Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies

Gavin Giovannoni, Giancarlo Comi, Kottil Rammohan, Peter Rieckmann, Fernando Dangond, Birgit Keller, Dominic Jack, Patrick Vermersch, Gavin Giovannoni, Giancarlo Comi, Kottil Rammohan, Peter Rieckmann, Fernando Dangond, Birgit Keller, Dominic Jack, Patrick Vermersch

Abstract

Introduction: In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets.

Methods: Patients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated-patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences.

Results: The median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0-3.5) compared with 3.0 (2.5-3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0-3.0) compared with 2.5 (2.5-3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline.

Conclusions: These findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose.

Trial registration: ClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension).

Trial registration: ClinicalTrials.gov NCT00213135 NCT00641537 NCT00021313.

Keywords: CLARITY; CLARITY Extension; Cladribine tablets; Disease stability; Multiple sclerosis.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
CLARITY/CLARITY Extension study treatment arms under analysis. The dashed line signifies that there was a delay in transitioning to CLARITY Extension for some patients, i.e. those who had already completed CLARITY prior to the sponsor initiating the CLARITY Extension study. This variable bridging interval ranged from 0.1 to 118 (median, 40.3) weeks. The difference in group sizes is an artefact of the re-randomization schedule, in that patients who received cladribine tablets in CLARITY were re-randomized (2:1) to cladribine tablets 3.5 mg/kg or placebo in CLARITY Extension. Consequently, the CC7 group contained twice as many patients as the CP3.5 group
Fig. 2
Fig. 2
EDSS scores over time in the CP3.5 and CC7 patient groups. Line = Median, Circles = Mean, Box = Q1, Q3. Lower and upper whiskers reflect the minimum and maximum EDSS score. CC7, patients randomized to cladribine tablets 3.5 mg/kg in both CLARITY and CLARITY Extension; CP3.5, patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY Extension; EDSS, Expanded Disability Status Scale. Reprinted with permission from ePresentation Sessions. Eur J Neurol 2020;27(Suppl. 1):468
Fig. 3
Fig. 3
Change in EDSS score in each 12-month period up to 5 years in the CP3.5 and CC7 patient groups. Improvement, worsening, and stability of EDSS score over 12 months were descriptively analysed using the minimum EDSS score for each 12-month period. CC7, patients randomized to cladribine tablets 3.5 mg/kg in both CLARITY and CLARITY Extension; CP3.5, patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY Extension; EDSS, Expanded Disability Status Scale. Reprinted with permission from ePresentation Sessions. Eur J Neurol 2020;27(Suppl. 1):468
Fig. 4
Fig. 4
Time to 3- and 6-month confirmed EDSS worsening from CLARITY entry in the CP3.5 and CC7 patient groups. CC7, patients randomized to cladribine tablets 3.5 mg/kg in both CLARITY and CLARITY Extension; CP3.5, patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY Extension; EDSS, Expanded Disability Status Scale

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