1161494 MSJ0010.1177/13524585231161494Multiple Sclerosis JournalG Giovannoni, A Boyko
`
`research-article20232023
`
`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Original Research Paper
`
`Long-term follow-up of patients with relapsing
`multiple sclerosis from the CLARITY/
`CLARITY Extension cohort of CLASSIC-MS:
`An ambispective study
`
`Multiple Sclerosis Journal
`
`2023, Vol. 29(6) 719 –730
`
`DOI: 10.1177/
`https://doi.org/10.1177/13524585231161494
`13524585231161494
`https://doi.org/10.1177/13524585231161494
`
`© The Author(s), 2023.
`
`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
`
`Abstract
`Background: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relaps-
`ing multiple sclerosis.
`Objective: Report long-term mobility and disability beyond treatment courses received in CLARITY/
`CLARITY Extension.
`Methods: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without
`participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435).
`Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior
`to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e.
`Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability
`status (no use of an ambulatory device (EDSS < 6) at any time since LPSD).
`Results: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median
`time since LPSD was 10.9 (range = 9.3–14.9) years. Cladribine tablets–exposed population: 90.6%
`(N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not
`using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an
`ambulatory device: exposed, 81.2%; unexposed, 75.6%.
`Conclusion: With a median 10.9 years’ follow-up after CLARITY/CLARITY Extension, findings sug-
`gest the sustained long-term mobility and disability benefits of cladribine tablets.
`
`Keywords: Cladribine tablets, CLARITY, CLARITY Extension, disability, disease-modifying therapy,
`employment, Expanded Disability Status Scale, multiple sclerosis
`
`Date received: 23 August 2022; revised: 20 January 2023; accepted: 12 February 2023
`
`Introduction
`Multiple sclerosis (MS) is a chronic, inflammatory,
`demyelinating, and neurodegenerative disease of the
`central nervous system that is most commonly diag-
`nosed in young adults between the ages of 20 and
`50 years,1–3 and is typically characterized by frequent
`relapses paralleled by disability progression and cog-
`nitive impairment.4
`
`Cladribine tablets (3.5 mg/kg cumulative dose over
`2 years) is a high-efficacy disease-modifying therapy
`(DMT) approved for use in the treatment of relapsing
`MS, having shown significant benefits in both
`
`treatment naïve and treatment-experienced patients.5–7
`This agent has novel posology among available
`DMTs, in that it comprises a short treatment course at
`the beginning of the first and second months of two
`consecutive treatment years; thereafter, no further
`treatment with cladribine tablets is required in years 3
`and 4, in view of sustained efficacy.
`
`The CLARITY (CLAdRIbine Tablets for treating
`MS orallY) study, which recruited patients between
`April 2005 and January 2007, was conducted at a time
`when limited high-efficacy treatments were available
`and the diagnosis of MS was based on the older 2001
`
`journals.sagepub.com/home/msj
`
`Correspondence to:
`G Giovannoni
`Blizard Institute, Barts
`and The London School of
`Medicine and Dentistry,
`Queen Mary University of
`London, 4 Newark Street,
`London E1 2AT, UK.
`g.giovannoni@qmul.ac.uk
`
`Gavin Giovannoni
`Blizard Institute, Barts
`and The London School of
`Medicine and Dentistry,
`Queen Mary University of
`London, London, UK
`
`Alexey Boyko
`Department of Neurology,
`Neurosurgery and Medical
`Genetics, Federal Center
`of Brain Research and
`Neurotechnologies, Pirogov
`Russian National Research
`Medical University, Moscow,
`Russia
`
`Jorge Correale
`Department of Neurology,
`FLENI Institute, Buenos
`Aires, Argentina
`
`Gilles Edan
`Department of Neurology,
`University Hospital of
`Rennes, Rennes, France
`
`Mark S Freedman
`Department of Medicine and
`the Ottawa Hospital Research
`Institute, University of
`Ottawa, Ottawa, ON, Canada
`
`Xavier Montalban
`Department of Neurology-
`Neuroimmunology, Centre
`d’Esclerosi Múltiple de
`Catalunya (Cemcat), Hospital
`Universitario Vall d’Hebron,
`Barcelona, Spain
`
`Kottil Rammohan
`MS Research Center, School
`of Medicine, University of
`Miami, Miami, FL, USA
`
`Dusan Stefoski
`Department of Neurological
`Sciences, Rush Medical
`College, Chicago, IL, USA
`
`Bassem Yamout
`Neurology Institute, Harley
`Street Medical Center, Abu
`
`719
`
`Merck 2015
`TWi v Merck
`IPR2023-00049
`
`

`

`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
`CLARITY showed that short-course treatment with
`cladribine tablets significantly reduced relapse rates,
`the risk of disability progression, and improved mag-
`netic resonance imaging (MRI) outcomes.5 In turn,
`CLARITY Extension provided further evidence of
`tablets.6
`the
`sustained efficacy of cladribine
`Subsequent analysis of CLARITY Extension has
`indicated the sustained benefits of cladribine tablets
`in terms of no evidence of disease activity (NEDA-3),
`and for up to 6 years from the baseline of CLARITY.8
`
`(NCT03961204) was
`The CLASSIC-MS study
`designed to further explore the long-term efficacy and
`durability of the effect of cladribine tablets beyond the
`two annual treatment courses in patients enrolled in
`the parent trials of the Phase III development program
`(CLARITY, CLARITY Extension, and ORACLE MS
`[ORAl CLadribine in Early Multiple Sclerosis]). The
`analysis presented here focuses on the CLASSIC-MS
`patient population previously enrolled in CLARITY
`with or without subsequent enrollment to CLARITY
`Extension. Findings for the ORACLE MS cohort are
`to be reported elsewhere.
`
`Methods
`
`The analysis presented here concerns data for patients
`who participated in CLARITY with or without subse-
`quent enrollment to CLARITY Extension, for which
`the median time to follow-up in CLASSIC-MS since
`the
`last parent study dose (LPSD) was 10.9
`(range = 9.3–14.9) years. The time since LPSD was
`defined as the time since the last treatment dose of
`cladribine tablets or placebo during the parent study;
`this timing varies between patients depending on their
`enrollment in the CLARITY Extension study and the
`number of
`treatment courses
`received during
`CLARITY/CLARITY Extension
`(Supplemental
`Figure 1). To be eligible for inclusion in the current
`analysis, patients must have received ⩾1 course of
`cladribine tablets or placebo during the parent studies
`and must have been able to provide informed consent
`at the time of enrollment.
`
`During the first study visit of CLASSIC-MS (hereaf-
`ter referred to as “Study Visit 1”), retrospective data
`on Expanded Disability Status Scale (EDSS) score,9
`use of ambulatory device(s), relapses, and subsequent
`use of DMTs were collected along with employment
`status. For the purposes of analysis, “actively
`employed” included people who were “employed for
`wages,” “self-employed,” or considered themselves a
`“homemaker” at the time of Study Visit 1.
`
`Study design and endpoints
`CLASSIC-MS was an exploratory, low-interven-
`tional, multicenter, ambispective, Phase IV study of
`patients with MS (Figure 1), in which the assessment
`of patients took place across 98 centers in 29 coun-
`tries between 2019 and 2021.
`
`The primary objective of CLASSIC-MS was to evalu-
`ate long-term mobility by determining the proportion
`of patients not using a wheelchair in the 3 months
`prior to Study Visit 1 and not bedridden at any time
`since LPSD, as determined by a level of functioning
`consistent with an EDSS score <7. Where EDSS
`
`720
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`

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`G Giovannoni, A Boyko et al.
`
`scores were not available, alternative clinical descrip-
`tions in the medical records were used.
`
`Secondary objectives were to assess long-term disa-
`bility status by determining the proportion of patients
`not using an ambulatory device since LPSD. This
`was determined by a level of functioning consistent
`with an EDSS score <6 or alternative clinical
`descriptions.
`
`The tertiary objectives were to determine real-world
`treatment patterns by assessing the number, type, and
`timing of subsequent DMT use, and the durability of
`clinical outcomes as assessed by the time from first
`[F]/[L]PSD to use of an ambulatory device.
`
`In this study, a positive treatment response during the
`4-year period since LPSD was defined using three
`variables, with responses categorized as “Yes,” “No,”
`and “Not determined”:
`
`(a) Not using further DMT(s);
`(b) No evidence of disease reactivation based on
`medical records and investigator assessments
`of clinical outcomes; and
`(c) Not using further DMT(s) and no evidence of
`disease reactivation.
`
`Safety data were not evaluated as part of the
`CLASSIC-MS study, having been reported on as part
`of the parent studies.
`
`Statistical analysis
`Data evaluation and interpretation are based on point
`estimates and 95% confidence intervals (CIs). Due to
`the exploratory and hypothesis-generating nature of
`the study, no testing of formal statistical hypotheses
`or adjustments for multiple comparisons was per-
`formed. Time-to-event analyses are presented using
`the Kaplan–Meier estimates and cumulative inci-
`dence curves. Findings are presented according to
`patient exposure/non-exposure to cladribine tablets
`in the parent studies (i.e. CLARITY/CLARITY
`Extension), and separately for those who received a
`cladribine tablets dose of 3.5 mg/kg over 2 years.
`Analyses were performed using SAS® software ver-
`sion 9.4 or higher.
`
`This population had a median age of 52.5 (range = 32–
`79) years and was predominantly female (67.8%).
`Concerning disability, patients had a median EDSS
`score of 3.5 (range = 0.0–9.0) at Study Visit 1 of
`CLASSIC-MS compared with 2.5 (range = 0.0–5.5)
`at the parent study baseline. For patients exposed to
`cladribine tablets, there was a 1.0-point increase in
`median EDSS scores between the parent study base-
`line and Study Visit 1 compared with a 1.5-point
`increase in patients who were never exposed to
`active treatment. Of the 435 patients included in this
`analysis, 90.6% (394/435) had been exposed to clad-
`ribine tablets in the parent studies, with 160 patients
`having received a cumulative dose of 3.5 mg/kg over
`2 years, with the other 234 patients having been
`exposed to varying doses of cladribine tablets during
`the parent studies (Supplemental Figure 1). Baseline
`characteristics of the exposed and never-exposed
`cohorts of CLASSIC-MS patients from CLARITY/
`CLARITY Extension were largely similar, as shown
`in Table 1. Overall, baseline disease characteristics
`of patients enrolled on CLASSIC-MS were similar
`to those who were not enrolled on the study
`(Supplemental Table 1).
`
`Primary endpoint (median 10.9 years since LPSD)
`In this study population, 88.9% of evaluable patients
`(369/415) were not using a wheelchair in the 3 months
`prior to Study Visit 1 and were not bedridden at any
`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
`patients who were exposed to cladribine tablets (odds
`ratio = 0.39, 95% CI = 0.17–0.93; p = 0.034) (Figure
`2). For patients receiving cladribine tablets 3.5 mg/kg
`over 2 years, 88.2% (134/152) were not using a wheel-
`chair and were not bedridden during these same time
`periods. When compared with the never-exposed
`cohort (36/41), this provided an odds ratio of 0.52
`(95% CI = 0.20–1.33; p = 0.173).
`
`In terms of time to the first use of an ambulatory
`device since LPSD (tertiary endpoint), 28.9%
`(114/394) of patients exposed to cladribine tablets
`and 46.3% (19/41) of never-exposed patients had an
`event with an estimated time of 9.9 and 7.2 years for
`25% of patients to reach an event, respectively
`(Figure 3).
`
`Results
`A total of 435 patients from CLARITY with or with-
`out subsequent enrollment to CLARITY Extension
`(of whom 345 patients participated in both studies)
`were included in this analysis of CLASSIC-MS.
`
`Secondary endpoint (median 10.9 years since
`LPSD)
`In this study population, 80.7% (351/435) of patients
`did not use an ambulatory device at any time since
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`Multiple Sclerosis Journal 29(6)
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`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
`cladribine tabletsa
`(N = 41)
`
`Exposed to cladribine tablets
`
`Total (N = 435)
`
`All exposed
`patientsb (N = 394)
`
`264 (67.0)
`52.8 ± 9.56
`22.36 ± 6.99
`
`Subgroup exposed
`to 3.5 mg/kg dosec
`(N = 160)
`
`103 (64.4)
`51.7 (9.76)
`21.32 ± 6.21
`
`295 (67.8)
`52.7 ± 9.62
`22.36 ± 6.97
`
`11.14 ± 1.17
`10.79 (9.3–14.9)
`
`11.05 ± 1.15
`10.65 (9.5–14.4)
`
`11.35 ± 1.31
`10.89 (9.3–14.9)
`
`1.86 ± 1.27
`1.01 (0.0–4.6)
`
`2.82 ± 1.29
`2.50 (0.0–5.5)
`
`3.82 ± 2.01
`3.50 (0.0–9.0)
`1.3 ± 0.59
`
`292 (74.1)
`102 (25.9)
`83 (21.1)
`
`110 (27.9)
`
`146 (37.1)
`23 (5.8)
`32 (8.1)
`74 (18.8)
`82 (20.8)
`37 (9.4)
`
`1.01 ± 0.05
`0.99 (0.9–1.2)
`
`2.74 ± 1.31
`2.50 (0.0–5.5)
`
`3.78 ± 2.07
`3.50 (0.0–9.0)
`1.3 ± 0.62
`
`116 (72.5)
`44 (27.5)
`34 (21.3)
`
`48 (30.0)
`
`60 (37.5)
`10 (6.3)
`16 (10.0)
`26 (16.3)
`34 (21.3)
`14 (8.8)
`
`1.77 ± 1.25
`1.00 (0.0–4.6)
`
`2.82 ± 1.29
`2.50 (0.0–5.5)
`
`3.87 ± 2.07
`3.50 (0.0–9.0)
`1.3 ± 0.62
`
`321 (73.8)
`114 (26.2)
`94 (21.6)
`
`128 (29.4)
`
`154 (35.4)
`23 (5.3)
`35 (8.0)
`81 (18.6)
`96 (22.1)
`46 (10.6)
`
`31 (75.6)
`51.6 ± 10.25
`22.38 ± 6.85
`
`2.74 ± 1.33
`3.00 (0.0–5.5)
`
`4.50 ± 2.59
`4.50 (0.0–9.0)
`1.6 ± 0.78
`
`Female, n (%)
`Age at Study Visit 1 (years), mean ± SD
`Disease duration at Study Visit 1d
`(years), mean ± SD
`Time since the last dose in the parent study to Study Visit 1 (years)
` Mean ± SD
`13.50 ± 0.47
` Median (range)
`13.40 (12.4–14.5)
`Duration of treatment during parent study (years)e
` Mean ± SD
`0.85 ± 0.31
` Median (range)
`0.99 (0.1–1.2)
`EDSS score at parent study baseline
` Mean ± SD
` Median (range)
`EDSS score at Study Visit 1
` Mean ± SD
` Median (range)
`Number of relapses in the 12 months
`before enrollment to parent study,
`mean ± SD
`Type of MS at CLASSIC-MS screening, n (%)
` RRMS
` SPMS
`Prior use of DMT at parent study
`baseline, n (%)
`HDAf status at parent study baseline,
`n (%)
`Employment status at Study Visit 1, n (%)
` Employed for wages
` Self-employed
` Homemaker
` Retired
` Out of work/unable to work
` Unknowng
`
`29 (70.7)
`12 (29.3)
`11 (26.8)
`
`18 (43.9)
`
`8 (19.5)
`0 (0)
`3 (7.3)
`7 (17.1)
`14 (34.1)
`9 (22.0)
`
`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
`exposed to active treatment, the corresponding pro-
`portion was 75.6% (31/41) compared with 81.2%
`(320/394) of patients who were exposed
`to
`
`cladribine tablets (Figure 4). For patients receiving
`cladribine tablets 3.5 mg/kg over 2 years, 78.8%
`(126/160) did not use an ambulatory device at any
`time since LPSD.
`
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`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.
`
`Patients exposed to cladribine tablets during the par-
`ent studies were less likely to use further DMTs after
`LPSD. This is indicated by 55.8% (220/394) of the
`exposed cohort, versus 26.8% (11/41) in the never-
`exposed cohort, receiving no subsequent treatments
`during follow-up (Figure 5). For patients receiving
`cladribine tablets 3.5 mg/kg over 2 years, 58.1%
`(93/160) received no further DMTs after LPSD.
`
`In terms of time-to-event analysis, patients exposed to
`cladribine tablets had an estimated median time of
`12.0 years until the first subsequent DMT; the corre-
`sponding timeframe for patients never exposed to
`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).
`
`A low proportion of patients received a second subse-
`quent DMT following treatment with cladribine tab-
`lets; 14.2% (56/394) of patients exposed to cladribine
`tablets and 29.2% (12/41) of never-exposed patients.
`For patients receiving cladribine tablets 3.5 mg/kg
`over 2 years, 18.8% (30/160) received a second subse-
`quent DMT.
`
`The proportions of patients receiving a third subse-
`quent DMT were lower still; 7.3% (3/41) never
`exposed, 4.6% (18/394) exposed to cladribine tablets,
`and 6.9% (11/160) of those who received the 3.5 mg/
`kg dose over 2 years.
`
`Relapses (median 10.9 years since LPSD)
`During the time period since LPSD to Study Visit 1, a
`total of 200 patients did not experience a relapse. The
`proportion of patients in the exposed cohort who were
`relapse-free was approximately two times higher than
`
`Figure 2. Patients not using a wheelchair in the 3 months
`prior to Study Visit 1 and not bedridden at any time since
`LPSD (EDSS < 7): CLARITY/CLARITY Extension
`cohort.
`CI: confidence interval; EDSS: Expanded Disability Status Scale;
`LPSD: last parent study dose; OR: odds ratio.
`Missing data were not included in the analysis (n = 5, n = 15, and
`n = 8 for never exposed, exposed, and exposed to cladribine tablets
`3.5 mg/kg over 2 years, respectively).
`aFrom a logistic regression model with fixed effects for treatment
`group and disease duration.
`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).
`
`Response at 4 years since LPSD
`Findings of the 4-year responder analyses indicated
`that 63.4% (276/435) of patients did not use a subse-
`quent DMT; 48.0% (209/435) showed no evidence of
`disease reactivation, and 32.6% (142/435) did not use
`a subsequent DMT and also showed no evidence of
`disease reactivation (Table 2).
`
`When analyzed by cohort, 66.2% (261/394) of
`patients exposed to cladribine tablets used no subse-
`quent DMT(s) compared with 36.6% (15/41) in the
`never-exposed cohort. No evidence of disease reacti-
`vation was observed in 50.3% (198/394) of patients
`exposed to cladribine tablets compared with 26.8%
`(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
`met these criteria compared with 14.6% (6/41) of
`patients in the never-exposed cohort. For patients
`receiving cladribine tablets 3.5 mg/kg over 2 years,
`results
`for
`the
`4-year
`responder
`analyses
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`Multiple Sclerosis Journal 29(6)
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`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:
`48.0% (189/394) and 26.8% (11/41), respectively
`(Table 3). The annualized relapse rate (ARR) since
`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%
`CI = 0.19–0.27)). For patients receiving cladribine
`tablets 3.5 mg/kg over 2 years, the ARR during the
`time period
`since LPSD was 0.13
`(95%
`
`CI = 0.11–0.14). Similar trends were apparent for the
`analysis of relapse rates since first parent study dose
`(FPSD) (Table 3).
`
`Employment (median 10.9 years since LPSD)
`Of the 435 patients included in this analysis, 48.7%
`(212/435) were in employment at Study Visit 1 (Table
`1). The proportion of patients in active employment at
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`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-
`pared to the never-exposed cohort; 51.0% (201/394)
`and 27.5% (11/40), respectively.
`
`Discussion
`Early treatment initiation is critical to the optimiza-
`tion of outcomes in people living with MS. Indeed,
`evidence-based clinical practice guidelines for the
`management of these individuals support prompt
`treatment decisions such as the use of high-efficacy
`DMTs earlier in the disease course, for appropriate
`patients.10 Such treatment decisions incorporate the
`degree of disease activity and other patient, clinical,
`biomarker, and intangible (e.g. reimbursement) fac-
`tors, a key aim being the ultimate prevention of disa-
`bility accumulation. However,
`the majority of
`high-efficacy DMTs achieve this benefit by apply-
`ing continuous immunosuppression, which may
`have a cumulative safety risk for patients. The overall
`
`findings of the present analysis also raise an interest-
`ing question as to the effects of timing of initiation of
`high-efficacy DMTs and long-term outcomes. Data
`from the MSBase and Swedish MS registries, for
`example, have identified that early initiation of high-
`efficacy therapies (within 2 years of disease onset)
`had a beneficial effect on disability when compared
`with later treatment initiation.11 The exploratory,
`ambispective CLASSIC-MS study, with a median of
`10.9 years’ follow-up since LPSD, therefore provides
`important new information on the long-term efficacy
`of cladribine tablets for patients who originally par-
`ticipated in CLARITY with or without subsequent
`enrollment in CLARITY Extension.
`
`The baseline median EDSS score of the CLARITY/
`CLARITY Extension population
`enrolled
`to
`CLASSIC-MS was 2.50, and this remained relatively
`stable over the median follow-up of 10.9 years. When
`the results of CLASSIC-MS are broken down by
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`Multiple Sclerosis Journal 29(6)
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`Table 2. Responder findings of CLASSIC-MS: CLARITY/CLARITY Extension cohort in the 4 years since LPSD.
`
`Responder
`definition, n (%)
`
`Never exposed
`to cladribine
`tabletsa (N = 41)
`
`Exposed to cladribine tablets
`
`All exposed
`patientsb (N = 394)
`
`Subgroup exposed to
`3.5 mg/kg dosec (N = 160)
`
`261 (66.2)
`108 (27.4)
`25 (6.3)
`
`A. Not using further DMTs
` Yes
`15 (36.6)
` No
`24 (58.5)
` Not determined
`2 (4.9)
`B. No evidence of disease reactivation
`198 (50.3)
` Yes
`11 (26.8)
`178 (45.2)
` No
`28 (68.3)
`18 (4.6)
` Not determined
`2 (4.9)
`C. Not using further DMTs and no evidence of disease reactivation
` Yes
`6 (14.6)
`136 (34.5)
` No
`34 (82.9)
`229 (58.1)
` Not determined
`1 (2.4)
`29 (7.4)
`
`106 (66.3)
`41 (25.6)
`13 (8.1)
`
`80 (50.0)
`70 (43.8)
`10 (6.3)
`
`57 (35.6)
`89 (55.6)
`14 (8.8)
`
`Total
`(N = 435)
`
`276 (63.4)
`132 (30.3)
`27 (6.2)
`
`209 (48.0)
`206 (47.4)
`20 (4.6)
`
`142 (32.6)
`263 (60.5)
`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
`cladribine tablets had a 1.0-point increase in median
`EDSS score over this timeframe (including those
`patients receiving the 3.5 mg/kg dose); however,
`
`patients who were never exposed to active treatment
`had a 1.5-point increase in median scores, thus indicat-
`ing a greater extent of disease worsening during fol-
`low-up. On one hand, these results are in line with
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`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
`cladribine tabletsa
`(N = 41)
`
`Exposed to cladribine tablets
`
`Total (N = 435)
`
`All exposed
`patientsb (N = 394)
`
`Subgroup exposed
`to 3.5 mg/kg dosec
`(N = 160)
`
`0.16 (0.15–0.17)
`0.12 (0.11–0.14)
`
`0.17 (0.16–0.19)
`0.13 (0.11–0.14)
`
`
`0.17 (0.16–0.18)
`0.14 (0.13–0.15)
`
`131 (30.1)
`86 (19.8)
`72 (16.6)
`46 (10.6)
`28 (6.4)
`20 (4.6)
`52 (12.0)
`
`200 (46.0)
`93 (21.4)
`56 (12.9)
`32 (7.4)
`16 (3.7)
`8 (1.8)
`30 (69.0)
`
`Annualized relapse rate, n (95% CI)d
` Since FPSD
`0.26 (0.22–0.31)
` Since LPSD
`0.23 (0.19–0.27)
`Number of relapses since FPSD, n (%)
` 0
`7 (17.1)
` 1
`7 (17.1)
` 2
`7 (17.1)
` 3
`7 (17.1)
` 4
`1 (2.4)
` 5
`1 (2.4)
` ⩾6
`11 (26.8)
`Number of relapses since LPSD, n (%)
` 0
`11 (26.8)
` 1
`7 (17.1)
` 2
`6 (14.6)
` 3
`5 (12.2)
` 4
`3 (7.3)
` 5
`1 (2.4)
` ⩾6
`8 (19.5)
`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.
`
`124 (31.5)
`79 (20.1)
`65 (16.5)
`39 (9.9)
`27 (6.9)
`19 (4.8)
`41 (10.4)
`
`189 (48.0)
`86 (21.8)
`50 (12.7)
`27 (6.9)
`13 (3.3)
`7 (1.8)
`22 (5.6)
`
`39 (24.4)
`34 (21.3)
`29 (18.1)
`21 (13.1)
`9 (5.6)
`10 (6.3)
`18 (11.3)
`
`75 (46.9)
`33 (20.6)
`27 (16.9)
`7 (4.4)
`5 (3.1)
`4 (2.5)
`9 (5.6)
`
`those seen in long-term follow-up studies of other
`DMTs. Results from
`the Tysabri Observational
`Program, for example, showed that EDSS scores
`remained stable over a 10-year period in patients
`treated with natalizumab.12 Similarly, EDSS scores for
`patients treated with fingolimod remained stable over
`10 years.13 It is important to consider that both natali-
`zumab and fingolimod are maintenance therapies that
`rely on constant immunosuppression to maintain effi-
`cacy. In contrast, patients who received cladribine tab-
`lets had exposure to the therapy for only very short
`periods, with lymphocyte recovery that begins soon
`after each treatment course in Years 1 and 2.14
`
`In the CLASSIC-MS study, other disability outcomes
`were consistent with EDSS scores for the respective
`exposed and never-exposed cohorts, and the subgroup
`of patients exposed to the cumulative 3.5 mg/kg dose.
`Specifically, we observed that patients who were
`
`never exposed to active treatment had seemingly
`worse disability outcomes compared with patients
`who received cladribine tablets. These are important
`findings since, as an example, the need to use an
`ambulatory device can have a detrimental impact on a
`person’s quality of life.15
`
`Increasing EDSS scores may also impact the ability
`of a person with MS to remain in employment.16
`Indeed, employment—and the known importance to
`personal identity—is very relevant to people living
`with MS, the majority of whom are diagnosed during
`their employment years. In the absence of cognitive,
`social, and emotional data in this study, the findings
`for employment status, therefore, represent an impor-
`tant proxy endpoint. It is therefore a notable finding
`that, at Study Visit 1, 51% of patients exposed to clad-
`ribine tablets were in employment compared to only
`27.5% of never-exposed patients. While such results
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`Multiple Sclerosis Journal 29(6)
`
`are covered by a caveat due to unknown employment
`status at the parent study baseline, findings for the
`never-exposed cohort are in line with reports of high
`rates of unemployment17 and early retirement18 among
`the MS community.
`
`possible to calculate responder rates for definitions
`based on imaging findings. Similarly, employment
`status at parent study baseline was not collected,
`thus limiting the interpretation of employment-
`related results.
`
`in CLARITY/CLARITY
`treatment
`Following
`Extension, we observed that patients exposed to
`cladribine tablets were less likely to use a subse-
`quent DMT since LPSD, with an approximate 10%
`increase in the use of subsequent DMTs between the
`4-year and median 1