Multiple sclerosisMonday, June 22, 2009, 17:30 - 19:00Safety of cladribine tablets in the treatment of Relapsing–Remitting Multiple Sclerosis (RRMS): results from the CLARITY study, a 96-week, phase III, double-blind, placebo-controlled trialS. Cook, P. Vermersch, G. Comi, G. Giovannoni, K. Rammohan, P. Rieckmann, P. Soelberg-Sørensen, P. Chang, A. Hamlett, B. Musch, V. Viglietta, S. Greenberg on behalf of the CLARITY Study Group
Objectives: Cladribine tablets are in development for the treatment of multiple sclerosis. Cladribine is a pro-drug, and activation in specific cell types provides targeted and sustained immunomodulation, permitting the investigation of an oral, short-course annual treatment. Here we assess the safety of cladribine tablets compared with placebo over 96 weeks in patients with RRMS participating in the CLARITY (CLAdRIbine tablets Treating multiple sclerosis orallY) study.
Methods: Patients with RRMS (McDonald criteria; Expanded Disability Status Scale score 0 to 5.5) were randomised to cladribine tablets (cumulative dose of 5.25 or 3.5 mg/kg) or matching placebo (1:1:1). Cladribine tablets were given in short courses (once daily for 4-5 days) for 4 (5.25 mg/kg arm) or 2 (3.5 mg/kg arm) consecutive months in the first 48 weeks, then 2 short courses at Weeks 48 and 52 (both arms). Safety and tolerability were assessed over the 96-week study.
Results: Of 456, 433 and 437 patients randomised to 5.25 or 3.5 mg/kg cladribine or placebo, 454, 430 and 435 received study drug and were evaluable for safety analysis, with 86.2%, 91.2% and 86.3% of patients successfully completing full-course treatment, respectively. Overall adverse event (AE) frequencies were comparable between groups. Lymphopenia occurred more frequently with cladribine 5.25 or 3.5 mg/kg than placebo, as anticipated from its mechanism of action (31.5%, 21.6% and 1.8% patients, respectively). Other AEs reported by >=10% patients were headache, nasopharyngitis, upper respiratory tract infection and nausea. Other AEs reported more frequently with cladribine than placebo included Herpes zoster (all dermatomal) and uterine leiomyomas. In the 5.25 mg/kg, 3.5 mg/kg and placebo groups, 7.9%, 3.5% and 2.1% patients discontinued treatment due to AEs, and 9.0%, 8.4% and 6.4% experienced serious AEs, respectively. Four isolated cases of single malignancies occurred during study in cladribine 5.25 mg/kg (n=1) and 3.5 mg/kg (n=3) groups (ovarian, cervical and pancreatic carcinomas and malignant melanoma); one case of choriocarcinoma was noted post-study.
Conclusions: The favourable safety and tolerability profile observed in the CLARITY study, together with strong efficacy (reported elsewhere) suggest that annual short-course treatment with cladribine tablets may provide an important new option in MS therapy.
This will be further supported by long-term safety and efficacy data from a 96-week CLARITY extension study.
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