Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies

Nicola De Stefano, Maria Pia Sormani, Gavin Giovannoni, Kottil Rammohan, Thomas Leist, Patricia K Coyle, Fernando Dangond, Birgit Keller, Nektaria Alexandri, Andrew Galazka, Nicola De Stefano, Maria Pia Sormani, Gavin Giovannoni, Kottil Rammohan, Thomas Leist, Patricia K Coyle, Fernando Dangond, Birgit Keller, Nektaria Alexandri, Andrew Galazka

Abstract

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment.

Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension.

Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98).

Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment.

Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

Keywords: Relapsing-remitting multiple sclerosis; cladribine tablets; disease-modifying therapy; hospitalisation; relapses; steroids.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.De.S. is a consultant for Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme and Teva; has grants or grants pending from FISM and Novartis; is on the speakers bureaus of Biogen, Merck KGaA (Darmstadt, Germany), Novartis, Roche and Sanofi-Genzyme; and has received travel funds from Merck KGaA (Darmstadt, Germany), Novartis, Sanofi-Genzyme, Roche and Teva. M.P.S. has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA (Darmstadt, Germany), Novartis, Roche and Teva. G.G. has received speaker honoraria and consulting fees from AbbVie, Actelion (Janssen/J&J), Atara Bio, Almirall, Bayer, Biogen, Celgene, FivePrime, GlaxoSmithKline, GW Pharma, Ironwood, Merck & Co., Merck KGaA (Darmstadt, Germany), Novartis, Pfizer Inc., Protein Discovery Laboratories, Roche, Sanofi-Genzyme, Teva Pharmaceutical Industries Ltd, UCB and Vertex Pharmaceuticals; and has received research support unrelated to this study from Biogen, Ironwood, Merck & Co., Novartis and Takeda. K.R. has received honoraria for lectures and steering committee meetings from Acorda, Biogen, EMD Serono, Genzyme, Novartis, Roche/Genentech, Sanofi-Aventis and Teva Neuroscience. T.L. has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer and Teva Neuroscience. P.K.C. is an advisor or consultant for Accordant, Alexion, Bayer, Biogen, EMD Serono, GlaxoSmithKline, Novartis, Roche/Genentech, Sanofi-Genzyme and TG Therapeutics; and received grants for clinical research from Actelion (Janssen/J&J), Alkermes, Corrona LLD, MedDay, NINDS, Novartis, PCORI and Roche/Genentech. F.D. is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, United States, an affiliate of Merck KGaA, Darmstadt, Germany. B.K. and N.A. are employees of Merck KGaA, Darmstadt, Germany. A.G. was an employee of Ares Trading S.A., Eysins, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany) at the time of the study and is currently a consultant to Merck KGaA, Darmstadt, Germany.

Figures

Figure 1.
Figure 1.
CLARITY and CLARITY Extension study design. Adapted from the study by Giovannoni et al. *Cladribine tablets 3.5 mg/kg over 2 years is the only approved dose. †Patients were re-assigned to cladribine tablets 3.5 mg/kg upon entry to CLARITY Extension. ‡Patients were re-randomised upon entry to CLARITY Extension. CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; PC 3.5 mg/kg: placebo in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; SUPF: supplemental follow-up. n: numbers are representative of the intention-to-treat population. Treatment groups shown in coloured and bolded text were analysed in this study.
Figure 2.
Figure 2.
Relapse rates at Month 6, Year 1 and Year 2 for patients treated with cladribine tablets 3.5 mg/kg versus placebo in CLARITY. RR: relative risk; CI: confidence interval.
Figure 3.
Figure 3.
Annualised relapse rates for overall and severe relapses (requiring steroid treatment or leading to hospitalisation) at Study Year 2 in CLARITY and Study Year 4 in CLARITY Extension (CP.3.5 mg/kg group only). The overall ARRs for qualifying relapses differ slightly from those published in the studies by Giovannoni et al. (CT 3.5 mg/kg ARR (95% CI): 0.14 (0.12; 0.17) and Giovannoni et al. (CP 3.5 mg/kg ARR (95% CI): 0.15 (0.09; 0.21)). The following adjustments to the methodology of the present analysis account for these differences: (1) CLARITY analyses: the calculated ARRs included imputed data for patients who experienced relapses after receiving rescue medication and the Poisson model used was not adjusted for region and (2) CLARITY Extension analyses: ARRs were calculated for the 96-week, double-blind period only, and did not include data collected over the gap period or the 24-week safety follow-up period. ARR: annualised relapse rate; CI: confidence interval; CT 3.5 mg/kg: cladribine tablets 3.5 mg/kg; CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension.

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