Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, MS, Fingolimod, Gilenya, ECG, Bradyarrythmia, conduction abnormalities, first dose observation
Brief summary
This study evaluated bradycardiac events during first dose observation of fingolimod in MS patients.
Interventions
DRUGFTY720
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subjects with relapsing remitting MS. * Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy. * Patients who had been previously on 2nd line therapies. It was understood that these patients satisfied the above mentioned criteria listed under a. in the past. This also included patients, who were previously treated with fingolimod (regardless of whether or not they had already been treated within the START study) but discontinued treatment due to medical reasons. \- or patients with rapidly evolving severe RRMS (e.g. \> 2 relapses with disease progression in one year and \> 1 Gd-enhancing lesion or with a significant increase in T2 lesions compared to a recent MRI). Key
Exclusion criteria
* immunocompromised patients * active infections * pregnant or nursing women, women of childbearing potential unless using 2 reliable forms of contraception * presence of malignancy (other than localized basal cell carcinoma of the skin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | baseline, during 6 hour monitoring post first dose observation | AV Blocks/Heart block is an abnormal heart rhythm where the heart beats too slowly; the electrical signals that tell the heart to contract are partially intermittent (Type 2:1) or slowed (1st and 2nd degree) or blocked (3rd degree) between the upper chambers (atria) and the lower chambers (ventricles). In 2nd degree AV Blocks, electrical impulses are intermittent (type 2:1) or delayed w/ each subsequent heartbeat (Mobitz type I) until a beat fails to reach the ventricles entirely. This type of block often is physiologic and observed in a highly relaxed state & during sleep. In 2nd degree AV Blocks type II, the atria electrical impulses are unable to reach the ventricles, a more serious condition. In 3rd degree AV Blocks (complete heart block), none of the electrical impulses reach either the atria or the ventricles. Patients can experience simultaneously both types of 2nd or 3rd degree AV Blocks without any symptoms. |
| Number of Patients With Heart Rate Below 45 Beats Per Minute (BPM) | baseline during 6 hour monitoring post dose | Number of patients with heart rate below 45 beats bpm in ECG during first dose observation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Prolonged QTc Interval (Friderica) | baseline post-dose | Number of patients with conduction abnormalities such as QT prolongation, first degree AV block during treatment initiation. The QT interval is a period between the activation and the regeneration of ventricular contraction. A prolonged QT interval can be a potential marker of cardiac arrhythmias. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients. |
| Number of Participants With Bradyarrhythmic Electrocardiogram (ECG) Events | up to day 7 | The number of participants with bradyarrhythmic electrocardiogram (ECG) events was assessed. Bradyarrhythmic ECG events are defined as QTc Fridericia time \> 450 ms for males and \> 470 ms for females. |
| Number of Patients With Cardiac Adverse Events | 7 days | The number of participants with the occurrence of subsequent cardiac adverse events (AEs) and serious cardiac AEs during study was assessed. Cardiac events were defined as the following Medical Dictionary for Regulatory Activities (MedDRA) preferred terms: angina pectoris, chest discomfort, dizziness, dyspnoea, dyspnoea exertional, fatigue, palpitations, syncope, vertigo, vertigo positional and vision blurred. |
Countries
Germany
Participant flow
Pre-assignment details
6998 participants were enrolled into the study and were considered as part of the safety set, but 2 participants discontinued from the study and did not take any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Fingolimod 0.5 mg by mouth once daily for 7 days. | 6,998 |
| Total | 6,998 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal test procedure results | 1 |
| Overall Study | Administrative problems | 4 |
| Overall Study | Adverse Event | 24 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Protocol deviation | 1 |
| Overall Study | Study completion was not documented. | 1 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Fingolimod |
|---|---|
| Age, Continuous | 39.2 Years STANDARD_DEVIATION 10.52 |
| Sex: Female, Male Female | 4924 Participants |
| Sex: Female, Male Male | 2074 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2,179 / 6,998 |
| serious Total, serious adverse events | 160 / 6,998 |
Outcome results
Primary
Number of Patients With Heart Rate Below 45 Beats Per Minute (BPM)
Number of patients with heart rate below 45 beats bpm in ECG during first dose observation
Time frame: baseline during 6 hour monitoring post dose
Population: Safety set: The safety set consisted of all enrolled participants for whom safety information was collected. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Number of Patients With Heart Rate Below 45 Beats Per Minute (BPM) | 63 Participants |
Primary
Participants With 2nd or 3rd Degree Atrioventricular (AV) Block
AV Blocks/Heart block is an abnormal heart rhythm where the heart beats too slowly; the electrical signals that tell the heart to contract are partially intermittent (Type 2:1) or slowed (1st and 2nd degree) or blocked (3rd degree) between the upper chambers (atria) and the lower chambers (ventricles). In 2nd degree AV Blocks, electrical impulses are intermittent (type 2:1) or delayed w/ each subsequent heartbeat (Mobitz type I) until a beat fails to reach the ventricles entirely. This type of block often is physiologic and observed in a highly relaxed state & during sleep. In 2nd degree AV Blocks type II, the atria electrical impulses are unable to reach the ventricles, a more serious condition. In 3rd degree AV Blocks (complete heart block), none of the electrical impulses reach either the atria or the ventricles. Patients can experience simultaneously both types of 2nd or 3rd degree AV Blocks without any symptoms.
Time frame: baseline, during 6 hour monitoring post first dose observation
Population: Safety set: The safety set consisted of all enrolled participants for whom safety information was collected. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | Any AV block ll degree or higher | 120 Participants |
| Fingolimod | Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | AV block ll degree: Mobitz type I degree | 117 Participants |
| Fingolimod | Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | AV block II degree: Mobitz type II degree | 0 Participants |
| Fingolimod | Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | AV block II degree: 2:1 | 43 Participants |
| Fingolimod | Participants With 2nd or 3rd Degree Atrioventricular (AV) Block | AV block III degree | 1 Participants |
Secondary
Number of Participants With Bradyarrhythmic Electrocardiogram (ECG) Events
The number of participants with bradyarrhythmic electrocardiogram (ECG) events was assessed. Bradyarrhythmic ECG events are defined as QTc Fridericia time \> 450 ms for males and \> 470 ms for females.
Time frame: up to day 7
Population: Safety set: The safety set consisted of all enrolled participants for whom safety information was collected. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Number of Participants With Bradyarrhythmic Electrocardiogram (ECG) Events | 26 Participants |
Secondary
Number of Participants With Prolonged QTc Interval (Friderica)
Number of patients with conduction abnormalities such as QT prolongation, first degree AV block during treatment initiation. The QT interval is a period between the activation and the regeneration of ventricular contraction. A prolonged QT interval can be a potential marker of cardiac arrhythmias. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients.
Time frame: baseline post-dose
Population: The safety set, which consisted of all enrolled participants for whom safety information was collected, was considered for the analysis. Only participants, who had baseline post-dose QTc interval data, were analyzed.~Of the 6998 patients, 6844 patients had complete baseline post-dose QTc interval data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Number of Participants With Prolonged QTc Interval (Friderica) | Female, QTcFridericia Interval > 470 ms | 7 Participants |
| Fingolimod | Number of Participants With Prolonged QTc Interval (Friderica) | Male, QTcF Interval > 450 ms | 6 Participants |
Secondary
Number of Patients With Cardiac Adverse Events
The number of participants with the occurrence of subsequent cardiac adverse events (AEs) and serious cardiac AEs during study was assessed. Cardiac events were defined as the following Medical Dictionary for Regulatory Activities (MedDRA) preferred terms: angina pectoris, chest discomfort, dizziness, dyspnoea, dyspnoea exertional, fatigue, palpitations, syncope, vertigo, vertigo positional and vision blurred.
Time frame: 7 days
Population: Safety set: The safety set consisted of all enrolled participants for whom safety information was collected. Two patients of the safety analysis set discontinued the study without having received treatment, but safety information was collected on these two patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Number of Patients With Cardiac Adverse Events | Cardiac events | 489 Participants |
| Fingolimod | Number of Patients With Cardiac Adverse Events | Serious cardiac AEs | 9 Participants |