Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD)

An adaptive, dose-ranging, randomised, phase 2 study

Krzysztof Selmaj, David K B Li, Hans Peter Hartung, Bernhard Hemmer, Ludwig Kappos, Mark S. Freedman, Olaf Stüve, Peter Rieckmann, Xavier Montalban, Tjalf Ziemssen, Lixin Zhang Auberson, Harald Pohlmann, Francois Mercier, Frank Dahlke, Erik Wallström

Research output: Contribution to journalArticle

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Abstract

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 ClinicalTrials.gov, number NCT00879658. 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.

Original languageEnglish (US)
Pages (from-to)756-767
Number of pages12
JournalThe Lancet Neurology
Volume12
Issue number8
DOIs
StatePublished - Aug 2013

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Relapsing-Remitting Multiple Sclerosis
Placebos
1-(4-(1-((E)-4-cyclohexyl-3-trifluoromethylbenzyloxyimino)-ethyl)-2-ethylbenzyl)-azetidine-3-carboxylic acid
Lysosphingolipid Receptors
Safety

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Selmaj, K., Li, D. K. B., Hartung, H. P., Hemmer, B., Kappos, L., Freedman, M. S., ... Wallström, E. (2013). Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): An adaptive, dose-ranging, randomised, phase 2 study. The Lancet Neurology, 12(8), 756-767. https://doi.org/10.1016/S1474-4422(13)70102-9

Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD) : An adaptive, dose-ranging, randomised, phase 2 study. / Selmaj, Krzysztof; Li, David K B; Hartung, Hans Peter; Hemmer, Bernhard; Kappos, Ludwig; Freedman, Mark S.; Stüve, Olaf; Rieckmann, Peter; Montalban, Xavier; Ziemssen, Tjalf; Auberson, Lixin Zhang; Pohlmann, Harald; Mercier, Francois; Dahlke, Frank; Wallström, Erik.

In: The Lancet Neurology, Vol. 12, No. 8, 08.2013, p. 756-767.

Research output: Contribution to journalArticle

Selmaj, K, Li, DKB, Hartung, HP, Hemmer, B, Kappos, L, Freedman, MS, Stüve, O, Rieckmann, P, Montalban, X, Ziemssen, T, Auberson, LZ, Pohlmann, H, Mercier, F, Dahlke, F & Wallström, E 2013, 'Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): An adaptive, dose-ranging, randomised, phase 2 study', The Lancet Neurology, vol. 12, no. 8, pp. 756-767. https://doi.org/10.1016/S1474-4422(13)70102-9
Selmaj, Krzysztof ; Li, David K B ; Hartung, Hans Peter ; Hemmer, Bernhard ; Kappos, Ludwig ; Freedman, Mark S. ; Stüve, Olaf ; Rieckmann, Peter ; Montalban, Xavier ; Ziemssen, Tjalf ; Auberson, Lixin Zhang ; Pohlmann, Harald ; Mercier, Francois ; Dahlke, Frank ; Wallström, Erik. / Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD) : An adaptive, dose-ranging, randomised, phase 2 study. In: The Lancet Neurology. 2013 ; Vol. 12, No. 8. pp. 756-767.
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abstract = "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 ClinicalTrials.gov, number NCT00879658. 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.",
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TY - JOUR

T1 - Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD)

T2 - An adaptive, dose-ranging, randomised, phase 2 study

AU - Selmaj, Krzysztof

AU - Li, David K B

AU - Hartung, Hans Peter

AU - Hemmer, Bernhard

AU - Kappos, Ludwig

AU - Freedman, Mark S.

AU - Stüve, Olaf

AU - Rieckmann, Peter

AU - Montalban, Xavier

AU - Ziemssen, Tjalf

AU - Auberson, Lixin Zhang

AU - Pohlmann, Harald

AU - Mercier, Francois

AU - Dahlke, Frank

AU - Wallström, Erik

PY - 2013/8

Y1 - 2013/8

N2 - 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 ClinicalTrials.gov, number NCT00879658. 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.

AB - 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 ClinicalTrials.gov, number NCT00879658. 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.

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