1161494 research-article20232023 MSJ0010.1177/13524585231161494Multiple Sclerosis JournalG Giovannoni, A Boyko MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper Long-term follow-up of patients with relapsing Multiple Sclerosis Journal 2023, Vol. 29(6) 719­–730 multiple sclerosis from the CLARITY/ DOI: 10.1177/ https://doi.org/10.1177/13524585231161494 13524585231161494 https://doi.org/10.1177/13524585231161494 CLARITY Extension cohort of CLASSIC-MS: © The Author(s), 2023. An ambispective study Article reuse guidelines: sagepub.com/journals- permissions Gavin Giovannoni, Alexey Boyko, Jorge Correale, Gilles Edan, Mark S Freedman, Xavier Montalban, Kottil Rammohan, Dusan Stefoski, Bassem Yamout, Thomas Leist, Aida Aydemir, Laszlo Borsi and Elisabetta Verdun di Cantogno Correspondence to: Abstract G Giovannoni Background: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relaps- Blizard Institute, Barts and The London School of ing multiple sclerosis. Medicine and Dentistry, Queen Mary University of Objective: Report long-term mobility and disability beyond treatment courses received in CLARITY/ London, 4 Newark Street, CLARITY Extension. London E1 2AT, UK. g.giovannoni@qmul.ac.uk Methods: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without Gavin Giovannoni participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Blizard Institute, Barts and The London School of Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior Medicine and Dentistry, to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Queen Mary University of London, London, UK Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability Alexey Boyko status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). Department of Neurology, Neurosurgery and Medical Results: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median Genetics, Federal Center time since LPSD was 10.9 (range = 9.3–14.9) years. Cladribine tablets–exposed population: 90.6% of Brain Research and Neurotechnologies, Pirogov (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not Russian National Research Medical University, Moscow, using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an Russia ambulatory device: exposed, 81.2%; unexposed, 75.6%. Jorge Correale Department of Neurology, Conclusion: With a median 10.9 years’ follow-up after CLARITY/CLARITY Extension, findings sug- FLENI Institute, Buenos gest the sustained long-term mobility and disability benefits of cladribine tablets. Aires, Argentina Gilles Edan Department of Neurology, University Hospital of Keywords: Cladribine tablets, CLARITY, CLARITY Extension, disability, disease-modifying therapy, Rennes, Rennes, France employment, Expanded Disability Status Scale, multiple sclerosis Mark S Freedman Department of Medicine and the Ottawa Hospital Research Date received: 23 August 2022; revised: 20 January 2023; accepted: 12 February 2023 Institute, University of Ottawa, Ottawa, ON, Canada Introduction treatment naïve and treatment-experienced patients.5–7 Xavier Montalban Department of Neurology- Multiple sclerosis (MS) is a chronic, inflammatory, This agent has novel posology among available Neuroimmunology, Centre demyelinating, and neurodegenerative disease of the DMTs, in that it comprises a short treatment course at d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital central nervous system that is most commonly diag- the beginning of the first and second months of two Universitario Vall d’Hebron, nosed in young adults between the ages of 20 and consecutive treatment years; thereafter, no further Barcelona, Spain Kottil Rammohan 50 years,1–3 and is typically characterized by frequent treatment with cladribine tablets is required in years 3 MS Research Center, School relapses paralleled by disability progression and cog- and 4, in view of sustained efficacy. of Medicine, University of Miami, Miami, FL, USA nitive impairment.4 Dusan Stefoski The CLARITY (CLAdRIbine Tablets for treating Department of Neurological Cladribine tablets (3.5 mg/kg cumulative dose over MS orallY) study, which recruited patients between Sciences, Rush Medical College, Chicago, IL, USA 2 years) is a high-efficacy disease-modifying therapy April 2005 and January 2007, was conducted at a time Bassem Yamout (DMT) approved for use in the treatment of relapsing when limited high-efficacy treatments were available Neurology Institute, Harley MS, having shown significant benefits in both and the diagnosis of MS was based on the older 2001 Street Medical Center, Abu journals.sagepub.com/home/msj 719 Multiple Sclerosis Journal 29(6) Dhabi, UAE/American University of Beirut Medical Center, Beirut, Lebanon Thomas Leist Division of Clinical Neuroimmunology, Comprehensive MS Center, Jefferson University, Philadelphia, PA, USA Aida Aydemir Elisabetta Verdun di Cantogno EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA Laszlo Borsi Merck Healthcare KGaA, Darmstadt, Germany Figure 1. CLASSIC-MS study design. EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging. aCan also be administered by telephone instead of in-person at clinic at Study Visit 1. bMay be determined through retrospective chart review and/or at Study Visit 1, for example, if conversion or disability progression occurred between last regular clinical visit and Study Visit 1. McDonald criteria. Despite this, the results from The analysis presented here concerns data for patients CLARITY showed that short-course treatment with who participated in CLARITY with or without subse- cladribine tablets significantly reduced relapse rates, quent enrollment to CLARITY Extension, for which the risk of disability progression, and improved mag- the median time to follow-up in CLASSIC-MS since netic resonance imaging (MRI) outcomes.5 In turn, the last parent study dose (LPSD) was 10.9 CLARITY Extension provided further evidence of (range = 9.3–14.9) years. The time since LPSD was the sustained efficacy of cladribine tablets.6 defined as the time since the last treatment dose of Subsequent analysis of CLARITY Extension has cladribine tablets or placebo during the parent study; indicated the sustained benefits of cladribine tablets this timing varies between patients depending on their in terms of no evidence of disease activity (NEDA-3), enrollment in the CLARITY Extension study and the and for up to 6 years from the baseline of CLARITY.8 number of treatment courses received during CLARITY/CLARITY Extension (Supplemental The CLASSIC-MS study (NCT03961204) was Figure 1). To be eligible for inclusion in the current designed to further explore the long-term efficacy and analysis, patients must have received ⩾1 course of durability of the effect of cladribine tablets beyond the cladribine tablets or placebo during the parent studies two annual treatment courses in patients enrolled in and must have been able to provide informed consent the parent trials of the Phase III development program at the time of enrollment. (CLARITY, CLARITY Extension, and ORACLE MS [ORAl CLadribine in Early Multiple Sclerosis]). The During the first study visit of CLASSIC-MS (hereaf- analysis presented here focuses on the CLASSIC-MS ter referred to as “Study Visit 1”), retrospective data patient population previously enrolled in CLARITY on Expanded Disability Status Scale (EDSS) score,9 with or without subsequent enrollment to CLARITY use of ambulatory device(s), relapses, and subsequent Extension. Findings for the ORACLE MS cohort are use of DMTs were collected along with employment to be reported elsewhere. status. For the purposes of analysis, “actively employed” included people who were “employed for wages,” “self-employed,” or considered themselves a Methods “homemaker” at the time of Study Visit 1. Study design and endpoints The primary objective of CLASSIC-MS was to evalu- CLASSIC-MS was an exploratory, low-interven- ate long-term mobility by determining the proportion tional, multicenter, ambispective, Phase IV study of of patients not using a wheelchair in the 3 months patients with MS (Figure 1), in which the assessment prior to Study Visit 1 and not bedridden at any time of patients took place across 98 centers in 29 coun- since LPSD, as determined by a level of functioning tries between 2019 and 2021. consistent with an EDSS score <7. Where EDSS 720 journals.sagepub.com/home/msj G Giovannoni, A Boyko et al. scores were not available, alternative clinical descrip- This population had a median age of 52.5 (range = 32– tions in the medical records were used. 79) years and was predominantly female (67.8%). Concerning disability, patients had a median EDSS Secondary objectives were to assess long-term disa- score of 3.5 (range = 0.0–9.0) at Study Visit 1 of bility status by determining the proportion of patients CLASSIC-MS compared with 2.5 (range = 0.0–5.5) not using an ambulatory device since LPSD. This at the parent study baseline. For patients exposed to was determined by a level of functioning consistent cladribine tablets, there was a 1.0-point increase in with an EDSS score <6 or alternative clinical median EDSS scores between the parent study base- descriptions. line and Study Visit 1 compared with a 1.5-point increase in patients who were never exposed to The tertiary objectives were to determine real-world active treatment. Of the 435 patients included in this treatment patterns by assessing the number, type, and analysis, 90.6% (394/435) had been exposed to clad- timing of subsequent DMT use, and the durability of ribine tablets in the parent studies, with 160 patients clinical outcomes as assessed by the time from first having received a cumulative dose of 3.5 mg/kg over [F]/[L]PSD to use of an ambulatory device. 2 years, with the other 234 patients having been exposed to varying doses of cladribine tablets during In this study, a positive treatment response during the the parent studies (Supplemental Figure 1). Baseline 4-year period since LPSD was defined using three characteristics of the exposed and never-exposed variables, with responses categorized as “Yes,” “No,” cohorts of CLASSIC-MS patients from CLARITY/ and “Not determined”: CLARITY Extension were largely similar, as shown in Table 1. Overall, baseline disease characteristics (a) Not using further DMT(s); of patients enrolled on CLASSIC-MS were similar (b) No evidence of disease reactivation based on to those who were not enrolled on the study medical records and investigator assessments (Supplemental Table 1). of clinical outcomes; and (c) Not using further DMT(s) and no evidence of disease reactivation. Primary endpoint (median 10.9 years since LPSD) In this study population, 88.9% of evaluable patients Safety data were not evaluated as part of the (369/415) were not using a wheelchair in the 3 months CLASSIC-MS study, having been reported on as part prior to Study Visit 1 and were not bedridden at any of the parent studies. time since LPSD (i.e. EDSS < 7). This represented 77.8% (28/36) of patients who were never exposed to active treatment, compared with 90.0% (341/379) of Statistical analysis patients who were exposed to cladribine tablets (odds Data evaluation and interpretation are based on point ratio = 0.39, 95% CI = 0.17–0.93; p = 0.034) (Figure estimates and 95% confidence intervals (CIs). Due to 2). For patients receiving cladribine tablets 3.5 mg/kg the exploratory and hypothesis-generating nature of over 2 years, 88.2% (134/152) were not using a wheel- the study, no testing of formal statistical hypotheses chair and were not bedridden during these same time or adjustments for multiple comparisons was per- periods. When compared with the never-exposed formed. Time-to-event analyses are presented using cohort (36/41), this provided an odds ratio of 0.52 the Kaplan–Meier estimates and cumulative inci- (95% CI = 0.20–1.33; p = 0.173). dence curves. Findings are presented according to patient exposure/non-exposure to cladribine tablets In terms of time to the first use of an ambulatory in the parent studies (i.e. CLARITY/CLARITY device since LPSD (tertiary endpoint), 28.9% Extension), and separately for those who received a (114/394) of patients exposed to cladribine tablets cladribine tablets dose of 3.5 mg/kg over 2 years. and 46.3% (19/41) of never-exposed patients had an Analyses were performed using SAS® software ver- event with an estimated time of 9.9 and 7.2 years for sion 9.4 or higher. 25% of patients to reach an event, respectively (Figure 3). Results A total of 435 patients from CLARITY with or with- Secondary endpoint (median 10.9 years since out subsequent enrollment to CLARITY Extension LPSD) (of whom 345 patients participated in both studies) In this study population, 80.7% (351/435) of patients were included in this analysis of CLASSIC-MS. did not use an ambulatory device at any time since journals.sagepub.com/home/msj 721 Multiple Sclerosis Journal 29(6) Table 1. Patient demographics and disease characteristics at parent study baseline and Study Visit 1 of CLASSIC-MS: CLARITY/CLARITY Extension cohort. Parameter Never exposed to Exposed to cladribine tablets Total (N = 435) cladribine tabletsa (N = 41) All exposed Subgroup exposed patientsb (N = 394) to 3.5 mg/kg dosec (N = 160) Female, n (%) 31 (75.6) 264 (67.0) 103 (64.4) 295 (67.8) Age at Study Visit 1 (years), mean ± SD 51.6 ± 10.25 52.8 ± 9.56 51.7 (9.76) 52.7 ± 9.62 Disease duration at Study Visit 1d 22.38 ± 6.85 22.36 ± 6.99 21.32 ± 6.21 22.36 ± 6.97 (years), mean ± SD Time since the last dose in the parent study to Study Visit 1 (years) Mean ± SD 13.50 ± 0.47 11.14 ± 1.17 11.05 ± 1.15 11.35 ± 1.31 Median (range) 13.40 (12.4–14.5) 10.79 (9.3–14.9) 10.65 (9.5–14.4) 10.89 (9.3–14.9) Duration of treatment during parent study (years)e Mean ± SD 0.85 ± 0.31 1.86 ± 1.27 1.01 ± 0.05 1.77 ± 1.25 Median (range) 0.99 (0.1–1.2) 1.01 (0.0–4.6) 0.99 (0.9–1.2) 1.00 (0.0–4.6) EDSS score at parent study baseline Mean ± SD 2.74 ± 1.33 2.82 ± 1.29 2.74 ± 1.31 2.82 ± 1.29 Median (range) 3.00 (0.0–5.5) 2.50 (0.0–5.5) 2.50 (0.0–5.5) 2.50 (0.0–5.5) EDSS score at Study Visit 1 Mean ± SD 4.50 ± 2.59 3.82 ± 2.01 3.78 ± 2.07 3.87 ± 2.07 Median (range) 4.50 (0.0–9.0) 3.50 (0.0–9.0) 3.50 (0.0–9.0) 3.50 (0.0–9.0) Number of relapses in the 12 months 1.6 ± 0.78 1.3 ± 0.59 1.3 ± 0.62 1.3 ± 0.62 before enrollment to parent study, mean ± SD Type of MS at CLASSIC-MS screening, n (%) RRMS 29 (70.7) 292 (74.1) 116 (72.5) 321 (73.8) SPMS 12 (29.3) 102 (25.9) 44 (27.5) 114 (26.2) Prior use of DMT at parent study 11 (26.8) 83 (21.1) 34 (21.3) 94 (21.6) baseline, n (%) HDAf status at parent study baseline, 18 (43.9) 110 (27.9) 48 (30.0) 128 (29.4) n (%) Employment status at Study Visit 1, n (%) Employed for wages 8 (19.5) 146 (37.1) 60 (37.5) 154 (35.4) Self-employed 0 (0) 23 (5.8) 10 (6.3) 23 (5.3) Homemaker 3 (7.3) 32 (8.1) 16 (10.0) 35 (8.0) Retired 7 (17.1) 74 (18.8) 26 (16.3) 81 (18.6) Out of work/unable to work 14 (34.1) 82 (20.8) 34 (21.3) 96 (22.1) Unknowng 9 (22.0) 37 (9.4) 14 (8.8) 46 (10.6) DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; FPSD: first parent study dose; HDA: high disease activity; LPSD: last parent study dose; MS: multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SD: standard deviation; SPMS: secondary progressive multiple sclerosis. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). dDisease duration = (Study Visit 1 − date of MS diagnosis + 1)/365.25. eTreatment duration = (LPSD − FPSD + 1)/365.25. fDefined as patients with ⩾2 relapses in the 12 months prior to parent study entry, regardless of prior DMT use, OR patients with ⩾1 relapse in the previous 12 months and ⩾1 T1 gadolinium-enhancing lesion or ⩾9 T2 lesions while on therapy with other DMTs. gIncludes those with missing/not reported data or information not collected at study site. LPSD (i.e. EDSS < 6). For patients who were never cladribine tablets (Figure 4). For patients receiving exposed to active treatment, the corresponding pro- cladribine tablets 3.5 mg/kg over 2 years, 78.8% portion was 75.6% (31/41) compared with 81.2% (126/160) did not use an ambulatory device at any (320/394) of patients who were exposed to time since LPSD. 722 journals.sagepub.com/home/msj G Giovannoni, A Boyko et al. were comparable to the exposed cohort. Results also indicate that patients with high relapse activity responded well to treatment with cladribine tablets (Supplemental Table 2). Subsequent DMT use (median 10.9 years since LPSD) Over the period since LPSD, 53.1% (231/435) of patients did not use any subsequent DMTs. The majority of patients who used a subsequent treatment received a platform injectable (137/204, 67.2%), namely, interferons (94/137, 68.6%) (Supplemental Table 3). These subsequent DMTs are reflective of those available in the intervening period (2010–2021) after the completion of the parent studies. Figure 2. Patients not using a wheelchair in the 3 months Patients exposed to cladribine tablets during the par- prior to Study Visit 1 and not bedridden at any time since LPSD (EDSS < 7): CLARITY/CLARITY Extension ent studies were less likely to use further DMTs after cohort. LPSD. This is indicated by 55.8% (220/394) of the CI: confidence interval; EDSS: Expanded Disability Status Scale; exposed cohort, versus 26.8% (11/41) in the never- LPSD: last parent study dose; OR: odds ratio. exposed cohort, receiving no subsequent treatments Missing data were not included in the analysis (n = 5, n = 15, and during follow-up (Figure 5). For patients receiving n = 8 for never exposed, exposed, and exposed to cladribine tablets 3.5 mg/kg over 2 years, respectively). cladribine tablets 3.5 mg/kg over 2 years, 58.1% aFrom a logistic regression model with fixed effects for treatment (93/160) received no further DMTs after LPSD. group and disease duration. bNever-exposed cohort received only placebo during the parent studies. In terms of time-to-event analysis, patients exposed to cExposed cohort includes all patients who received ⩾1 dose of cladribine tablets had an estimated median time of cladribine tablets during the parent studies. 12.0 years until the first subsequent DMT; the corre- dA subgroup of the exposed cohort in which patients received sponding timeframe for patients never exposed to 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). cladribine tablets was 2.8 years (Figure 6). The corre- sponding time-to-event analysis for the subgroup receiving 3.5 mg/kg indicates that the data are similar to those for the exposed cohort (Figure 6). Response at 4 years since LPSD Findings of the 4-year responder analyses indicated A low proportion of patients received a second subse- that 63.4% (276/435) of patients did not use a subse- quent DMT following treatment with cladribine tab- quent DMT; 48.0% (209/435) showed no evidence of lets; 14.2% (56/394) of patients exposed to cladribine disease reactivation, and 32.6% (142/435) did not use tablets and 29.2% (12/41) of never-exposed patients. a subsequent DMT and also showed no evidence of For patients receiving cladribine tablets 3.5 mg/kg disease reactivation (Table 2). over 2 years, 18.8% (30/160) received a second subse- quent DMT. When analyzed by cohort, 66.2% (261/394) of patients exposed to cladribine tablets used no subse- The proportions of patients receiving a third subse- quent DMT(s) compared with 36.6% (15/41) in the quent DMT were lower still; 7.3% (3/41) never never-exposed cohort. No evidence of disease reacti- exposed, 4.6% (18/394) exposed to cladribine tablets, vation was observed in 50.3% (198/394) of patients and 6.9% (11/160) of those who received the 3.5 mg/ exposed to cladribine tablets compared with 26.8% kg dose over 2 years. (11/41) in the never-exposed cohort. For patients not using a subsequent DMT and showing NEDA, 34.5% (136/394) of patients exposed to cladribine tablets Relapses (median 10.9 years since LPSD) met these criteria compared with 14.6% (6/41) of During the time period since LPSD to Study Visit 1, a patients in the never-exposed cohort. For patients total of 200 patients did not experience a relapse. The receiving cladribine tablets 3.5 mg/kg over 2 years, proportion of patients in the exposed cohort who were results for the 4-year responder analyses relapse-free was approximately two times higher than journals.sagepub.com/home/msj 723 Multiple Sclerosis Journal 29(6) Figure 3. Kaplan–Meier curve for time to use of an ambulatory device since parent study dosing in CLARITY/ CLARITY Extension. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). Figure 4. Patients who were not using an ambulatory device at any time since last parent study dose (EDSS < 6) in CLARITY/CLARITY Extension. EDSS: Expanded Disability Status Scale. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). that observed in the cohort of never-exposed patients: CI = 0.11–0.14). Similar trends were apparent for the 48.0% (189/394) and 26.8% (11/41), respectively analysis of relapse rates since first parent study dose (Table 3). The annualized relapse rate (ARR) since (FPSD) (Table 3). LPSD for patients exposed to cladribine tablets was 0.12 (95% CI = 0.11–0.14), approximately half the ARR of the never-exposed cohort (0.23 (95% Employment (median 10.9 years since LPSD) CI = 0.19–0.27)). For patients receiving cladribine Of the 435 patients included in this analysis, 48.7% tablets 3.5 mg/kg over 2 years, the ARR during the (212/435) were in employment at Study Visit 1 (Table time period since LPSD was 0.13 (95% 1). The proportion of patients in active employment at 724 journals.sagepub.com/home/msj G Giovannoni, A Boyko et al. Figure 5. Patterns of DMT use at any time since last parent study dose in CLARITY/CLARITY Extension, by exposure to cladribine tablets. DMT: disease-modifying therapy. aSubsequent DMTs are reflective of those available in the intervening period (2010–2021) after completion of the parent studies. bNever-exposed cohort received only placebo during the parent studies. cExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. dA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). Study Visit 1 was higher in the exposed cohort com- findings of the present analysis also raise an interest- pared to the never-exposed cohort; 51.0% (201/394) ing question as to the effects of timing of initiation of and 27.5% (11/40), respectively. high-efficacy DMTs and long-term outcomes. Data from the MSBase and Swedish MS registries, for example, have identified that early initiation of high- Discussion efficacy therapies (within 2 years of disease onset) Early treatment initiation is critical to the optimiza- had a beneficial effect on disability when compared tion of outcomes in people living with MS. Indeed, with later treatment initiation.11 The exploratory, evidence-based clinical practice guidelines for the ambispective CLASSIC-MS study, with a median of management of these individuals support prompt 10.9 years’ follow-up since LPSD, therefore provides treatment decisions such as the use of high-efficacy important new information on the long-term efficacy DMTs earlier in the disease course, for appropriate of cladribine tablets for patients who originally par- patients.10 Such treatment decisions incorporate the ticipated in CLARITY with or without subsequent degree of disease activity and other patient, clinical, enrollment in CLARITY Extension. biomarker, and intangible (e.g. reimbursement) fac- tors, a key aim being the ultimate prevention of disa- The baseline median EDSS score of the CLARITY/ bility accumulation. However, the majority of CLARITY Extension population enrolled to high-efficacy DMTs achieve this benefit by apply- CLASSIC-MS was 2.50, and this remained relatively ing continuous immunosuppression, which may stable over the median follow-up of 10.9 years. When have a cumulative safety risk for patients. The overall the results of CLASSIC-MS are broken down by journals.sagepub.com/home/msj 725 Multiple Sclerosis Journal 29(6) Table 2. Responder findings of CLASSIC-MS: CLARITY/CLARITY Extension cohort in the 4 years since LPSD. Responder Never exposed Exposed to cladribine tablets Total definition, n (%) to cladribine (N = 435) tabletsa (N = 41) All exposed Subgroup exposed to patientsb (N = 394) 3.5 mg/kg dosec (N = 160) A. Not using further DMTs Yes 15 (36.6) 261 (66.2) 106 (66.3) 276 (63.4) No 24 (58.5) 108 (27.4) 41 (25.6) 132 (30.3) Not determined 2 (4.9) 25 (6.3) 13 (8.1) 27 (6.2) B. No evidence of disease reactivation Yes 11 (26.8) 198 (50.3) 80 (50.0) 209 (48.0) No 28 (68.3) 178 (45.2) 70 (43.8) 206 (47.4) Not determined 2 (4.9) 18 (4.6) 10 (6.3) 20 (4.6) C. Not using further DMTs and no evidence of disease reactivation Yes 6 (14.6) 136 (34.5) 57 (35.6) 142 (32.6) No 34 (82.9) 229 (58.1) 89 (55.6) 263 (60.5) Not determined 1 (2.4) 29 (7.4) 14 (8.8) 30 (6.9) DMT: disease-modifying therapy; LPSD: last parent study dose. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). Figure 6. Kaplan–Meier curve for time to first subsequent DMT after last parent study dose in CLARITY/CLARITY Extension. DMT: disease-modifying therapy. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). treatment cohort, we observed that patients exposed to patients who were never exposed to active treatment cladribine tablets had a 1.0-point increase in median had a 1.5-point increase in median scores, thus indicat- EDSS score over this timeframe (including those ing a greater extent of disease worsening during fol- patients receiving the 3.5 mg/kg dose); however, low-up. On one hand, these results are in line with 726 journals.sagepub.com/home/msj G Giovannoni, A Boyko et al. Table 3. Number of relapses since parent study dosing to Study Visit 1 of CLASSIC-MS: CLARITY/CLARITY Extension cohort. Never exposed to Exposed to cladribine tablets Total (N = 435) cladribine tabletsa (N = 41) All exposed Subgroup exposed patientsb (N = 394) to 3.5 mg/kg dosec (N = 160) Annualized relapse rate, n (95% CI)d Since FPSD 0.26 (0.22–0.31) 0.16 (0.15–0.17) 0.17 (0.16–0.19) 0.17 (0.16–0.18) Since LPSD 0.23 (0.19–0.27) 0.12 (0.11–0.14) 0.13 (0.11–0.14) 0.14 (0.13–0.15) Number of relapses since FPSD, n (%) 0 7 (17.1) 124 (31.5) 39 (24.4) 131 (30.1) 1 7 (17.1) 79 (20.1) 34 (21.3) 86 (19.8) 2 7 (17.1) 65 (16.5) 29 (18.1) 72 (16.6) 3 7 (17.1) 39 (9.9) 21 (13.1) 46 (10.6) 4 1 (2.4) 27 (6.9) 9 (5.6) 28 (6.4) 5 1 (2.4) 19 (4.8) 10 (6.3) 20 (4.6) ⩾6 11 (26.8) 41 (10.4) 18 (11.3) 52 (12.0) Number of relapses since LPSD, n (%) 0 11 (26.8) 189 (48.0) 75 (46.9) 200 (46.0) 1 7 (17.1) 86 (21.8) 33 (20.6) 93 (21.4) 2 6 (14.6) 50 (12.7) 27 (16.9) 56 (12.9) 3 5 (12.2) 27 (6.9) 7 (4.4) 32 (7.4) 4 3 (7.3) 13 (3.3) 5 (3.1) 16 (3.7) 5 1 (2.4) 7 (1.8) 4 (2.5) 8 (1.8) ⩾6 8 (19.5) 22 (5.6) 9 (5.6) 30 (69.0) CI: confidence interval; FPSD: first parent study dose; LPSD: last parent study dose. aNever-exposed cohort received only placebo during the parent studies. bExposed cohort includes all patients who received ⩾1 dose of cladribine tablets during the parent studies. cA subgroup of the exposed cohort in which patients received 3.5 mg/kg cumulative dose over 2 years during the parent studies (N = 160/394). dAnnualized relapse rate calculated as the (total number of relapses × 365.25)/total time on study until Study Visit 1. Confidence intervals were estimated using a Poisson regression model of the relapse count as dependent variable, fixed effect for treatment group, and the log of time on study as offset variable. those seen in long-term follow-up studies of other never exposed to active treatment had seemingly DMTs. Results from the Tysabri Observational worse disability outcomes compared with patients Program, for example, showed that EDSS scores who received cladribine tablets. These are important remained stable over a 10-year period in patients findings since, as an example, the need to use an treated with natalizumab.12 Similarly, EDSS scores for ambulatory device can have a detrimental impact on a patients treated with fingolimod remained stable over person’s quality of life.15 10 years.13 It is important to consider that both natali- zumab and fingolimod are maintenance therapies that Increasing EDSS scores may also impact the ability rely on constant immunosuppression to maintain effi- of a person with MS to remain in employment.16 cacy. In contrast, patients who received cladribine tab- Indeed, employment—and the known importance to lets had exposure to the therapy for only very short personal identity—is very relevant to people living periods, with lymphocyte recovery that begins soon with MS, the majority of whom are diagnosed during after each treatment course in Years 1 and 2.14 their employment years. In the absence of cognitive, social, and emotional data in this study, the findings In the CLASSIC-MS study, other disability outcomes for employment status, therefore, represent an impor- were consistent with EDSS scores for the respective tant proxy endpoint. It is therefore a notable finding exposed and never-exposed cohorts, and the subgroup that, at Study Visit 1, 51% of patients exposed to clad- of patients exposed to the cumulative 3.5 mg/kg dose. ribine tablets were in employment compared to only Specifically, we observed that patients who were 27.5% of never-exposed patients. While such results journals.sagepub.com/home/msj 727 Multiple Sclerosis Journal 29(6) are covered by a caveat due to unknown employment possible to calculate responder rates for definitions status at the parent study baseline, findings for the based on imaging findings. Similarly, employment never-exposed cohort are in line with reports of high status at parent study baseline was not collected, rates of unemployment17 and early retirement18 among thus limiting the interpretation of employment- the MS community. related results. Following treatment in CLARITY/CLARITY An important consideration, in terms of contextualiz- Extension, we observed that patients exposed to ing the study findings, is that we do not know why cladribine tablets were less likely to use a subse- more patients appeared to have disease reactivation quent DMT since LPSD, with an approximate 10% than had another DMT (and the reason for switching), increase in the use of subsequent DMTs between the while the subsequent DMTs used by patients after the 4-year and median 10.9-year analyses (a change completion of the parent studies were reflective of from 66.2% to 55.8% for patients exposed to clad- those available in the intervening follow-up period ribine tablets vs a change of 36.6%–26.8% in the (2010–2021). Indeed, there were limited high-effi- never-exposed cohort). Nearly one-third of the cacy treatments available for MS at the time of the patients (34.5%) exposed to cladribine did not use CLARITY study (initiated in 2007). In addition, when another DMT and had no evidence of disease reacti- considering the time to first subsequent DMT, it is vation 4 years after LPSD as opposed to 14.6% of important to consider that local access to healthcare never-exposed patients. This mirrors the disability and/or the availability of DMTs within individual and ARR findings, in that the proportion of patients countries may be a factor. not using a wheelchair in the 3 months prior to Study Visit 1 and not bedridden at any time since LPSD was 90.0% and 77.8%, respectively, for the exposed Conclusion and never-exposed cohorts, while ARR in the latter The results from this analysis of the CLARITY/ cohort was almost double that observed in the CLARITY Extension cohort of the CLASSIC-MS exposed cohort. This greater relapse rate may have study indicate that patients treated with cladribine had an impact on the initial time to treatment switch tablets had a lower risk of reaching EDSS 6 or 7 dur- findings. ing the median 10.9 years of follow-up compared with patients who were never exposed to active treatment with cladribine tablets. The majority of patients who Study limitations were exposed to cladribine tablets were also less Due to the exploratory nature of the CLASSIC-MS likely to use further DMTs during the median 10.9- study, no formal sample size calculations were con- year period since LPSD. In addition, the time-to-event ducted. The study planned to enroll 788 patients, yet a analyses indicated that these patients had a longer final population of 662 patients was actually included. estimated median time until the first subsequent DMT Feasibility assessments were conducted, and there (12 years vs 2.5 years for the never-exposed cohort), were various reasons why some of the original parent with better outcomes over the 4 years since LPSD in study sites were not included in CLASSIC-MS, the responder analyses. Favorable outcomes were including the absence of the former/a new site inves- also observed in the subgroup of patients exposed to a tigator, a limited number/no patients at a site, and no cladribine tablets dose of 3.5 mg/kg over 2 years. retrospective data on file. Although it is unknown Together, these findings support previous studies that what happened to patients who did not enroll to the have reported on the sustained efficacy of cladribine CLASSIC-MS study, baseline disease characteristics tablets following treatment. of patients who did enroll were considered to be gen- erally representative of patients from the parent stud- Acknowledgements ies and therefore partially addresses the potential The authors thank patients and their families, investi- selection bias (Supplemental Table 1). The population gators, co-investigators, and study teams at each of of CLASSIC-MS is also considered representative of the participating centers and at Merck Healthcare the general MS population due to similarities with the KGaA, Darmstadt, Germany. The authors also thank recently reported mean age of MS diagnosis (32 years) Kristin Gabriel for her expert contributions in devel- and the higher proportion of female patients living oping the study protocol for CLASSIC-MS. Medical with MS.19 writing assistance was provided by Claire Mwape of inScience Communications, Springer Healthcare Ltd, The MRI data collected during the CLASSIC-MS UK, and supported by Merck Healthcare KGaA, study were limited, and therefore, it was not Darmstadt, Germany. 728 journals.sagepub.com/home/msj G Giovannoni, A Boyko et al. Consent to Participate Teva, TG Therapeutics, Excemed, MSIF, and NMSS. Informed consent was obtained from all individual K.R. has received honoraria for lectures and steering participants included in the study. committee meetings from Acorda, Biogen, EMD Serono Research & Development Institute, Inc., Declaration of Conflicting Interests Billerica, MA, USA, an affiliate of Merck KGaA, The author(s) declared the following potential conflicts Novartis, Roche, Sanofi, and Teva. D.S. has received of interest with respect to the research, authorship, and/ consulting fees from Acorda, Biogen, EMD Serono or publication of this article: G.G. has received speaker Research & Development Institute, Inc., Billerica, honoraria and consulting fees from AbbVie, Actelion MA, USA, an affiliate of Merck KGaA, and Teva, and (Janssen/J&J), Atara Bio, Almirall, Bayer, Biogen, speaker fees from Acorda, Biogen, Elan, EMD Serono Celgene (BMS), FivePrime, GlaxoSmithKline, GW Research & Development Institute, Inc., Billerica, Pharmaceuticals, Ironwood, Merck & Co., Merck, MA, USA, an affiliate of Merck KGaA, and Teva. B.Y. Novartis, Pfizer Inc., Protein Discovery Laboratories, has received honoraria for lectures and advisory boards Roche, Sanofi, Teva, UCB, and Vertex Pharmaceuticals, from Bayer, Biogen, Genpharm, Merck, Novartis, and and has received research support unrelated to this Sanofi, and has received research grants from Bayer, study from Biogen, Ironwood, Merck & Co., Merck, Biogen, Merck, Novartis, and Pfizer. T.L. has received Novartis, and Takeda. A.B. has received honoraria as consultancy fees or clinical research grants from member of working groups, advisory boards and par- Acorda, Bayer, Biogen, Daiichi Sankyo, EMD Serono ticipated in clinical trials supported by Actelion Research & Development Institute, Inc., Billerica, (Janssen/J&J), Bayer, Biocad, Biogen, Generium, MA, USA, an affiliate of Merck KGaA, Novartis, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. J.C. ONO, Pfizer, and Teva. A.A. and E.V.d.C. are employ- is a board member of Merck-Serono Argentina, an ees of EMD Serono Research & Development Institute, affiliate of Merck KGaA, Biogen LATAM, Merck- Inc., Billerica, MA, USA, an affiliate of Merck KGaA. Serono LATAM, an affiliate of Merck KGaA, and L.B. is a medical consultant to Merck Healthcare Genzyme Global. Dr J.C. has received reimbursement KGaA, Darmstadt, Germany. for developing educational presentations for Merck- Serono Argentina, an affiliate of Merck KGaA, Merck- Ethical Approval Serono LATAM, an affiliate of Merck KGaA, Biogen This study was performed in line with the principles Argentina, Genzyme Argentina, and TEVA Argentina, of the Declaration of Helsinki. Approvals were as well as professional travel/accommodations sti- granted by the Ethics Committee specific to each pends. G.E. has received consulting fees and research study site involved in the CLASSIC-MS study. A full support from Biogen, Merck, Novartis, Roche, Sanofi, list of these Ethics Committees is provided in and Teva. M.S.F. has received honoraria or consulta- Supplemental Appendix 2. tion fees from Alexion, Apotex, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), EMD Inc., Canada, Funding an affiliate of Merck KGaA, Janssen (J&J), Merck, The author(s) disclosed receipt of the following finan- Novartis, Roche, and Sanofi; has been a member of a cial support for the research, authorship, and/or publi- company advisory board, board of directors, or other cation of this article: This study was sponsored by similar group for Alexion, Atara Biotherapeutics, Merck (CrossRef Funder ID: 10.13039/100009945). Bayer, BMS (Celgene), Janssen (J&J), McKesson, Merck, Novartis, Roche, and Sanofi; has participated Data Availability Statement in a company sponsored speaker’s bureau for EMD Any requests for data by qualified scientific and med- Serono Research & Development Institute, Inc., ical researchers for legitimate research purposes will Billerica, MA, USA, an affiliate of Merck KGaA and be subject to Merck’s Data Sharing Policy. All Sanofi; and has been in receipt of research or educa- requests should be submitted in writing to Merck’s tional grants from Sanofi. X.M. has received speaking data sharing portal https://www.merckgroup.com/en/ honoraria and travel expenses for participation in sci- research/our-approach-to-research-and-development/ entific meetings, and has been a steering committee healthcare/clinical-trials/commitment-responsi- member of clinical trials or participated in advisory ble-data-sharing.html. When Merck has a co-research, boards of clinical trials in the past years with Actelion co-development, or co-marketing or co-promotion (Janssen/J&J), Alexion, Bayer, Biogen, Celgene agreement, or when the product has been out-licensed, (BMS), EMD Serono Research & Development the responsibility for disclosure might be dependent Institute, Inc., Billerica, MA, USA, an affiliate of on the agreement between parties. Under these cir- Merck KGaA, Immunic, Janssen (J&J), MedDay, cumstances, Merck will endeavor to gain agreement Merck, Mylan, NervGen, Novartis, Roche, Sanofi, to share data in response to requests. journals.sagepub.com/home/msj 729 Multiple Sclerosis Journal 29(6) Supplemental Material treatment of people with multiple sclerosis. Mult Supplemental material for this article is available Scler 2018; 24: 96–120. online. 11. He A, Merkel B, Brown JWL, et al. Timing of high-efficacy therapy for multiple sclerosis: A retrospective observational cohort study. 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