Background
Methods
Study design
Endpoints
Safety assessments
Clinical relevance of continuous ECG monitoring
Approval and participants
Study procedures
Results
Study patients and conduct
Fingolimod 0.5 mg (N = 3951) | |
---|---|
Age groups in years, n (%) | |
18–30 | 880 (22.3) |
> 30–40 | 1222 (30.9) |
> 40–55 | 1622 (41.1) |
> 55–65 | 208 (5.3) |
> 65 | 18 (0.5) |
Sex | |
Female, n (%) | 2779 (70.3) |
Duration of MS since first symptoms in years, mean ± SD | 10.0 ± 7.6 |
Number of relapses in previous year, mean ± SD | 1.6 ± 1.2 |
EDSS, mean ± SD | 2.8 ± 1.6 |
DMT treatment within the last 6 months, n (%) | |
No | 827 (20.9) |
Yes | 3124 (79.1) |
Overall population | Patients with bradycardia | Patients with second-degree AV block | Patients with AE | Patients with symptoms suggestive of cardiac events at visit 2 | Patients who discontinued study drug due to AE | |
---|---|---|---|---|---|---|
N = 3951 |
N = 31 |
N = 62a
|
N = 1350 |
N = 120 |
N = 38 | |
Demographics | ||||||
Age (years), mean ± SD | 39.3 ± 10.4 | 42.1 ± 10.9 | 40.4 ± 11.7 | 39.3 ± 10.4 | 39.6 ± 10.4 | 42.3 ± 12.4 |
Female, n (%) | 2779 (70.3) | 14 (45.2) | 57 (91.9) | 1023 (75.8) | 96 (80.0) | 29 (76.3) |
Concomitant medication known to prolong QT interval: | ||||||
SSRI n (%) | 339 (10.1) | 1 (3.2) | 4 (6.5) | 152 (11.3) | 17 (14.2) | 6 (15.8) |
TCA n (%) | 92 (2.3) | 0 | 0 | 38 (2.8) | 2 (1.7) | 1 (2.6) |
Amantadin n (%) | 42 (1.1) | 0 | 0 | 18 (1.3) | 2 (1.7) | 0 |
Carbamazepin n (%) | 29 (0.7) | 0 | 1 (1.6) | 14 (1.0) | 3 (2.5) | 1 (2.6) |
Fampridine n (%) | 299 (7.6) | 3 (9.7) | 5 (8.1) | 81 (6.0) | 8 (6.7) | 1 (2.6) |
Heart rate at visit 2 pre-dose | ||||||
Heart rate (bpm), mean ± SD | 73.9 ± 10.4 | 59.5 ± 8.0 | 75.0 ± 8.5 | 73.4 ± 10.4 | 73.3 ± 11.6 | 75.8 ± 10.6 |
Blood pressure at visit 2 pre-dose | ||||||
Systolic (mmHg), mean ± SD | 121.8 ± 14.0 | 125.7 ± 20.3 | 117.5 ± 13.7 | 122.0 ± 14.1 | 123.9 ± 14.5 | 120.4 ± 15.4 |
Diastolic (mmHg), mean ± SD | 78.5 ± 9.7 | 78.1 ± 13.1 | 75.7 ± 9.0 | 78.7 ± 9.8 | 79.9 ± 10.0 | 76.1 ± 11.1 |
Potassium levels at visit 2 | ||||||
< 3.5 mmol/L | 13 (0.3) | 0 | 0 | 5 (0.4) | 0 | 0 |
≥ 3.5–5.5 mmol/L | 3853 (98.3) | 31 (100) | 61 (98.4) | 1320 (98.5) | 119 (99.2) | 38 (100.0) |
> 5.5 mmol/L | 54 (1.4) | 0 | 1 (1.6) | 15 (1.1) | 1 (0.8) | 0 |
Symptoms suggestive of cardiac eventsb during 6 h first-dose observation | ||||||
Patients with symptoms, n (%) | 120 (3.0) | 1 (3.2)c
| 1 (1.6)d
| 120 (8.9) | 120 (100.0) | 1 (2.6) |
Fingolimod 0.5 mg N = 50 | |
---|---|
Number of capsules taken | n (%) |
1 | 17 (34.0) |
2 | 8 (16.0) |
3–7 | 21 (42.0) |
> 7 | 3 (6.0) |
Missing | 1 (2.0) |
Changes in heart rate
Number of patients | Pre-dose heart ratea (bpm) | Lowest post-dose heart ratea (bpm) | Maximum decline in heart ratea (bpm) | |
---|---|---|---|---|
n (%) | Mean (range) | Mean (range) | Mean (SD) | |
Fingolimod, N = 3951 | ||||
Overall population | ||||
Overall population | 3951 (100.0) | 73.9 (45–132) | 62.1 (31–101) | 11.8 (8.47) |
By time of lowest heart rate | ||||
Patients with lowest heart rate at < 6 h | 3455 (87.4) | 73.8 (45–132) | 61.9 (31–101) | 11.9 (8.42) |
Patients with lowest heart rate at 6 h | 496 (12.6) | 74.6 (48–114) | 63.5 (38–90) | 11.1 (8.76) |
p-valueb
| 0.0394 | |||
By presence of bradycardia | ||||
Patients with bradycardia | 31 (0.8) | 59.5 (46–80) | 41.6 (31–44) | 17.9 (8.30) |
Patients without bradycardia | 3920 (99.2) | 74.0 (45–132) | 62.2 (45–101) | 11.7 (8.45) |
p-valueb
| 0.0001 | |||
By presence of second-degree AV block | ||||
Patients with second-degree AV block | 62 (1.6) | 75.0 (56–95) | 62.7 (42–83) | 12.2 (8.12) |
Patients without second-degree AV block | 3889 (98.4) | 73.8 (45–132) | 62.1 (31–101) | 11.8 (8.48) |
p-valueb
| 0.691 |
AV conduction abnormalities
Fingolimod 0.5 mg N = 3951 | |
---|---|
Patients with 12-lead ECG recording, n |
N = 3951 |
Patients with first-degree AV block, n (%) | 280 (7.1) |
Pre-dose | 96 (2.7) |
Post-dose | 206 (5.8) |
Patients with Holter ECG recording, n |
N = 3906 |
Patients with second-degree AV block, n (%) | 62 (1.6) |
Mobitz Type I (Wenckebach) | 60 (1.5)a
|
2:1 | 18 (0.5)a
|
Mobitz Type II (Mobitz) | 0 |
Patients with third-degree AV block, n (%) | 0 |
Effects on repolarisation
Adverse events and cardiac symptoms
Fingolimod 0.5 mg N = 3951 | ||
---|---|---|
Number of patients, n (%) | Number of events, n | |
Summary of adverse events | ||
Any adverse event | 1350 (34.17) | 2207 |
Any serious adverse event | 117 (2.96) | 152 |
Any adverse event leading to discontinuation of study drug | 38 (0.96) | 69 |
Common adverse events (>1% in SOC/PT) | ||
Nervous system disorders | 403 (10.20) | 464 |
Headache | 199 (5.04) | 205 |
Dizziness | 72 (1.82) | 73 |
MS relapse | 58 (1.47) | 59 |
General disorders and administration site conditions | 240 (6.07) | 265 |
Fatigue | 135 (3.42) | 138 |
Cardiac disorders | 231 (5.85) | 263 |
AV block first degree | 69 (1.75) | 70 |
AV block second degree | 65 (1.65) | 67 |
Bradycardia | 45 (1.14) | 45 |
Gastrointestinal disorders | 217 (5.49) | 246 |
Nausea | 91 (2.30) | 92 |
Diarrhoea | 52 (1.32) | 52 |
Infections and infestations | 170 (4.30) | 178 |
Nasopharyngitis | 78 (1.97) | 78 |
Investigations | 130 (3.29) | 150 |
Blood and lymphatic disorders | 115 (2.91) | 140 |
Lymphopenia | 73 (1.85) | 74 |
Musculoskeletal and connective tissue disorders | 94 (2.38) | 102 |
Skin and subcutaneous tissue disorders | 66 (1.67) | 69 |
Psychiatric disorders | 61 (1.54) | 63 |
Vascular disorders | 60 (1.52) | 61 |
Respiratory, thoracic and mediastinal disorders | 59 (1.49) | 60 |
Ear and labyrinth disorders | 47 (1.19) | 49 |
Common serious adverse events (>0.1% in SOC/PT) | ||
Cardiac disorders | 52 (1.32) | 65 |
AV block second-degree | 31 (0.78) | 33 |
Bradycardia | 15 (0.38) | 15 |
AV block | 5 (0.13) | 5 |
Nervous system disorders | 33 (0.84) | 36 |
MS relapse | 18 (0.46) | 19 |
General disorders and administration site conditions | 7 (0.18) | 7 |
Infections and infestations | 7 (0.18) | 7 |
Gastrointestinal disorders | 6 (0.15) | 8 |
Vascular disorders | 6 (0.15) | 6 |
Symptoms that might have resulted from cardiac events (at Visit 2) | ||
Fatigue | 68 (1.72) | |
Dizziness | 26 (0.66) | |
Chest discomfort | 8 (0.20) | |
Vertigo | 7 (0.18) | |
Palpitations | 7 (0.18) | |
Dyspnea | 5 (0.13) | |
Angina pectoris | 3 (0.08) | |
Blurred vision | 2 (0.05) | |
Syncope | 1 (0.03) | |
Exertional dyspnoe | 1 (0.03) |
Fingolimod 0.5 mg N = 38 | ||
---|---|---|
Number of patients, n (%) | Number of events, n | |
Adverse events leading to discontinuation of study drug (<4% in SOC/PT) | ||
Cardiac disorders | 16 (42.1) | 20 |
AV block second-degree | 9 (23.7) | 10 |
Bradycardia | 3 (7.9) | 3 |
Gastrointestinal disorders | 8 (21.1) | 10 |
Nausea | 4 (10.5) | 4 |
Diarrhoea | 3 (7.9) | 3 |
Nervous system disorders | 8 (21.1) | 8 |
Dizziness | 2 (5.3) | 2 |
Headache | 2 (5.3) | 2 |
Vascular disorders | 5 (13.2) | 5 |
Hypertension | 4 (10.5) | 4 |
Investigations | 5 (13.2) | 5 |
QT prolongation | 2 (5.3) | 2 |
Skin and subcutaneous tissue disorders | 5 (13.2) | 5 |
Psychiatric disorders | 4 (10.5) | 4 |
General disorders and administration site conditions | 3 (7.9) | 4 |
Asthenia | 2 (5.3) | 2 |
Eye disorders | 2 (5.3) | 2 |
Vision blurred | 2 (5.3) | 2 |
Pregnancy, puerperium and perinatal conditions | 2 (5.3) | 2 |
Pregnancy | 2 (5.3) | 2 |