Merck Europe B.V., 2021. MAVENCLAD Summary of Product Characteristics. ceutical. KR has received speaking honoraria and travel expenses for Oreja-Guevara, C., 2015. Overview of magnetic resonance imaging for management of relapsing-remitting multiple sclerosis in everyday practice. Eur. J. Neurol. 22 (Suppl participation in scientific meetings, and participated in advisory boards 2), 22–27. in the past years with Bayer, Biogen, Merck Healthcare KGaA, Darm­ Orme, M., Kerrigan, J., Tyas, D., Russell, N., Nixon, R., 2007. The effect of disease, stadt, Germany, Novartis, Roche, Sanofi-Genzyme, and Teva Pharma­ functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health 10, 54–60. ceutical. EKH has received honoraria/research support from Actelion Pashazadeh Kan, F., Hoseinipalangi, Z., Ahmadi, N., Hosseinifard, H., Dehnad, A., Sadat (Janssen/J&J), Biogen, Celgene (BMS), Genzyme, Merck Healthcare Hoseini, B., Tohidi Asl, M., Ghashghaee, A., 2020. Epub ahead of print. Global, KGaA, Darmstadt, Germany, Novartis, Roche, and Teva; has served on regional and national quality of life in patients with multiple sclerosis: a global advisory boards for Actelion (Janssen/J&J), Biogen, Celgene (BMS), systematic review and meta-analysis. BMJ. Support Palliat Care. Vermersch, P., Hobart, J., Dive-Pouletty, C., Bozzi, S., Hass, S., Coyle, P.K., 2017. Genzyme, Merck Healthcare KGaA, Darmstadt, Germany, Novartis, and Measuring treatment satisfaction in MS: is the Treatment Satisfaction Questionnaire Roche; and has been supported by the Czech Ministry of Education, for Medication fit for purpose? Mult. Scler. 23 (4), 604–613. 6