Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study

Abstract

The aim of this study was to evaluate short-term safety and tolerability of fingolimod in a real-world population with relapsing multiple sclerosis, focusing on cardiac safety during treatment initiation. Patients received fingolimod 0.5 mg once daily for four months. Patients excluded from the pivotal studies with certain pre-existing cardiac conditions or baseline cardiac findings (PCCs), and those receiving beta blockers (BBs) and/or calcium channel blockers (CCBs), were eligible. Heart rate (HR) and electrical conduction events were monitored using ambulatory electrocardiography for at least 6 h after the first dose. Of 2,417 enrolled patients, 2,282 (94.4 %) completed the study. Fingolimod initiation was associated with a transient, mostly asymptomatic decrease in HR. Bradycardia adverse events occurred in 0.6 % of patients and were more frequent in individuals receiving BBs/CCBs (3.3 %) than in other patient subgroups (0.5-1.4 %); most events were asymptomatic, and all patients recovered without pharmacological intervention. In the 6 h post-dose, the incidences of Mobitz type I second-degree atrioventricular block (AVB) and 2:1 AVB were higher in patients with PCCs (4.1 and 2.0 %, respectively) than in those without (0.9 and 0.3 %, respectively); at pre-dose screening, patients with PCCs had the same incidence of Mobitz type I second-degree AVB (4.1 %) and a slightly lower incidence of 2:1 AVB (0.7 %) than 6 h post-dose. All recorded conduction abnormalities were asymptomatic. This study adds to the evidence showing that cardiac effects during fingolimod initiation remain consistent with those known from previous, controlled studies, even if patients with PCCs are included.

Fig. 1

Hourly mean change in pulse rate from pre-dose sitting pulse rate (a) and mean change in pulse rate across visits from pre-dose sitting pulse rate (b) for patients who had/did not have pre-existing cardiac conditions or baseline cardiac findings (PCCs), and hourly mean change in pulse rate from pre-dose sitting pulse rate (c) and mean change in pulse rate across visits from pre-dose sitting pulse rate (d) for patients who were receiving/not receiving beta blockers/calcium channel blockers (BBs/CCBs). bpm beats per minute, NBB/NCCB not receiving BBs/CCBs, NPCC no PCCs

Fig. 2

Time to nadir hourly heart rate (HR) in patients who had/did not have pre-existing cardiac conditions or baseline cardiac findings (PCCs) (a) and who were receiving/not receiving concomitant beta blockers/calcium channel blockers (BBs/CCBs) (b), and time to maximal change in HR 6 h following first-dose administration from equivalent time of day at screening for patients who had/did not have PCCs (c) and who were receiving/not receiving BBs/CCBs (d) Percentages were calculated using the total number of patients in each subpopulation (PCCs, n = 295; NPCCs, n = 2,120; BBs/CCBs, n = 120; NBB/NCCB, n = 2,295). NBB/NCCB not receiving BBs/CCBs, NPCC no PCCs, SD standard deviation