- 作者：Krzysztof Selmaj ; David KB Li ; Hans-Peter Hartung ; Bernhard Hemmer ; Ludwig Kappos ; Mark S Freedman ; Olaf St¨¹ve ; Peter Rieckmann ; Xavier Montalban ; Tjalf Ziemssen ; Lixin Zhang Auberson ; Harald Pohlmann ; Francois Mercier ; Frank Dahlke ; Erik Wallstr?m
- 刊名：Lancet Neurology
- 出版年：2013
- 出版时间：August, 2013
- 年：2013
- 卷：12
- 期：8
- 页码：756-767
- 全文大小：425 K
Summary
Background
Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis.Methods
In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0¡¤5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1¡¤25 mg, siponimod 0¡¤25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with , number .
Findings
Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0¡¤0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35 % (95 % CI 17-57) for siponimod 0¡¤25 mg (51 patients included in the primary endpoint analysis), 50 % (29-69) for siponimod 0¡¤5 mg (43 patients), 66 % (48-80) for siponimod 1¡¤25 mg (42 patients), 72 % (57-84) for siponimod 2 mg (45 patients), and 82 % (70-90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86 % ) of 43 patients who received siponimod 0¡¤5 mg had adverse events (eight serious), as did 48 (98 % ) of 49 patients who received siponimod 2 mg (four serious), 48 (96 % ) of 50 patients who received siponimod 10 mg (three serious), and 36 (80 % ) of 45 controls (none serious). For individuals treated to 3 months, 38 (74 % ) of 51 patients who received siponimod 0¡¤25 mg had adverse events (none serious), as did 29 (69 % ) of 42 patients who received siponimod 1¡¤25 mg (two serious) and 13 (81 % ) of 16 controls (none serious).
Interpretation
Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial.
Funding
Novartis Pharma AG.