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1 Supplementary Online Content Kappos L, Li DKB, Stüve O, et al. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol. Published online July 5, doi: / jamaneurol eappendix. Methods ereference efigure. Study Design and Dose-Titration Schedule etable 1. Annualized Relapse Rate (Confirmed Relapses) per Treatment Group for the Treatment Interruption Period Between the End of BOLD and the Start of the Extension (Dose-Blinded Extension Full Analysis Set) etable 2. Within-Group Comparison of Estimated Mean Gd-Enhancing T1 lesion Counts Between Last Assessment in BOLD and Extension Visits for Patients Who Switched From Placebo to and for Patients Who Continuously Received 2 mg or 1.25 mg (Dose-Blinded Extension Set) etable 3. Between-Dose Group Pairwise Comparison of Estimated Mean Gd-Enhancing T1 Lesion Counts at Extension Month 18 (Dose-Blinded Extension Set) etable 4. Extended Cardiac Monitoring During Dose Titration (Dose-Blinded Extension Set) This supplementary material has been provided by the authors to give readers additional information about their work.

2 eappendix. Methods Key exclusion criteria related to cardiac function As in BOLD, 1 key exclusion criteria related to cardiac function were: a history of significant cardiac disease, including symptomatic bradycardia, significant atrioventricular block (AVB) or corrected QT (QTc, Fridericia) interval of more than 440 msec, sick-sinus syndrome, ischemic heart disease, congestive heart failure, arrhythmias of clinical significance or prescription of medication that suppresses cardiac conduction (such as β-blockers, non-dihydropyridine calcium-channel blockers [e.g. verapamil] and cardiac glycosides). Procedures and schedule of clinical and MRI assessments MRI assessments were performed every 6 months thereafter (to assess gadolinium [Gd]- enhancing T1-weighted lesions, and new/newly enlarging T2-weighted lesions); scans were processed centrally at Perceptive Informatics (Berlin, Germany). Standardized Expanded Disability Status Scale (EDSS) assessments by specially trained and certified physicians not otherwise involved in the care of study participants were scheduled every 3 months during the dose-blinded extension phase and within 10 days of the occurrence of relapses. Relapse assessments were conducted as previously reported. 1 Relapses, AEs and serious AEs (SAEs) were recorded at each clinical visit. Cardiac monitoring procedures and discharge criteria after first-dose of siponimod Twenty-four-hour Holter ECG monitoring was performed at screening and day 1. Sixhour Holter ECG monitoring was performed on days 2 and 7. During the 10-day dosetitration period, mobile cardiac telemetry was performed at the discretion of the investigator. At screening, patients initiated Holter monitoring before 12 pm and used a similar schedule on other visits to support effective within-patient comparison of HR changes and diurnal variation. Longer term cardiac monitoring included 24-hour Holter monitoring at months 3, 6 and 12. Patients were discharged after the 6-hour post-firstdose monitoring if they met all of the following criteria: HR higher than 80% of baseline and higher than the lowest hourly post-dose value, no symptoms associated with decreased HR and no new significant ECG abnormalities other than sinus bradycardia. If any of the above criteria were not met, monitoring was extended. Within-group statistical comparison of Gd-enhancing T1 lesion count A negative binomial model accounting for repeated measures was used in post hoc analyses to investigate the effect of siponimod over time on Gd-enhancing T1 lesion counts. These within-group comparisons between the last assessment from BOLD and

3 extension months 6, 12 and 18 were only performed for the group of patients who switched from placebo during BOLD to siponimod during the extension. ereference 1. Selmaj K, Li DK, Hartung HP, et al. for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):

4 efigure. (A) Study Design and (B) Dose-Titration Schedule Patients with washout were defined as those with more than 7 days study-drug interruption between the date of the last intake of study drug in BOLD and the date of the first intake of extension-study drug. MRI, magnetic resonance imaging.

5 etable 1. Annualized Relapse Rate (Confirmed Relapses) per Treatment Group for the Treatment Interruption Period Between the End of BOLD and the Start of the Extension (Dose-Blinded Extension Full Analysis Set) 10mg (N=25) 2mg (N=22) 1.25mg (N=34) 0.5mg (N=21) 0.25mg (N=48) Placebo (N=34) Confirmed relapses, n Time on study, days ARR 0.23 (0.69) 0.07 (0.34) 0.12 (0.38) 0.65 (2.49) Data are mean (standard deviation) ARR, annualized relapse rate.

6 etable 2. Within-Group Comparison of Estimated Mean Gd-Enhancing T1 lesion Counts Between Last Assessment in BOLD and Extension Visits for Patients Who Switched From Placebo to and for Patients Who Continuously Received 2 mg or 1.25 mg (Dose-Blinded Extension Set) Visit Estimated mean Gdenhancing T1 lesion count Within-group lesion ratio (relative to last assessment in BOLD) 95% CI of lesion ratio p value Placebo siponimod switch group (all siponimod doses) (n = 34) Last BOLD 2.97 assessment Extension (0.02; 0.18) < month 6 Extension (0.02; 0.79) month 12 Extension month (0.02; 0.55) Patients maintained on siponimod 2 mg (n = 22) Last BOLD 0.40 assessment Extension month (0.35; 2.90) Extension (0.60; 1.87) month Extension month (0.10; 1.28) Patients maintained on siponimod 1.25 mg (n = 34) Last BOLD 0.26 assessment Extension (0.20; 3.32) month 6 Extension (0.13 ; 1.07) month 12 Extension month (0.24; 2.58) Mean Gd-enhancing T1 lesion counts were estimated using a negative binomial regression model adjusted for treatment group, age and baseline Gd-enhancing T1 lesion count. Pairwise comparisons are based on a negative binomial regression model accounting for repeated measures at last assessment in BOLD and the stipulated extension time point on each patient, adjusted for baseline number of Gd-enhanced T1 lesions, age and treatment group by visit interaction, using the log link.

7 Lesion ratio (and corresponding 95% CI) is the ratio between the estimated number of lesions at the extension visits relative to last assessment in BOLD. CI, confidence interval; Gd, gadolinium.

8 etable 3. Between-Dose Group Pairwise Comparison of Estimated Mean Gd-Enhancing T1 Lesion Counts at Extension Month 18 (Dose-Blinded Extension Set) Treatment Estimated mean Gdenhancing T1 lesion count at month 18 Pairwise comparison between siponimod doses Betweengroup lesion ratio 95% CI of lesion ratio p value mg vs 0.25 mg 0.11 (0.03; 0.50) mg mg vs 0.25 mg 0.05 (0.01; 0.32) mg mg vs (0.03; 0.37) mg mg mg vs 0.25 mg 0.29 (0.08; 1.08) mg Mean Gd-enhancing T1 lesion counts were estimated using a negative binomial regression model adjusted for treatment group, age and baseline Gd-enhancing T1 lesion count. Pairwise comparison are based on a negative binomial regression model, adjusted for baseline number of Gd-enhanced T1 lesions, age and treatment group, using the log link. Note: At core month 3, lesion counts in the 0.25 mg dose and placebo were 0.96 and 1.73 respectively; p value for between group comparison was CI, confidence interval

9 etable 4. Extended Cardiac Monitoring During Dose Titration (Dose-Blinded Extension Set) Patient dose Extended monitoring day Reason mg 1 Heart rate less than 80% of baseline (21% decrease from day 1 pre-dose mg 1 Heart rate less than 80% of baseline (27% decrease from day 1 pre-dose) 3 2 mg 1 Somnolence AE and drowsiness Additional vital signs and duration Yes, 30 minutes Yes, 1 hour Yes, 30 minutes 4 10 mg 2 Sinus bradycardia Yes, 30 minutes 5 10 mg 2 Heart rate at 6 hour post dose lowest during the interval (14% decrease from day 2 pre-dose) 6 2 mg 7 Low pulse, heart rate at 6 hour post dose lowest during the interval (6% decrease from day 7 pre-dose) mg 8 Heart rate less than 80% of baseline (28% decrease from day 7 pre-dose) 8 10 mg 8 Heart rate at 6 hour post dose lowest during the interval (19% decrease from day 7 pre-dose) AE, adverse event Yes, 1 hour Yes, 1 hour No Yes, 2 hours