Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study

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, Elisabetta Verdun di Cantogno, 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, Elisabetta Verdun di Cantogno

Abstract

Background: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing 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 suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Keywords: CLARITY; CLARITY Extension; Cladribine tablets; Expanded Disability Status Scale; disability; disease-modifying therapy; employment; multiple sclerosis.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.G. has received speaker honoraria and consulting fees from AbbVie, Actelion (Janssen/J&J), Atara Bio, Almirall, Bayer, Biogen, Celgene (BMS), FivePrime, GlaxoSmithKline, GW Pharmaceuticals, Ironwood, Merck & Co., Merck, Novartis, Pfizer Inc., Protein Discovery Laboratories, Roche, Sanofi, Teva, UCB, and Vertex Pharmaceuticals, and has received research support unrelated to this study from Biogen, Ironwood, Merck & Co., Merck, Novartis, and Takeda. A.B. has received honoraria as member of working groups, advisory boards and participated in clinical trials supported by Actelion (Janssen/J&J), Bayer, Biocad, Biogen, Generium, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. J.C. is a board member of Merck-Serono Argentina, an affiliate of Merck KGaA, Biogen LATAM, Merck-Serono LATAM, an affiliate of Merck KGaA, and Genzyme Global. Dr J.C. has received reimbursement for developing educational presentations for Merck-Serono Argentina, an affiliate of Merck KGaA, Merck-Serono LATAM, an affiliate of Merck KGaA, Biogen Argentina, Genzyme Argentina, and TEVA Argentina, as well as professional travel/accommodations stipends. G.E. has received consulting fees and research support from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. M.S.F. has received honoraria or consultation fees from Alexion, Apotex, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), EMD Inc., Canada, an affiliate of Merck KGaA, Janssen (J&J), Merck, Novartis, Roche, and Sanofi; has been a member of a company advisory board, board of directors, or other similar group for Alexion, Atara Biotherapeutics, Bayer, BMS (Celgene), Janssen (J&J), McKesson, Merck, Novartis, Roche, and Sanofi; has participated in a company sponsored speaker’s bureau for EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA and Sanofi; and has been in receipt of research or educational grants from Sanofi. X.M. has received speaking honoraria and travel expenses for participation in scientific meetings, and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion (Janssen/J&J), Alexion, Bayer, Biogen, Celgene (BMS), EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Immunic, Janssen (J&J), MedDay, Merck, Mylan, NervGen, Novartis, Roche, Sanofi, Teva, TG Therapeutics, Excemed, MSIF, and NMSS. K.R. has received honoraria for lectures and steering committee meetings from Acorda, Biogen, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Novartis, Roche, Sanofi, and Teva. D.S. has received consulting fees from Acorda, Biogen, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and Teva, and speaker fees from Acorda, Biogen, Elan, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and Teva. B.Y. has received honoraria for lectures and advisory boards from Bayer, Biogen, Genpharm, Merck, Novartis, and Sanofi, and has received research grants from Bayer, Biogen, Merck, Novartis, and Pfizer. T.L. has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi Sankyo, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Novartis, ONO, Pfizer, and Teva. A.A. and E.V.d.C. are employees of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. L.B. is a medical consultant to Merck Healthcare KGaA, Darmstadt, Germany.

Figures

Figure 1.
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.
Figure 2.
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 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).
Figure 3.
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.
Figure 4.
Patients who were not using an ambulatory device at any time since last parent study dose (EDSS 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 5.
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).
Figure 6.
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).

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