NCT01585298: START

STudy to vAlidate telemetRic ECG Systems for firsT Dose Administration of Fingolimod (START)

Completed Phase 4 Results posted Last updated 23 September 2019

What this trial tests

Phase 4 trial testing FTY720 in Multiple Sclerosis in 6,998 participants. Completed in 12 December 2016.

Timeline

29 April 2012

Primary endpoint
12 December 2016

12 December 2016

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	6,998
Start date	29 April 2012
Primary completion	12 December 2016
Estimated completion	12 December 2016
Sites	258 locations across Germany

Drugs / interventions tested

• FTY720 — full drug profile →

Conditions studied

• Multiple Sclerosis — all drugs for Multiple Sclerosis →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Multiple Sclerosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Participants With 2nd or 3rd Degree Atrioventricular (AV) Block Primary · 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 B

Any AV block ll degree or higher

Group	Value	95% CI
Fingolimod	120

AV block ll degree: Mobitz type I degree

Group	Value	95% CI
Fingolimod	117

AV block II degree: Mobitz type II degree

Group	Value	95% CI
Fingolimod	0

AV block II degree: 2:1

Group	Value	95% CI
Fingolimod	43

AV block III degree

Group	Value	95% CI
Fingolimod	1

Number of Patients With Heart Rate Below 45 Beats Per Minute (BPM) Primary · baseline during 6 hour monitoring post dose

Number of patients with heart rate below 45 beats bpm in ECG during first dose observation

Group	Value	95% CI
Fingolimod	63

Number of Participants With Prolonged QTc Interval (Friderica) Secondary · 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.

Female, QTcFridericia Interval > 470 ms

Group	Value	95% CI
Fingolimod	7

Male, QTcF Interval > 450 ms

Group	Value	95% CI
Fingolimod	6

Number of Participants With Bradyarrhythmic Electrocardiogram (ECG) Events Secondary · 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.

Group	Value	95% CI
Fingolimod	26

Number of Patients With Cardiac Adverse Events Secondary · 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.

Cardiac events

Group	Value	95% CI
Fingolimod	489

Serious cardiac AEs

Group	Value	95% CI
Fingolimod	9

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events (AEs) were collected for each patient from first administration of study drug until end of study visit, usually for one week. Furthermore, serious suspected adverse drug reactions (SADRs) had to be documented until 6 weeks after the patient has stopped study participation.. Reporting threshold: 0.0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Fingolimod

Serious: 160/6998 (2%)

Deaths: —

Serious adverse events (75 terms)

Reaction	System	Fingolimod
Atrioventricular block second degree	Cardiac disorders	—
Multiple sclerosis relapse	Nervous system disorders	—
Bradycardia	Cardiac disorders	—
Electrocardiogram QT prolonged	Investigations	—
Heart rate decreased	Investigations	—
Atrial fibrillation	Cardiac disorders	—
Dizziness	Nervous system disorders	—
Optic neuritis	Nervous system disorders	—
Hypertension	Vascular disorders	—
Coronary artery disease	Cardiac disorders	—
Myocardial infarction	Cardiac disorders	—
Sinus bradycardia	Cardiac disorders	—
Supraventricular extrasystoles	Cardiac disorders	—
Vertigo	Ear and labyrinth disorders	—
Diarrhoea	Gastrointestinal disorders	—
Non-cardiac chest pain	General disorders	—
Epilepsy	Nervous system disorders	—
Leukocytosis	Blood and lymphatic system disorders	—
Leukopenia	Blood and lymphatic system disorders	—
Lymphopenia	Blood and lymphatic system disorders	—
Angina pectoris	Cardiac disorders	—
Arrhythmia	Cardiac disorders	—
Atrioventricular block complete	Cardiac disorders	—
Ischaemic cardiomyopathy	Cardiac disorders	—
Macular oedema	Eye disorders	—

Other adverse events (439 terms — click to expand)

Reaction	System	Fingolimod
Headache	Nervous system disorders	—
Fatigue	General disorders	—
Nausea	Gastrointestinal disorders	—
Nasopharyngitis	Infections and infestations	—
Dizziness	Nervous system disorders	—
Lymphopenia	Blood and lymphatic system disorders	—
Atrioventricular block first degree	Cardiac disorders	—
Diarrhoea	Gastrointestinal disorders	—
Atrioventricular block second degree	Cardiac disorders	—
Multiple sclerosis relapse	Nervous system disorders	—
Leukopenia	Blood and lymphatic system disorders	—
Vertigo	Ear and labyrinth disorders	—
Hypertension	Vascular disorders	—
Abdominal pain upper	Gastrointestinal disorders	—
Bradycardia	Cardiac disorders	—
Back pain	Musculoskeletal and connective tissue disorders	—
Lymphocyte count decreased	Investigations	—
Non-cardiac chest pain	General disorders	—
Paraesthesia	Nervous system disorders	—
Oral herpes	Infections and infestations	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—
Palpitations	Cardiac disorders	—
Chest discomfort	General disorders	—
Pruritus	Skin and subcutaneous tissue disorders	—
Influenza	Infections and infestations	—
Alanine aminotransferase increased	Investigations	—
Dysgeusia	Nervous system disorders	—
Vision blurred	Eye disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Influenza like illness	General disorders	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—
Depression	Psychiatric disorders	—
White blood cell count decreased	Investigations	—
Sleep disorder	Psychiatric disorders	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—
Pyrexia	General disorders	—
Migraine	Nervous system disorders	—
Arthralgia	Musculoskeletal and connective tissue disorders	—
Myalgia	Musculoskeletal and connective tissue disorders	—
Urinary tract infection	Infections and infestations	—

Most-reported serious reactions: Atrioventricular block second degree, Multiple sclerosis relapse, Bradycardia, Electrocardiogram QT prolonged, Heart rate decreased, Atrial fibrillation, Dizziness, Optic neuritis.

Data from ClinicalTrials.gov NCT01585298 adverse events section.

Sponsor's own description

This study evaluated bradycardiac events during first dose observation of fingolimod in MS patients.

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.
   Chaudhry BZ, Cohen JA, Conway DS. · · 2017 · cited 99× · PMID 28812220 · DOI 10.1007/s13311-017-0565-4
2. The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives.
   Lucaciu A, Brunkhorst R, Pfeilschifter JM, Pfeilschifter W, et al · · 2020 · cited 53× · PMID 32580348 · DOI 10.3390/cells9061515
3. Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study.
   Limmroth V, Ziemssen T, Lang M, Richter S, et al · · 2017 · cited 17× · PMID 28100182 · DOI 10.1186/s12883-016-0789-7
4. Modulation of Cardiac Autonomic Function by Fingolimod Initiation and Predictors for Fingolimod Induced Bradycardia in Patients with Multiple Sclerosis.
   Li K, Konofalska U, Akgün K, Reimann M, et al · · 2017 · cited 14× · PMID 29075174 · DOI 10.3389/fnins.2017.00540
5. Fingolimod Leads to Immediate Immunological Changes Within 6 h After First Administration.
   Sehr T, Akgün K, Haase R, Ziemssen T. · · 2020 · cited 9× · PMID 32477253 · DOI 10.3389/fneur.2020.00391
6. Cardiac Safety Profile of First Dose of Fingolimod for Relapsing-Remitting Multiple Sclerosis in Real-World Settings: Data from a German Prospective Multi-Center Observational Study.
   Linker RA, Wendt G. · · 2016 · cited 8× · PMID 27624575 · DOI 10.1007/s40120-016-0051-7
7. A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose-Possible Predictors of Cardiac Outcomes.
   Limmroth V, Ziemssen T, Kleiter I, Wagner B, et al · · 2020 · cited 6× · PMID 32903376 · DOI 10.3389/fneur.2020.00818