Safety and tolerability of short-course oral therapy with cladribine tablets for relapsing-remitting multiple sclerosis in the 96-week, Phase III, double-blind, placebo-controlled CLARITY study

BACKGROUND: Following activation, cladribine produces targeted and sustained reductions in specific lymphocyte subtypes, providing the rationale for short-course annual treatment. We assessed the safety and tolerability of cladribine tablets vs. placebo over 96 weeks in the CLARITY study. METHODS: Patients with McDonald relapsing–remitting multiple sclerosis (RRMS) randomized to short-course oral therapy with cladribine tablets (cumulative dose 5.25 or 3.5mg/kg) or placebo were assessed for safety over 96 weeks. RESULTS: Of 456, 433 and 437 patients randomized to cladribine 5.25 or 3.5mg/kg or placebo, 454, 430 and 435 received study drug, respectively. Total adverse event (AE) rates were comparable across treatment groups. Lymphopenia was more common with cladribine 3.5mg/kg (21.6%) or 5.25mg/kg (31.5%) than placebo (1.8%) as anticipated based on cladribine’s mechanism of action. Other common AEs occurred in a similar percentage of patients across treatment groups. Less common AEs (<2% patients) reported in more cladribine than placebo recipients included herpes zoster (all dermatomal) and uterine leiomyomas. Treatment was discontinued due to AEs for 3.5% and 7.9% vs. 2.1% patients in cladribine 3.5 and 5.25mg/kg vs. placebo groups, and 8.4% and 9.0% vs. 6.4% experienced serious AEs, respectively. Malignancies in cladribine recipients were isolated events in different organ systems. CONCLUSIONS: Together with efficacy data (reported elsewhere) these results, in a controlled clinical setting with appropriate monitoring and assessment, suggest an acceptable benefit–risk profile for cladribine tablets. Long-term safety and efficacy are being evaluated in a 96 week CLARITY EXTENSION study.