An Investigator-Initiated Prospective Randomized Open-Label Blinded-Endpoint Crossover Trial Comparing the Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse
Phase: PHASE3
Conditions: Mitral Valve Prolapse, Ventricular Arrhythmias and Cardiac Arrest
Sponsor: Oslo University Hospital

Protocol 
 
Date:                 05 March 2024 
EU CT: 2022-500814-24-00 
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Protocol 
Title: An Investigator-Initiated Prospective Randomized Open-Label Blinded-Endpoint Crossover Trial 
Comparing the Effect and Safety of Flecainide and Metoprolol versus Metoprolol Alone to Suppress 
Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse (FLECAPRO). 
 
 
 
EU CT No: 2022-500814-24-00 
Sponsor: Oslo University Hospital, Oslo, Norway 
Department of Cardiology 
Chief of Department: Dr. Lars Aaberge 
Principal Investigator: Dr Eivind Westrum Aabel 
 
 

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Contents 
1.0 Protocol Summary ............................................................................................................................. 8 
1.1 Protocol Synopsis .......................................................................................................................... 8 
1.2 Schedule of Activities .................................................................................................................. 12 
2.0 Introduction ..................................................................................................................................... 15 
2.1 Study Rationale ........................................................................................................................... 15 
2.2 Background .................................................................................................................................. 15 
2.3 Benefit/Risk Assessment ............................................................................................................. 17 
3.0 Objectives and Endpoints ................................................................................................................ 18 
3.1 Objective ..................................................................................................................................... 18 
3.2 Hypothesis ................................................................................................................................... 18 
3.3 Primary Endpoint ......................................................................................................................... 18 
3.4 Secondary Endpoints ................................................................................................................... 19 
3.4.1 Key secondary endpoints (hierarchical) ............................................................................... 19 
3.4.2 Secondary safety endpoints ................................................................................................. 20 
3.4.3 Exploratory secondary endpoints......................................................................................... 20 
3.5 Corresponding Objectives and Endpoints ................................................................................... 21 
4.0 Study Design .................................................................................................................................... 22 
4.1 Overall Design .............................................................................................................................. 22 
4.1.1 Study Duration ...................................................................................................................... 23 
4.1.2 Estimated Study Period ........................................................................................................ 23 
4.2 Scientific Rationale for Study Design ........................................................................................... 23 
4.2.1 Patient Input into Design ...................................................................................................... 24 
4.3 Justification for Dose ................................................................................................................... 24 
4.3.1 Flecainide + Metoprolol SR (Intervention): .......................................................................... 24 
4.3.2 Metoprolol SR (Control) ....................................................................................................... 25 
4.4 End-of-Study Definition ............................................................................................................... 25 
5.0 Study Population ............................................................................................................................. 26 
5.1 Inclusion Criteria .......................................................................................................................... 26 
5.2 Exclusion Criteria ......................................................................................................................... 26 
5.2.1 Coronary Artery Disease/Anomaly Assessment ................................................................... 28 
5.3 Lifestyle Considerations .............................................................................................................. 28 
5.4 Screening Failures........................................................................................................................ 28 
6.0 Study Interventions and Concomitant Therapy .............................................................................. 28 
6.1 Study Interventions Administered .............................................................................................. 29 
6.1.1 Flecainide .............................................................................................................................. 31 

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6.1.2 Metoprolol ............................................................................................................................ 32 
6.2 Preparation, Handling, Storage, and Accountability ................................................................... 32 
6.3 Assignment to Study Intervention............................................................................................... 32 
6.4 Blinding ........................................................................................................................................ 33 
6.4.1 Implantable loop recorder ................................................................................................... 33 
6.4.2 Holter monitoring ................................................................................................................. 33 
6.5 Study Intervention Compliance ................................................................................................... 34 
6.6 Dose Modification ....................................................................................................................... 34 
6.7 Continued Access to Study Intervention after the End of the Study .......................................... 34 
6.8 Treatment of Overdose ............................................................................................................... 34 
6.9 Prior and Concomitant Medication ............................................................................................. 35 
7.0 Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal ................... 35 
7.1 Discontinuation of Study Intervention ........................................................................................ 35 
7.2 Participant Discontinuation/Withdrawal from the Study ........................................................... 36 
7.3 Trial Discontinuation ................................................................................................................... 36 
7.4 Lost to Follow-up ......................................................................................................................... 36 
8.0 Study Assessments and Procedures ................................................................................................ 37 
8.1 Administrative and Baseline Procedures .................................................................................... 37 
8.1.1 Informed Consent ................................................................................................................. 37 
8.1.2 Physical Examination ............................................................................................................ 38 
8.1.3 Vital Signs ............................................................................................................................. 38 
8.1.4 Medical History .................................................................................................................... 38 
8.1.5 Concomitant Medication ...................................................................................................... 38 
8.1.6 Laboratory Analyses ............................................................................................................. 38 
8.1.7 Transthoracic Echocardiography .......................................................................................... 39 
8.1.8 Cardiac Magnetic Resonance Imaging .................................................................................. 40 
8.2 Efficacy Assessments ................................................................................................................... 40 
8.2.1 Implantable Loop Recorder .................................................................................................. 40 
8.2.1.1 Implantation Procedure ................................................................................................ 41 
8.2.1.2 LINQ II programming ..................................................................................................... 42 
8.2.2 Holter Monitoring ................................................................................................................. 42 
8.2.3 Health-related Quality of Life ............................................................................................... 42 
8.3 Safety Assessments ..................................................................................................................... 43 
8.3.1 Coronary Artery Disease Assessment ................................................................................... 43 
8.3.2 Visits and Telephone Contact ............................................................................................... 43 
8.3.4 Electrocardiogram ................................................................................................................ 43 

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8.3.5 Exercise ECG ......................................................................................................................... 43 
8.3.6 Pregnancy Testing ................................................................................................................ 44 
8.4 End of Treatment Visits ............................................................................................................... 44 
8.5 Clinical Events .............................................................................................................................. 44 
8.5.1 Ventricular Fibrillation .......................................................................................................... 44 
8.5.2 Ventricular Tachycardia ........................................................................................................ 44 
8.5.3 Syncope ................................................................................................................................ 45 
8.5.4 Ventricular fibrillation or ventricular tachycardia during flecainide treatment .................. 45 
8.6 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting....................... 46 
8.6.1 Definitions ............................................................................................................................ 47 
8.6.1.1 Adverse Event (AE) ........................................................................................................ 47 
8.6.1.2 Adverse Event of Special Interest (AESI) ....................................................................... 47 
8.6.1.3 Serious Adverse Event (SAE).......................................................................................... 47 
8.6.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) .......................................... 48 
8.6.1.5 Medical Device Deficiency (MDD) ................................................................................. 48 
8.6.2 Methods of Detecting AEs and SAEs .................................................................................... 48 
8.6.3 Recording of AE .................................................................................................................... 49 
8.6.4 Reporting Procedure ............................................................................................................ 49 
8.6.4.1 AE and SAE ..................................................................................................................... 49 
8.6.4.2 SUSAR ............................................................................................................................ 50 
8.6.5 Follow-up of AEs and SAEs ................................................................................................... 50 
8.6.6 Pregnancy and Contraceptives ............................................................................................. 50 
8.6.6.1 Definitions ..................................................................................................................... 50 
8.6.6.2 Mandatory contraceptive use ....................................................................................... 51 
8.6.6.3 Pregnancy reporting ...................................................................................................... 52 
8.7 Pharmacokinetics ........................................................................................................................ 52 
8.8 Pharmacodynamics ..................................................................................................................... 52 
8.9 Genetics ....................................................................................................................................... 52 
8.10 Biomarkers ................................................................................................................................ 52 
8.11 Immunogenicity Assessments ................................................................................................... 52 
8.12 Medical Resource Utilization and Health Economics ................................................................ 53 
9.0 Statistical Considerations ................................................................................................................ 53 
9.1 Statistical Hypothesis .................................................................................................................. 53 
9.2 Population for Analysis ................................................................................................................ 53 
9.3 Statistical Analysis ....................................................................................................................... 54 
9.3.1 Primary Endpoint .................................................................................................................. 54 

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9.3.2 Pre-defined subgroup analyses ............................................................................................ 54 
9.3.3 Key Secondary Endpoints ..................................................................................................... 55 
9.3.4 Secondary Safety Endpoints ................................................................................................. 55 
9.3.5 Exploratory Secondary Endpoints ........................................................................................ 55 
9.3.6 Missing Data ......................................................................................................................... 55 
9.4 Interim Analysis ........................................................................................................................... 56 
9.5 Sample Size Determination ......................................................................................................... 56 
10.0 Supporting Documentation and Operational Considerations ....................................................... 57 
10.1 Regulatory and Ethical and Study Oversight Considerations .................................................... 57 
10.1.1 Ethical Considerations for Participants .............................................................................. 58 
10.1.2 Ethics Committee Approval ................................................................................................ 58 
10.1.3 Financial Disclosure ............................................................................................................ 58 
10.1.4 Informed Consent Procedure ............................................................................................. 58 
10.1.5 Recruitment Procedure ...................................................................................................... 59 
10.1.6 Data Protection .................................................................................................................. 59 
10.1.6.1 Electronic Case Report Forms (eCRF) .......................................................................... 59 
10.1.6.2 Source Data ................................................................................................................. 60 
10.1.6.3 Database Management ............................................................................................... 60 
10.1.6.4 Data Sharing ................................................................................................................ 61 
10.1.8 Study Monitoring ................................................................................................................ 61 
10.1.9 Data Monitoring Committee and Safety Data Review ....................................................... 61 
10.1.10 Confidentiality .................................................................................................................. 62 
10.1.11 Trial Registration .............................................................................................................. 62 
10.1.12 Trial insurance .................................................................................................................. 62 
10.1.13 Cost-benefit Consideration .............................................................................................. 62 
10.1.14 Publication Policy ............................................................................................................. 62 
10.1.15 Cost ................................................................................................................................... 63 
10.2 Spin-offs ..................................................................................................................................... 63 
10.3 Partners ..................................................................................................................................... 64 
10.3.1 Section for Outpatient Clinic, Oslo University Hospital, Rikshospitalet ............................. 64 
10.3.2 ProCardio Center for Innovation, Oslo University Hospital, Rikshospitalet ....................... 64 
10.3.3 Section for Electrophysiology, Oslo University Hospital, Rikshospitalet ............................ 64 
10.3.4 Section for Echocardiography, Oslo University Hospital, Rikshospitalet ........................... 64 
10.3.5 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Rikshospitalet
 ....................................................................................................................................................... 65 
10.4 Study Committee Structure and Contact Details ...................................................................... 65 

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11.0 References ..................................................................................................................................... 67 
12.0 Signature Page ............................................................................................................................... 70 
 
 
 
 

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List of abbreviations 
AE 
 
adverse events 
AESI 
 
adverse event of special interest 
BID 
 
“bis in die”, two times a day  
eCRF 
 
electronic case report form 
ICD 
 
implantable cardioverter-defibrillator 
ICF 
 
informed consent form 
ILR 
 
implantable loop recorder 
MDD 
 
medical device deficiency 
MVP 
 
mitral valve prolapse 
NSVT 
 
non-sustained ventricular tachycardia 
NYHA  
New York Heart Association  
PVC 
 
premature ventricular complex 
QD 
 
“quaque die”, once a day 
SAE 
 
serious adverse events 
SmPC  
summary of product characteristics 
SUSAR  
suspected unexpected serious adverse reaction 
WOCBP 
women of childbearing potential 
 
 

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1.0 Protocol Summary 
1.1 Protocol Synopsis 
Protocol Title: 
An Investigator-Initiated Prospective Randomized Open-Label 
Blinded-Endpoint Crossover Trial Comparing the Effect and Safety of 
Flecainide and Metoprolol versus Metoprolol Alone to Suppress 
Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse. 
Brief title: 
Effect and safety of flecainide and metoprolol versus metoprolol 
alone to suppress ventricular arrhythmias in arrhythmic mitral valve 
prolapse 
Sponsor: 
 
 
Oslo University Hospital 
Phase and study type: 
Phase III, Prospective randomized open-label blinded-endpoint 
(PROBE) crossover trial 
Investigational Compound: 
Flecainide and metoprolol antiarrhythmic therapy versus the 
standard metoprolol antiarrhythmic therapy 
Centers: 
Oslo University Hospital, Rikshospitalet, Oslo, Norway 
Study period: 
Study start January 4th, 2023 
 
Anticipated recruitment duration 3 years until January 31st, 2026 
 
Last subject last visit (end-of-study): March 31st, 2028 
Treatment duration: 
13 months (metoprolol alone) and 13 months (flecainide + 
metoprolol) 
Rationale: 
Patients with arrhythmic mitral valve prolapse are at risk of life-
threatening ventricular arrhythmias. To date, no medical therapy has 
shown to be effective in these patients. In general, beta blockers are 
considered first-line therapy, but treatment is often unsuccessful. 
Flecainide is an antiarrhythmic drug that is used to suppress 
ventricular arrhythmias in patients with structurally normal hearts, 
but is not studied in patients with arrhythmic mitral valve prolapse. 
Objectives: 
The main goal of this study is to evaluate the effect and safety of 
adding flecainide to standard beta blocker therapy to reduce burden 

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of ventricular arrhythmias in patients with arrhythmic mitral valve 
prolapse. 
 
Primary Endpoint: 
 
Number of ventricular tachyarrhythmias, composite of: 
- 
Ventricular tachycardia 
- 
Ventricular fibrillation 
Secondary Endpoints: 
Key secondary endpoints: 
- 
Burden of premature ventricular complexes (by Holter 
monitoring) 
- 
Health-related quality of life (number of patients with ≥5 
points increase in SF-36 overall summary score) 
- 
Number of severe ventricular tachycardias, composite of 
o Non-sustained ventricular tachycardia with 
syncope 
o Sustained ventricular tachycardia 
o Ventricular fibrillation 
Secondary safety endpoints: 
- 
Safety composite, composite of: 
o The number of adverse events 
▪ 
The number of adverse reactions 
o The number of serious adverse events 
▪ 
The number of serious adverse reactions 
o Higher degree AV-block (Mobitz type 2 or 3rd 
degree AV-block) 
Exploratory secondary endpoints: 
- 
Components of primary composite endpoint 
o Ventricular tachycardia 
o Ventricular fibrillation 
- 
Components of key secondary endpoints 
o Burden of premature ventricular complexes 

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o Health-related quality of life 
o Number of severe ventricular arrhythmias, 
composite of: 
▪ 
Non-sustained ventricular tachycardia 
with syncope 
▪ 
Sustained ventricular tachycardia 
▪ 
Ventricular fibrillation 
- 
Left ventricular ejection fraction (change) 
- 
Mitral regurgitation (change) 
- 
N-terminal pro-B-type natriuretic peptide (change) 
- 
NYHA class (change) 
- 
Health-related quality of life as assess by the HADS 
questionnaire 
- 
Per-protocol primary endpoint sensitivity analysis 
- 
Intention-to-treat secondary safety endpoint sensitivity 
analysis 
 
Study design: 
Active, single center, prospective, randomized open-label, blinded-
endpoint (PROBE) crossover trial 
Main inclusion criteria: 
Symptomatic arrhythmic mitral valve prolapse in patients 18 years of 
age or older at time of inclusion and clinical indication for 
antiarrhythmic therapy, with one of the following: 
- 
PVC burden ≥3% per 24-hours. 
- 
PVC burden ≥1% per 24-hours if occurring in bi-/trigemini 
and/or couplets, or if multifocal. 
- 
Sustained or non-sustained ventricular tachycardia 
- 
Aborted cardiac arrest 
Main exclusion criteria:  
Strict contraindication for flecainide or metoprolol 
 
 
 
 
Prior flecainide therapy 
Concomitant use of inducers or inhibitors of CYP2D6, MAO inhibitors, 
or class I, III or IV antiarrhythmic drugs (other than flecainide) 
Failure to obtain written informed consent 

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Sample size: 
 
 
50 patients 
Efficacy assessment: 
Implantable loop recorder, Holter monitoring, questionnaire 
Safety assessment: 
Implantable loop recorder, Holter monitoring, ECG and physical visits 
 
Figure 1. FLECAPRO study design 
 
 
 

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1.2 Schedule of Activities 
Procedure 
Screening 
(up to 6 
weeks 
before 0) 
1st treatment period (months) 
2nd treatment period (months) 
Discontinuation 
Notes 
Washout 
and Run-in 
(1 month) 
Treatment phase           
(12 months) 
Washout 
and Run-in 
(1 month) 
Treatment phase           
(12 months) 
Early 
termination 
visit 
 
0 
0-1* 
1 
7 
13 
End of 
treatment 
visit 
13-14* 
 
14 
20 
26 
End of 
treatment 
visit 
 
Visits in the treatment phase are allowed to 
vary ±2 weeks. *Allowed to vary ±3 days. 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
HRQoL questionnaire 
X 
 
 
 
 
X 
 
 
 
X 
X 
SF-36 and HADS. 
Concomitant Medication 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Laboratory Analysis 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Hb, white blood cell count, platelet count, 
K, Na, glucose, HbA1c, creatinine, eGFR, 
ALT, AST, bilirubin, albumin, INR, NT-
proBNP and troponin T. 
Biobank 
 
X 
 
 
 
X 
 
 
 
X 
 
Extra blood will be appropriately labelled 
and stored in a biobank. 
Flecainide serum 
concentration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Therapeutic range 200-1000 ng/ml (0.4-2.0 
µmol/L). 
Pregnancy Test 
 
X 
 
 
 
 
X 
 
 
X 
 
Only in WOBCP. Urinary pregnancy tests 
will be provided free-of-charge throughout 
the whole study. 
Holter Monitoring 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 

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12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Echocardiography 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
Exercise ECG 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Cardiac magnetic 
resonance 
 
X 
 
X* 
 
 
 
 
 
X** 
 
If not contraindicated or performed within 
the last 24 months. *10 patients without 
prior ICD will perform CMR shortly after ILR 
implantation. **Last CMR will be done in 
participants randomized to flecainide in the 
second treatment period.  
ILR Implantation 
 
X 
 
 
 
 
 
 
 
 
 
 
Coronary Angiography 
X 
 
 
 
 
 
 
 
 
 
 
If not performed within the last 24 months 
prior to screening, we will perform a CT or 
invasive coronary angiography in patients 
with possible coronary artery disease 
according to guidelines in force. 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug distribution 
 
X 
 
 
 
X 
 
 
 
 
 
 
Collection of study 
intervention 
 
 
 
 
 
X 
 
 
 
X 
X 
Collection of metoprolol only after the last 
visit. 
Evaluation of dose 
escalation 
 
 
X 
 
 
 
X 
 
 
 
 
 
Study Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory contraceptive 
use 
 
 
 
 
 
 
 
 
 
 
 
Only in WOCBP. Until 3 days after 
discontinuation of study medication 
Carelink Continuous 
Heart Rhythm Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
AE Review 
 
 
 
 
 
 
 
 
 
 
X 
 
SAE Review 
 
 
 
 
 
 
 
 
 
 
X 
 
Device Deficiency 
 
 
 
 
 
 
 
 
 
 
X 
 

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ECG = electrocardiogram, CMR = cardiac magnetic resonance, HRQoL = health-related quality of life, ILR = implantable loop recorder, AE = adverse event, 
SAE= serious adverse event.

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2.0 Introduction 
2.1 Study Rationale 
Patients with arrhythmic mitral valve prolapse have frequent ventricular arrhythmias that are 
potentially life threatening1-9, and there is no established medical treatment8,9. Flecainide, a drug 
primarily used to suppress atrial tachyarrhythmias10, has shown to suppress ventricular arrhythmias 
in other cardiomyopathies11-13, but its effect in patients with arrhythmic mitral valve prolapse has not 
been studied. 
2.2 Background 
Mitral valve prolapse (MVP) is a common condition14,15 characterized by the bulging of one or both 
mitral leaflets into the left atrium. Although mostly a benign cardiac condition, a subgroup of 
patients develop severe ventricular arrhythmias that is a significant cause of sudden cardiac death in 
young adults 1-4. Arrhythmic MVP is defined as the presence of mitral valve prolapse with or without 
mitral annulus disjunction (MAD) combined with frequent ventricular ectopy, complex ectopy or 
sustained ventricular arrhythmia in the absence of another well-defined arrhythmic substrate5,9,16. In 
these patients, ventricular arrhythmias most commonly originate from the mitral annulus, papillary 
muscles and outflow tracts 5-8. Several risk markers have been proposed, but clinical risk stratification 
remains challenging. Ventricular arrhythmias in patients with arrhythmic mitral valve prolapse are 
associated with excess long-term mortality9. 
There is no established medical therapy to suppress ventricular arrhythmias and relieve arrhythmic 
symptoms in these patients, and conventional beta blocker therapy is often unsuccessful for both8,9. 
Invasive catheter ablation can suppress ventricular arrhythmias, and thus relieve symptoms, in a 
subset of patients. However, many patients have multifocal ventricular ectopy, often originating 
from deep in the myocardium or papillary muscles not easily accessible for catheter ablation. 
Furthermore, recurrence of ventricular arrhythmias is common despite initial successful catheter 
ablation procedures8. The only strategy to prevent sudden cardiac death for high-risk patients is to 
implant an ICD, but this approach does not provide any symptomatic relief. Thus, most patients with 
arrhythmic mitral valve prolapse lack effective treatment options with proven efficacy in clinical 
trials. 

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Flecainide is a class 1c antiarrhythmic drug with a potent sodium channel blocking effect frequently 
used in atrial tachyarrhythmias10. Flecainide was developed as treatment for ventricular 
arrhythmias17, but its use subsided due to safety concerns when used in patients with acute 
myocardial infarction18. However, this knowledge stems from a patient population before modern 
revascularization strategies after myocardial infarction, and is extrapolated to patients with other 
structural heart disease. Lately, flecainide has been shown to be safe in patients with stable coronary 
artery disease19,20. Furthermore, flecainide reduce ventricular arrhythmias in patients with PVC-
mediated cardiomyopathy11, arrhythmogenic cardiomyopathy12 and catecholaminergic polymorphic 
ventricular tachycardia13 without short-term adverse effects. 
Flecainide has not been studied in arrhythmic mitral valve prolapse patients, but a case series on 
patients with arrhythmic mitral valve prolapse proposed that flecainide in combination with beta 
blocker had better efficacy in suppressing ventricular arrhythmias than beta blocker alone without 
imparting increase in short-term arrhythmic risk21. Due to the lack of effective treatment options, the 
results from this limited case series could lead to a clinical utility of flecainide in these patients 
without robust evidence. Thus, a randomized, controlled trial is in order. 
Previous studies have shown that patients with arrhythmic mitral valve prolapse have symptoms of 
palpitation, dyspnea, atypical chest pain and presyncope/syncope. However, whether these 
symptoms impact health-related quality of life is unknown. Furthermore, health-related quality of life 
has never before been systematically assessed in patients with arrhythmic mitral valve prolapse. 
Figure 2. Ventricular fibrillation registered on a loop recorder in a study patient with MAD and 
MVP. A) Cardiac magnetic resonances showing mitral annulus disjunction (red). B) 3D 
echocardiographic image showing mitral valve prolapse. C) Ventricular fibrillation detected by 
implantable loop recorder (Reveal LINQ, Medtronic). 

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Short-form 36 questionnaire and Hospital Anxiety and Depression Scale (HADS) questionnaire are 
validated questionnaires for assessing general health-related quality of life in a wide variety of 
patient populations, assessing both physical and mental components22,23. Using these validated 
questionnaires makes it possible to compare health-related quality of life between arrhythmic mitral 
valve prolapse and other patient populations. 
We aim to assess whether the combination of flecainide and beta blocker is superior to beta blocker 
therapy alone in suppressing ventricular arrhythmias and reduce self-reported symptoms in patients 
with arrhythmic mitral valve prolapse. 
2.3 Benefit/Risk Assessment 
There are certain potential risks associated with participation in the trial. All investigational products 
have potential adverse effects. Flecainide has previously been associated with increased mortality in 
patients after myocardial infarction18. Because of this, flecainide use is discouraged in the presence 
of ischemic and structural heart disease10. However, this knowledge stems from a study performed 
on a vastly different clinical entity than arrhythmic mitral valve prolapse. It is challenging to translate 
the harmful effects of flecainide previously observed in patients after acute myocardial infarction 
before modern revascularization, to patients with other structural heart diseases24. Recently, 
flecainide in combination with beta blocker has shown to reduce ventricular arrhythmias in both 
patients with PVC-mediated cardiomyopathy and arrhythmogenic cardiomyopathy, without concerns 
of safety11,12. Furthermore, preliminary data have suggested that flecainide reduced PVC burden and 
device-detected non-sustained ventricular tachycardias with no short-term adverse events in 
patients with arrhythmic mitral valve prolapse21 . However, we cannot dismiss a potential 
proarrhythmic effect of flecainide in the study participants, which can occur due to reentry 
mechanisms in myocardial scars or by the QT prolonging effect of flecainide. 
Metoprolol is a beta blocker and class II antiarrhythmic drug considered standard care in most 
cardiac diseases predisposing for ventricular arrhythmias10, and metoprolol is associated with 
favorable outcome in heart failure with reduced ejection fraction25. Beta blockers are also considered 
standard care in arrhythmic mitral valve prolapse in the lack of head-to-head trials on different 
treatment approaches. However, metoprolol has certain potential adverse effects frequently leading 
to reduced compliance, possibly affecting the role of beta blockers in prevention of ventricular 
arrhythmias. 
Prevalence of adverse events after implantable loop recorder (ILR) implantation is reported to be 
low26, with a prevalence of infection at 1%27. It is plausible that infection risk and overall complication 
risk today is even lower, given the small size, easy insertion technique and fast procedure of the LINQ 

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II™. Anticoagulant and antiplatelet therapy represents increased risk of local hemorrhage, and such 
therapy will be dosage-adjusted or paused at the operating physician’s discretion if clinically safe. 
Local hematomas are generally easily controlled and treated and pose no risk of major bleeding 
because of location of operative site. The added safety of continuous heart rhythm monitoring from 
an ILR in FLECAPRO weighs up for the minimal risk of implantation. 
Potential benefits should also be considered. If the trial hypothesis proves to be correct, all 
participants will have access to superior treatment for half of the study duration. Importantly, 
today’s standard of care treatment with beta blockers alone is ineffective, leaving these patients with 
high symptomatic arrhythmic burden and high risk of experiencing severe ventricular arrhythmias. 
Participants will have close contact with the outpatient clinic at Oslo University Hospital, 
Rikshospitalet and may consider it favorable to have closer follow-up than standard clinical care at a 
specialized center. 
Overall, we consider participation in FLECAPRO to be of relatively low risk. The balance between 
potential risks, benefits and clinical implications seems to justify the investigation. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of flecainide and metoprolol, as well as the risk of loop recorder 
implantation, may be found in the Summary of Product Characteristics (SmPC) for flecainide and 
metoprolol and Investigational Directions for Use (IDFU) for LINQ II. 
3.0 Objectives and Endpoints 
3.1 Objective 
The main goal of FLECAPRO is to evaluate the effect and safety of adding flecainide to standard beta 
blocker therapy to reduce burden of ventricular arrhythmias in patients with arrhythmic mitral valve 
prolapse. 
3.2 Hypothesis 
A flecainide-based strategy is superior to a beta blocker-based strategy to suppress ventricular 
arrhythmias in patients with arrhythmic mitral valve prolapse. 
3.3 Primary Endpoint  
The main objective of FLECAPRO is to assess whether the combination of flecainide and metoprolol 
can reduce the number of ventricular tachyarrhythmias without imposing worse short-term 
arrhythmic risk, compared to standard beta blocker therapy. Since the most feared adverse event is 

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ventricular tachycardia or ventricular fibrillation, this study question translates into a composite 
primary endpoint: 
- Number of ventricular tachyarrhythmias over 12 months of treatment, sum of: 
• 
Ventricular fibrillation 
• 
Ventricular tachycardia (broad complex tachycardias with heart rate 
>140/min) 
We will monitor for ventricular tachyarrhythmias using continuous heart rhythm monitoring with an 
implantable loop recorder. Ventricular fibrillation is an abnormal fast heart rhythm causing cardiac 
arrest. Ventricular tachycardia is traditionally defined as broad complex tachycardia for more than 3 
consecutive beats with heart rate >100 beats per minute28. However, loop recorders are 
programmed to store tachycardias above a certain preprogrammed threshold, most commonly the 
estimated maximum heart rate of the patient (230 – age for LINQ II). This threshold is set to avoid 
recording of normal sinus tachycardia (e.g. during exercise). Thus, the definition of ventricular 
tachycardia for the primary endpoint in FLECAPRO will relate to the programmed detection zones of 
the loop recorders. We will program the ILRs for optimally detecting ventricular tachycardias, with 
automatic detection of rapid onset tachycardias with rate above 140 per minute (see section 7.3.2). 
The advantage for such a definition is that the primary endpoint will be more robust due to including 
only ventricular tachycardias faster than the traditional definition, and thus possibly more clinically 
relevant. However, a disadvantage will be that the definition is not based on traditional consensus. 
To detect possible ventricular tachycardias below the programmed detection zones, we will also 
perform Holter monitoring (see SoA), but ventricular tachycardias detected on Holter monitoring will 
not be included in the primary endpoint. 
We expect some patients to have implanted a cardioverter defibrillator (ICD) prior to screening. In 
these patients, the primary endpoint will only be assessed by the implantable loop recorder and not 
the ICD itself. This is due to the difference in detection zones between loop recorder and ICD, and 
between different ICD manufacturers. 
3.4 Secondary Endpoints 
Secondary endpoints are categorized as key secondary endpoints (hierarchical testing only), 
secondary safety endpoints and exploratory secondary endpoints (all tested for hypothesis 
generation). 
3.4.1 Key secondary endpoints (hierarchical) 
- Burden of premature ventricular complexes, intention-to-treat, superiority 

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- Health-related quality of life (number of patients with ≥5-point increase in SF-36 overall 
summary score), intention-to-treat, superiority  
- Number of severe ventricular tachycardias, intention-to-treat, superiority, sum of: 
 
- Non-sustained ventricular tachycardia with syncope 
- Sustained ventricular tachycardia (broad complex tachycardias with heart rate 
>140/min lasting for more than 30 seconds or requiring cardioversion) 
 
- Ventricular fibrillation 
3.4.2 Secondary safety endpoints 
- Safety composite, safety population, sum of: 
 
 
- The number of adverse events 
 
 
 
- Adverse reactions 
 
 
- The number of serious adverse events 
 
 
 
- Serious adverse reactions 
- Higher degree AV block (Mobitz type 2 or 3rd degree AV block) 
3.4.3 Exploratory secondary endpoints 
- Components of primary composite endpoint: 
 
- Ventricular tachycardia 
 
- Ventricular fibrillation 
- Components of key secondary endpoints: 
 
- Burden of premature ventricular complexes 
- Improved health-related quality of life (number of patients with ≥5-point increase in 
SF-36 overall summary score) 
 
- Number of severe ventricular tachycardias 
 
 
- Non-sustained ventricular tachycardia with syncope 
 
 
- Sustained ventricular tachycardia 
 
 
- Ventricular fibrillation 

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- Left ventricular ejection fraction (change) 
- N-terminal pro-B-type natriuretic peptide (change) 
 
- NYHA class 
 
- T-wave inversions (change) 
 
- Degree of mitral regurgitation (change) 
 
- Health-related quality of life as assess by the HADS questionnaire 
 
- Per-protocol primary efficacy endpoint sensitivity analysis 
 
- Intention-to-treat secondary safety endpoint sensitivity analysis 
 
If other secondary endpoints become of interest during the study period, they will be highlighted as 
not pre-defined. 
3.5 Corresponding Objectives and Endpoints 
 
Objective 
Endpoint measured at 13 and 26 months 
Primary 
To assess whether flecainide 
and metoprolol can reduce 
number of ventricular 
tachyarrhythmias without 
imposing worse short-term 
arrhythmic risk 
Primary endpoint: 
- Number of ventricular tachyarrhythmias (composite of 
ventricular tachycardia and ventricular fibrillation) 
Secondary 
To assess the efficacy of 
flecainide and metoprolol in 
reducing ventricular 
arrhythmias and arrhythmic 
symptoms compared to 
metoprolol alone 
Key secondary endpoints: 
- Burden of premature ventricular complexes 
- Improved health-related quality of life assessed by SF-
36 questionnaire 
- Number of severe ventricular tachycardias (composite 
of non-sustained ventricular tachycardia with syncope, 
sustained ventricular tachycardia and ventricular 
fibrillation) 
Safety 
To assess the safety of 
flecainide and metoprolol 
compared to metoprolol 
alone 
Secondary safety endpoints: 
- The number of adverse events 
- The number of serious adverse events 
- Higher degree AV block 
Exploratory 
To generate hypotheses of 
potential beneficial effects of 
flecainide and metoprolol 
compared to metoprolol 
alone in patients with 
arrhythmic mitral valve 
prolapse 
Exploratory secondary endpoints: 
- Components of primary composite endpoint: 
 
- Ventricular tachycardia 
- Ventricular fibrillation 
- Components of key secondary endpoints: 
- Burden of premature ventricular complexes 
- Improved health-related quality of life assessed 
by SF-36 questionnaire 
- Number of severe ventricular tachycardias: 

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- Non-sustained ventricular 
 
tachycardia with syncope 
 
- Sustained ventricular tachycardia 
 
- Ventricular fibrillation 
- Left ventricular ejection fraction (change) 
- N-terminal pro-B-type natriuretic peptide (change) 
- NYHA class 
- Health-related quality of life as assess by the HADS 
questionnaire 
- Per-protocol primary efficacy endpoint sensitivity 
analysis 
- Intention-to-treat primary safety endpoint sensitivity 
analysis 
4.0 Study Design 
4.1 Overall Design 
We will design the study as a prospective randomized open-label blinded-endpoint (PROBE) 
crossover trial. Participants will receive equal time-periods of 12 months with the study intervention 
(flecainide + metoprolol) and with control (metoprolol) in a 1:1 randomized order. Randomization 
will be performed after inclusion and at the time of ILR implantation. Participants will have a run-
in/washout period of 1 month at the beginning of the two treatment periods. The total duration of 
participation in FLECAPRO is 26 months (2 periods of 1 month run-in/washout and 12 months of fixed 
dose). 
For assessing the primary endpoint and safety, every patient will have continuous heart rhythm 
monitoring using an implantable loop recorder (ILR). The device will be implanted prior to 
randomization and initiation of study intervention. Patients with a prior cardiac device (pacemaker or 
ICD) will also receive an implantable loop recorder. Additionally, at screening and after 1, 6 and 12 
months of both treatment periods, we will perform 24-hour ambulatory Holter monitoring, which is a 
portable device for continuous recording the heart rhythm during 24 hours. This will detect 
ventricular tachycardias below the programmed detection zone of the implantable loop recorder and 
quantify premature ventricular complexes. 
The end of the study is defined as the date of the last visit of the last participant in the study. A 
participant is considered to have completed the study if he/she has completed all phases of the study 
including the last visit. 
Note: “Enrolled” means a participant's agreement to participate in a clinical study following 
completion of the informed consent process and screening. Potential participants who are screened 

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for the purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled.  
4.1.1 Study Duration 
Participants will be treated with the intervention arm for 13 months and the control arm for 13 
months. Each arm will have a run-in/washout period of 1 month. 
4.1.2 Estimated Study Period 
The outpatient clinic at Oslo University Hospital, Rikshospitalet treats many patients with arrhythmic 
mitral valve prolapse per year, and this number is steadily increasing. We retrospectively assessed 
study inclusion and exclusion criteria in the patient population of 3 months from October to 
December 2021 at the outpatient Clinic of Oslo University Hospital, Rikshospitalet, prior to 
performing these calculations and observed that 13 of 18 patients (72%) would have been eligible for 
inclusion. Additionally, we will screen patients with arrhythmic mitral valve prolapse admitted to 
Department of Cardiology for symptomatic ventricular arrhythmias. This implies a realistic eligibility 
of at least 55 patients per year, meaning that inclusion will be completed within 1 year after study 
start. With study start on January 4th 2023, we estimate complete recruitment by January 31st 2026, 
and last subject last visit by March 31st 2028. 
4.2 Scientific Rationale for Study Design 
The crossover design of FLECAPRO was chosen because the number of arrhythmic mitral valve 
prolapse patients eligible for such a study is small, making recruitment difficult for a standard 
randomized parallel group trial design. Additionally, the added safety monitoring with using ILRs in 
FLECAPRO leads to an economic and an ethical limitation of group size when other study designs with 
fewer patients are suited. Furthermore, a crossover design reduces the random skewed distribution 
of known and unknown variables between randomized groups. 
The traditional trial design to minimize bias is the double blind placebo design. Placebo control was 
discussed during the planning of FLECAPRO. Firstly, proper patient blinding provides only a small 
benefit and will include manufacturing several drug combinations of flecainide and metoprolol, 
which is non-feasible practically and economically. Secondly, measuring flecainide serum 
concentrations at each visit will lead to unblinding of trial personnel. Measuring flecainide serum 
concentration is necessary in patients with arrhythmic events during the course of FLECAPRO to 
avoid overdosing and potential risk of proarrhythmias. Thirdly, the aim of FLECAPRO is to assess the 
efficacy of the treatment strategy rather than a head-to-head comparison between flecainide and 
metoprolol. The randomization process will reduce potential bias. Fourthly, the primary endpoint 
and key secondary endpoints, except quality-of-life assessment, are not likely influenced by the lack 

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of patient blinding. Furthermore, adequately blinded adjudication of the pivotal study endpoints can 
be achieved using the PROBE-design. 
Metoprolol is considered the standard of care for patients with arrhythmic mitral valve prolapse and 
is thus a natural control. Because participants of FLECAPRO is considered high risk of ventricular 
arrhythmias, having a control without active compound cannot be justified ethically. 
4.2.1 Patient Input into Design 
A panel of users has been recruited via the outpatient clinic at Oslo University Hospital, 
Rikshospitalet. The user panel has participated in the trial planning. They have emphasized the 
importance of close follow-up and that information regarding enrollment in the study should be 
duplicated in the patient’s electronic medical record and provided to the primary care physician and 
local hospital. 
Furthermore, they have been consulted in establishing the rate of physical visits and Holter 
monitoring during follow-up, which is aimed at creating a compromise between good safety 
monitoring and individual intrusiveness. Lastly, they have been consulted in establishing the 
hierarchical order of key secondary endpoints. 
Further user representation is planned at the following time-points (all approximate): 
- 
October 2022 
o Start-up meeting prior to enrollment of first patient, discussion of approved study 
proceedings and incorporations of previous feedback. Discussions of whether 
additional alterations should be made before inclusion starts. 
- 
May 2023 
o Early evaluation meeting after 6 months of inclusion experience and early follow-up. 
Discussion of challenges. 
- 
November 2023, 2024 
o Yearly evaluations and discussions of progression and interaction with trial 
participants. Considerations of remarks to be made in the yearly rapport. 
The user panel will receive re-imbursement for any expenses and will receive a non-monetary 
gratification for their efforts. 
4.3 Justification for Dose 
4.3.1 Flecainide + Metoprolol SR (Intervention): 
Flecainide will be initiated in as immediate-release formulation at a dose of 50 mg BID, and increased 
to the maximum tolerable dose, with a dosage target of 100 mg BID. The first dose of flecainide (100 

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mg) will be initiated in-hospital with 12-lead ECG taken after 3 hours (at maximum plasma 
concentration). Then, the participant will continue with 50 mg BID from the next day. The decision to 
proceed to the next dose level (either an increase or decrease) will be made by the Study Team and 
the investigator based on safety, tolerability, ECG changes and measurements of plasma 
concentration of flecainide. The maximum daily dose of flecainide will not exceed 300 mg. Whether 
Flecainide will be initiated on an inpatient or outpatient basis, will be decided on a case-by-case basis 
based on clinical features and current recommendations. 
Study Team or investigator can change the immediate-release formulation to controlled-release form 
QD in case participants are stable on Flecainide 100 mg BID and have one of the following; (1) 
reduced compliance to twice a day dosing of flecainide, (2) preference for once a day dosing or (3) 
large fluctuations in plasma concentrations.  
Flecainide has the potential to convert atrial fibrillation to atrial flutter with slow atrial rate leading to 
1:1 atrioventricular conduction with high ventricular rate. This phenomenon can be prevented by 
concomitant therapy with negative dromotropic agents (e.g. beta blockers, verapamil, diltiazem or 
digoxin). A few of our patients will have moderate mitral regurgitation, with the potential of 
developing atrial fibrillation. Because of this safety concern, the study intervention will include a 
negative dromotropic agent. To avoid different medications with unknown efficacy, we will only 
permit metoprolol sustained release as this dromotropic agent, with a targeted daily dose identical 
to the control arm (see section 4.4.2 below), but will not exceed 200 mg. The starting dosage will be 
decided by the Study Team and investigator based on individual patient’s prior dose, tolerability and 
safety. The decision to proceed to the next dose level will be based on safety and tolerability.  
4.3.2 Metoprolol SR (Control) 
The Study Team and investigator will decide the starting dosage of metoprolol taking into 
consideration prior beta blocker use and concomitant medications. The decision to proceed to the 
next dose level (either increase or decrease) will be based on safety and tolerability. Whether 
metoprolol sustained release will be dosed QD or BID, will be up to the investigator and patient 
preference. The maximum daily dose of metoprolol will not exceed 200 mg. 
4.4 End-of-Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. A 
participant is considered to have completed the study if he/she has completed all phases of the study 
including last visit or the last scheduled procedure shown in the SoA. 

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5.0 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be 18 years of age or older at the time of signing the informed consent 
Mitral valve prolapse 
2. Participants must have mitral valve prolapse evident by echocardiography or cardiac 
magnetic resonance imaging, defined as: 
a. More than or equal to 2 mm atrial displacement of any part of the mitral leaflets 
(mitral valve prolapse) 
Ventricular arrhythmias 
3. Participants must have ventricular arrhythmias, defined as at least one of the following: 
a. Premature ventricular complex burden ≥3% per 24-hours by Holter monitoring 
b. Premature ventricular complex burden ≥1% per 24-hours if multifocal or occurring in 
bi-/trigemini and/or couplets by Holter monitoring 
c. Sustained or non-sustained ventricular tachycardia 
d. Aborted cardiac arrest 
4. Participants must have a clinical indication for antiarrhythmic treatment due to ventricular 
arrhythmias 
Informed consent 
5. Participants must be capable of giving signed informed consent, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) 
For women of childbearing potential 
6. Participants must accede to mandatory use of a contraceptive method for the duration of 
the trial and until 3 days after discontinuation of study medication. 
Rescreening will be allowed if a participant at a later time point develops ventricular arrhythmias 
as per definition stated above. Participants will only be eligible for rescreening two times. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 

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Contraindication to Study Medications 
1. Strict contraindication to flecainide or metoprolol use 
Medical Conditions 
2. Heart failure (signs or symptoms, elevated NT-proBNP) according to ICD10 
3. Abnormal liver or kidney function (AST/ALT three times upper normal, eGRF <60) 
4. Prior myocardial infarction or ischemic heart disease 
5. Ion channelopathy, including Brugada syndrome and long QT syndrome according to ICD10 
and ECG 
6. Genetic cardiomyopathy (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, 
dilated cardiomyopathy, including genotype positive phenotype negative individuals) 
according to ICD10 
7. Atrial flutter or permanent atrial fibrillation according to ICD10 and ECG 
8. Sinus node dysfunction according to ICD10 and ECG 
9. Ongoing electrolyte disorders 
10. More than moderate valvular disease according to international guidelines29 
Electrocardiogram 
11. Pre-excitation 
12. Any degree of AV-block, except due to enhanced vagal tone (e.g. Wencheback-block at 
night in young athletes or 1st degree AV block that disappears during exercise) 
13. Bundle branch block (QRS duration >120 ms) or intraventricular conduction defect with 
QRS >120 ms 
Prior/Concomitant Therapy 
14. Prior flecainide therapy 
15. Concomitant use of the following medications: 
a. CYP2D6 inhibitors/inducers 
b. Class I, III or IV antiarrhythmic drugs 
c. Clozapine, quinidine, cimetidine, bupropion 
d. Monoaminoxydase (MAO) inhibitors 
Women of Childbearing Potential 
16. Pregnancy 
17. Not willing to use a mandatory contraceptive method for the duration of the trial 

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5.2.1 Coronary Artery Disease/Anomaly Assessment 
Because of the results of the CAST trial showing increased mortality in patients treated with 
flecainide after myocardial infarction, we will exclude coronary artery disease in the participants of 
FLECAPRO. Most participants recruited will already have excluded coronary artery disease, as this 
condition is an important differential diagnosis of arrhythmic mitral valve prolapse. However, we 
will assess all patients for symptoms of coronary artery disease at screening. Participants not 
already assessed by coronary angiography within the last two years prior to screening will be 
evaluated with CT or invasive coronary angiography at baseline if symptomatic.  
We will not perform coronary angiography in patients without symptoms of coronary artery 
disease, as this will expose participants to potential unnecessary and dangerous invasive 
procedures. A screening CT coronary angiography has been discussed in the planning of FLECAPRO. 
However, uncertain findings or uncertain degree of obstructive coronary artery disease will need 
further assessment by invasive coronary angiography with potential for deleterious events in 
asymptomatic individuals. 
5.3 Lifestyle Considerations  
Participants should refrain from consumption of Seville oranges, grapefruit or grapefruit juice, 
from the day of starting the study intervention until after the final dose. There are no restrictions 
on ingesting caffeine- or xanthine-containing products (coffee, tea, cola drinks and chocolate), or 
use of tobacco products. 
5.4 Screening Failures 
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) due to not 
fulfilling inclusion criteria may be rescreened. A participant who is rescreened is not required to 
sign another ICF if the rescreening occurs within 3 months from the previous ICF signature date. 
6.0 Study Interventions and Concomitant Therapy 
Study intervention is defined as any investigational interventions intended to be administered to a 
study participant according to the protocol. All participants enrolled in FLECAPRO will be treated with 
both the intervention arm (flecainide and metoprolol) and control arm (metoprolol), and all 
participants enrolled will be have an ILR implanted.  

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6.1 Study Interventions Administered 
Each study period will start with a run-in/washout period of 1 month. The first dose of flecainide will 
be 100 mg initiated in-hospital with 12-lead ECG taken 3 hours after intake (at maximum plasma 
concentration). Then the participant will continue with 50 mg BID from the next day. Flecainide 
dosage will be initiated at 50 mg BID and evaluated for increasing dose after 7 days to a maximum of 
300 mg daily dose.  
The flecainide dosage will be kept unchanged during the course of the treatment period, or 
according to plasma measurements and development of AEs. 
Metoprolol will be initiated at a dosage that takes into account prior beta blocker use, and will be 
evaluated for increasing dose after 7 days to the maximum tolerated dose. Dosage will be kept at 
maximum tolerated dose during both the intervention arm and control arm. 
Table 1. Study Interventions Administered 
Intervention Name 
Flecainide 
Metoprolol 
Type  
Drug 
Drug 
Formulation 
Tablets (immediate-release) 
Capsules (controlled-release) 
Tablets 
Unit Dose Strength(s) 
100 mg (immediate-release) 
200 mg (controlled-release) 
200 mg 
Targeted dose 
200 mg daily (100 mg BID 
immediate-release or 200 mg QD 
controlled release) 
200 mg QD 
Route of Administration 
Oral 
Oral 
Use 
Experimental treatment strategy 
Background intervention 
IMP or AxMP 
Investigational medicinal product 
(IMP) 
Investigational medicinal product 
(IMP) 
Sourcing 
Shelf product 
Shelf product 
Packaging and Labeling 
Study intervention will be 
provided in original package. Each 
package will be labeled as 
required per country 
requirement. 
Study intervention will be 
provided in original package. 
Each package will be labeled as 
required per country 
requirement. 
Current/Former Names 
or Aliases 
Immediate-release: Flecainide, 
Tambocor 
Metoprolol, Selo-Zok, Bloxazoc 

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Controlled-release: Tambocor 
Retard 
 
Table 2. Study Arms 
Arm Title 
Flecainide and Metoprolol 
Metoprolol Alone 
Arm Type 
Experimental 
Active Comparator 
Arm Description 
Participants will receive Flecainide 50 
mg BID, with a dosage target of 100 mg 
BID. The maximum daily dose of 
flecainide will not exceed 300 mg. 
The first dose of flecainide will be 100 
mg and initiated in-hospital with 12-
lead ECG taken after 3 hours (at 
maximum plasma concentration). The 
participant will continue with 50 mg BID 
from the next day. 
Participants will receive a dosage of 
Metoprolol taking into consideration 
prior beta blocker use and concomitant 
medications. The maximum daily dose 
of metoprolol will not exceed 200 mg. 
Within the run-in period, the dosage of 
both Flecainide and Metoprolol will be 
increased to the maximum tolerable 
dose.  
The Study Team can change the 
immediate-release formulation of 
Flecainide to controlled-release at the 
same daily dose of flecainide (see 
section 4.3). Whether metoprolol 
sustained release will be dosed QD or 
BID, will be up to the investigator and 
patient preference.  
Participants will receive a dosage of 
Metoprolol taking into 
consideration prior beta blocker 
use and concomitant medications. 
Within the run-in period, the 
dosage will be increase to the 
maximum tolerable dose. Whether 
metoprolol sustained release will 
be dosed QD or BID, will be up to 
the investigator and patient 
preference. The maximum daily 
dose of metoprolol will not exceed 
200 mg. 
Associated 
Intervention 
Labels 
Flecainide immediate-release: 
Flecainide, Tambocor 
Flecainide controlled-release: 
Tambocor Retard 
Metoprolol: Metoprolol, Selo-Zok, 
Bloxazoc 
Metoprolol, Selo-Zok, Bloxazoc 
 

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6.1.1 Flecainide 
Flecainide is a class Ic antiarrhythmic drug that was approved by the Food and Drug Administration in 
1984 for the treatment of symptomatic sustained ventricular tachycardia, with a 90% efficacy and 
without significant adverse events17,30. The main mechanism of flecainide is blocking myocardial 
sodium channels leading to a reduction in ventricular myocardium conduction velocity. In addition, 
flecainide has an inhibitory action on potassium channels, which increases the duration of the action 
potential and the effective refractory period in the myocardium. Because of these 
pharmacodynamics effects, flecainide prolongs the PR (17-29%) and widens the QRS complex (11-
27%), but the effect of flecainide on JT-interval is negligible. The third mechanism of action is the 
blocking of ryanodine receptor 2 calcium channels, making it a good treatment option for patients 
with catecholaminergic polymorphic ventricular tachycardia13. 
Currently, flecainide is mainly used for pharmacological conversion in rhythm control strategies in 
patients with atrial tachyarrhythmias10. The Cardiac Arrhythmia Suppression Trial (CAST) investigated 
the efficacy of class Ic antiarrhythmic therapy on morbidity and mortality in patients with reduced 
ejection fraction and frequent premature ventricular complexes after myocardial infarction18. This 
study recorded significantly higher mortality among patients treated with IC antiarrhythmic drugs 
compared to placebo and the study was prematurely dismissed. The CAST study provided a major 
revision of the role of flecainide, which is now recommended in selected patients with preserved 
systolic function and without ischemic heart disease. However, the CAST trial was performed prior to 
modern myocardial infarction treatment, and flecainide use in stable coronary artery disease has 
recently been shown to be safe19,20. In addition, current guidelines extended the CAST findings to 
non-ischemic structural heart disease despite limited evidence10. Thus, we have seen a fall in 
employment of class IC antiarrhythmic drugs in favor of class III antiarrhythmic drugs, exposing 
patients to the numerous adverse reactions and toxicities of the latter drugs, in the absence of 
robust evidence.  
On the other hand, recent studies demonstrated safety and efficacy of flecainide in patients with 
PVC-induced cardiomyopathy11 and arrhythmogenic cardiomyopathy12. A randomized placebo-
controlled crossover trial on flecainide in patients with arrhythmogenic cardiomyopathy is ongoing 
(ClinicalTrials.gov Identifier: NCT03685149). Furthermore, guidelines state a class I recommendation 
level of evidence C for treatment with class IC antiarrhythmic drugs in patients with symptomatic 
ventricular tachycardia originating from the mitral annulus, outflow tracts, papillary muscles or left 
ventricle in the absence of structural heart disease10. These areas of arrhythmia origins are similar to 
areas where ventricular arrhythmias originate in patients with arrhythmic mitral valve prolapse1,2,6,7. 

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According to the Summary of Product Characteristics (SmPC) for flecainide, measuring plasma levels 
is recommended in case of reduced heart function, high-dose treatment or long-term treatment. We 
will be measuring plasma levels at each study visit (after 1, 6 and 12 months) during both study arms 
where the therapeutic range will be 200-1000 ng/ml (0.4-2.0 µmol/L). 
The medication will be managed in agreement with the SmPC for flecainide. All reference safety 
information will be based on the SmPC for flecainide.  A detailed description of the chemistry, 
pharmacology, efficacy, and safety of flecainide is provided in the SmPC for flecainide. 
6.1.2 Metoprolol 
Metoprolol is a beta-blocker and class II antiarrhythmic drug considered standard care in most 
cardiac diseases predisposing for ventricular arrhythmias10, and is associated with decreased 
mortality in patients with heart failure with reduced ejection fraction25. Beta-blockers are also 
considered standard care in arrhythmic mitral valve prolapse in lack of trials on other treatment 
strategies. However, metoprolol has certain potential adverse effects frequently leading to reduced 
compliance, especially in younger patients, possibly affecting the role of beta-blockers in prevention 
of ventricular arrhythmias. 
The medication will be managed in agreement with the SmPC for metoprolol. All reference safety 
information will be based on the SmPC for metoprolol.  A detailed description of the chemistry, 
pharmacology, efficacy, and safety of metoprolol is provided in the SmPC for metoprolol. 
6.2 Preparation, Handling, Storage, and Accountability 
The investigators will prescribe the investigational products and local pharmacies will supply the 
investigational products as per clinical practice. This will ensure than only participants enrolled in the 
study receive study interventions. Handling, storage, reconciliation, accountability and record 
maintenance of the investigational products will be handled as by regulatory requirements. All batch 
numbers are systematically stored in the electronic patient journal (Kjernejournal). This will enable 
secure identification of batches involved in any adverse events. 
6.3 Assignment to Study Intervention 
All participants will be assigned to a randomized sequence of study arms executed on the online, 
password protected platform designed for study purposes (Viedoc®) once eligibility has been 
confirmed, informed consent has been signed and loop recorder has been successfully implanted.  
Due to small sample size, the allocation to treatment using permuted block randomization could lead 
to imbalance in prognostic factors in the two groups, especially in terms of arrhythmic risk profile. 
This could lead to problems when interpreting the results of the study. As a measure to prevent such 

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allocation bias and ensure balance of baseline prognostic factors between groups, we will use a 
computerized randomization procedure with probabilistic minimization with 80% balanced allocation 
(in a 1:1 ratio for the sequencing of the study arms). The prognostic factors we include are gender, 
age (<40 and ≥40years), sustained ventricular tachycardia or aborted cardiac arrest, NSVT, presence 
of late gadolinium enhancement, presence of mitral annular disjunction, bileaflet mitral valve 
prolapse and ECG T-wave inversions. All of the prognostic factors, including female gender and 
younger age, are linked to increased risk of ventricular arrhythmias in observational studies.  
After randomization, the study personnel will enter a statement to the patient’s electronic medical 
record declaring the allocation, treatment sequence and duration. This statement will be distributed 
to other physicians caring for the patients and will include a recommendation to only alter the study 
medication if it is critically important, documenting reasons and time of changes of study’s 
medications. 
If more than 4 weeks have passed since the screening visit, the physical exam should be repeated, 
vital signs recorded anew, and blood samples should be repeated.  
6.4 Blinding 
It is vital for an open-label blinded-endpoint randomized trial to maintain proper blinding to uphold 
scientific integrity of data. Therefore, careful logistic arrangements will be made to avoid bias in the 
endpoint adjudication. Only the investigators assessing the outcome measures will be actively 
blinded for the allocation. 
6.4.1 Implantable loop recorder 
Events recorded by the implantable loop recorder stored in the Carelink system will be de-identified 
and coded with the patient study ID to ensure that the reader will not come across details of the 
treatment. A second expert reader will be contacted by a principal investigator if the primary reader 
finds: 
- 
Blinding is compromised. The primary reader ensures proper blinding and forwards the exam for 
blinded analysis. 
- 
There is uncertainty in the adjudication. Consensus will be achieved. 
6.4.2 Holter monitoring 
Holter monitoring data will be de-identified and coded with the patient study ID to ensure that the 
reader will not come across details of the treatment. A second expert reader will be contacted by a 
principal investigator if the primary reader finds: 

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- 
Blinding is compromised. The primary reader ensures proper blinding and forwards the exam for 
blinded analysis. 
- 
There is uncertainty in the adjudication. Consensus will be achieved. 
6.5 Study Intervention Compliance 
Participant compliance to the investigational products will be self-reported by asking the participant 
to report their compliance as either full, partial or low. Full compliance is defined as taking the 
treatment as prescribed, partial compliance is less than full but more than 70% compliance to 
prescribed treatment, and low compliance is less than 70% compliant. Deviation from the prescribed 
dosage regiment will be recorded. The compliance of flecainide use will also be reflected in the 
plasma concentration measurements. Intervention start and stop dates, including dates for 
intervention delays and/or dose reductions, will also be recorded. The data will be reported with the 
trial results. The batch numbers of used study medication will be found in the electronic patient 
journal (Kjernejournal). 
6.6 Dose Modification 
After the run-in period, the dosage of study intervention will be held constant throughout the 
treatment periods. However, if a dose reduction is necessary, flecainide will be reduced with 50 mg 
daily and metoprolol with 50 mg daily. The dose reduction can be greater if the medical monitor or 
Data Monitoring Committee see it necessary due to safety concerns. 
6.7 Continued Access to Study Intervention after the End of the Study 
Participants can continue with any of the study arms after end of the study. The combination of 
flecainide and metoprolol can only be continued if the participant is under continuous heart rhythm 
monitoring with ICD or ILR. 
6.8 Treatment of Overdose 
Overdose will be defined and managed according to the SmPC for flecainide and metoprolol. In the 
event of an overdose, the investigator or treating physician should: 
o Contact the Medical Monitor immediately. 
o Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be discontinued or whether the dose should be reduced. 
o Closely monitor the participant for any AE/SAE and laboratory abnormalities until flecainide 
is within the treatment range defined in section 6.1.1. 
o Document the quantity of the excess dose as well as the duration of the overdose. 
o Report the overdose as a protocol deviation. 

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6.9 Prior and Concomitant Medication 
Use of concomitant medication is permitted if not a trial exclusion criterion (i.e. not a known 
inhibitor or inducer of CYP2D6, MAO-inhibitors, or class I, III or IV antiarrhythmic drugs other than 
flecainide). Starting these medications during the trial period is not permitted. For other and 
permitted concomitant medication, potential interactions and notions of care from the SmPC shall be 
considered and noted at inclusion. 
There might be cases where other antiarrhythmic drugs, especially amiodarone (class III 
antiarrhythmic drug), will be administered due to ventricular tachyarrhythmias occurring in 
FLECAPRO participants. It is important to stress the fact that no antiarrhythmic drug, even 
amiodarone, has been studied in patients with arrhythmic mitral valve prolapse. In case not 
permitted drugs has be to administered, patients will be discontinued from treatment in FLECAPRO.  
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Paracetamol, at doses of 2 grams/day, is permitted for use and time during the study. Other 
concomitant medications may be considered on a case-by-base basis by the investigator in 
consultation with the medical monitor, if required. 
7.0 Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 Discontinuation of Study Intervention 
The study participants may discontinue study drug treatment at any time according to their 
preferences. The investigator may also advise study drug discontinuation in case of: 
- 
Starting other anti-arrhythmic drug (e.g. amiodarone, sotalol or carvedilol). 
- 
Diagnosis of coronary artery disease, including unstable angina or myocardial infarction. 
- 
Hospitalization due to ventricular arrhythmias, cardiac arrest, symptomatic bradycardia or new 
onset of heart failure. 
- 
QRS prolongation >25% compared to baseline QRS duration. 
- 
Contraindication to the continued use of flecainide or metoprolol arises. 
- 
AEs/SAEs 
Discontinuation and the reason why must be documented in the eCRF as well as in the hospital 
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the patient no longer takes the study drug. All available data will be used, unless the patient 
specifically disagrees to let the investigator use his or her data.  
7.2 Participant Discontinuation/Withdrawal from the Study 
Participants may be discontinued from study treatment and assessments at any time. Specific 
reasons for discontinuing a patient are: 
- 
Voluntary discontinuation: participants are free to discontinue their participation in the study at 
any point in time, without prejudice to further treatment. 
- 
Patient lost to follow-up 
Patient withdrawal and the reason must be documented in the eCRF as well as in hospital records. If 
possible, a final assessment should be obtained (Early Termination Visit, see SoA). The investigator is 
obliged to follow up any significant adverse events until the outcome either is recovered or resolved, 
recovering/resolving, not recovered/not resolved, recovered/resolved with sequela, fatal or 
unknown. The implantable loop recorder could be removed after agreement with the study 
participant. 
7.3 Trial Discontinuation 
The whole trial may be discontinued at the discretion of the Principal Investigator/Sponsor in the 
event of any of the following: 
- 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
- 
Medical or ethical reasons affecting the continued performance of the trial 
- 
Difficulties in the recruitment of patients 
The Sponsor and Principal Investigator will inform all investigators, the relevant Competent 
Authorities and Ethics Committees of the termination of the trial, along with the reasons for such 
action. If the study is terminated early because of safety concerns, the Competent Authorities and 
Ethics Committees will be informed within 15 days. 
7.4 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. The following actions must be taken if a 
participant fails to return to the clinic for a required study visit: 
- 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 

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schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
- 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record. 
- 
Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study.  
8.0 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions are 
not allowed. Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. All screening evaluations must be completed and reviewed 
to confirm that potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g. laboratory 
analyses) and obtained before signing of the ICF may be utilized for screening purposes provided the 
procedures met the protocol-specified criteria. 
In the event of a significant study-continuity issue (e.g. caused by a pandemic), alternate strategies 
for participant visits, assessments, medication distribution and monitoring may be implemented by 
the sponsor or the investigator, as per local health authority/ethics requirements. 
Repeat or unscheduled blood samples may be taken for safety reasons or for technical issues with 
the samples. 
8.1 Administrative and Baseline Procedures 
8.1.1 Informed Consent 
Voluntary, written informed consent must have been obtained for each subject before any study 
specific procedure is initiated. At this time, the patient will be registered in the electronic Case 
Report Form (eCRF), and a unique identifier will be assigned. 

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8.1.2 Physical Examination 
A physical examination (including examination of heart, lungs, abdomen, neck and assessment of 
peripheral circulation and edema) must be performed; vital signs (blood pressure and heart rate, and 
height and weight) will be recorded. 
8.1.3 Vital Signs 
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and diastolic 
blood pressure, and pulse. 
8.1.4 Medical History 
A medical history will be obtained, along with age, gender, NYHA functional status, risk factors 
(hypertension, smoking and diabetes mellitus) and concomitant disease must be recorded. 
Additionally, every participant will undergo clinical evaluation for assessing pre-test probability of 
coronary artery disease. 
8.1.5 Concomitant Medication 
All concomitant medication used by the participant within 28 days of the start of treatment must be 
recorded in the eCRF by generic name and dose. 
8.1.6 Laboratory Analyses 
Non-fasting blood samples will be obtained at maximum 9 different time points (see SoA). Six blood 
samples (24 ml) will be taken 7 times. Blood samples for biobanking will be taken 3 times (4 samples, 
22 ml) and be appropriately labelled and stored in a trial specific biobank for the duration of the trial 
and later analyzed for vasoactive peptides such as ST2 and markers of fibrosis. Flecainide serum 
concentration will be assessed 8 times (1 sample, 4 ml). The maximum number of blood samples on 
one single occasion will be 10 (46 ml total volume). Samples will be labeled and marked with initials 
and date of birth of the participant. A dedicated study nurse, as well as the respective analyzing 
units, will have access to the samples.  
The baseline blood samples will be part of routine health care, but the additional blood samples 
obtained will be trial specific. Standard blood samples will be used to determine: Hemoglobin, white 
blood cell count, platelet count, serum potassium, serum sodium, glucose, glycosylated hemoglobin 
(HbA1c), creatinine, eGFR, ALT, AST, bilirubin, albumin, INR, NT-proBNP and troponin T. 
All samples, except flecainide serum concentration, will be analysed within Oslo University Hospital. 
Flecainide serum concentration will be analysed at St. Olav’s Hospital, Trondheim, Norway. Samples 
sent to St. Olav’s Hospital will be destroyed after the analyses are completed. 

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8.1.7 Transthoracic Echocardiography 
Echocardiography is the most widely used imaging method in cardiology for assessing valvular and 
myocardial function, and predict outcome. The echocardiographic study will be performed on a Vivid 
E9 or higher (GE Healthcare, Horten, Norway). Data will be analyzed with EchoPac (GE Healthcare). 
Measurements of cardiac cavities will be performed using M-mode and 2D modalities for internal 
linear dimensions and volumes. Ejection fraction is calculated by using Simpson`s modified biplane 
method utilizing endocardial contours in the apical 4-chamber and 2-chamber view. Assessment of 
heart valves will be performed using color Doppler, and pulsed and continuous wave Doppler. 
Diastolic function will be evaluated by transmitral pulsed Doppler, tissue Doppler and left atrial 
volume assessment31. Tissue Doppler from the 4-chamber view will be recorded and e’ will be 
calculated as the average from septal and lateral samplings 32. Atrial volumes and areas will be 
averaged as the end-systolic area measured from apical four-chamber and apical two chamber views 
32.  
We will assess mitral annular disjunction (MAD) in end-systole, and measure the distance from the 
left atrial wall-valve leaflet junction to the top of the left ventricular wall 33-35. We will assess the 
presence of MAD in both the parasternal long-axis view, and all apical long-axis views. 
Myocardial strain measurements have 
been proven to be superior to 2D echo 
for assessing regional LV function36. 
Myocardial global longitudinal strain 
will be obtained by speckle tracking 
technique. Peak systolic strain by 2D 
speckle tracking echocardiography will 
be determined using a 16-segment left ventricular model 
recommended by the American Heart Association. 
Myocardial systolic strain will be studied to characterize 
regional myocardial function and timing in all study patients. 
The time to maximum shortening in each patient’s 16 left 
ventricular segments will be calculated37. The standard 
deviation of these time measurements will be calculated as 
mechanical dispersion, reflecting contraction heterogeneity 
(Figure 3)37. 
Figure 3: Strain curves in 4-chamber view after 
myocardial infarction. Maximum myocardial 
shortening in septal apical segment is indicated 
(white arrow) and time from ECG onset Q/onset 
R wave to maximum myocardial shortening (time 
line). Global strain: average value of maximum 
myocardial shortening in 16 left ventricular 
segments. Mechanical dispersion: Standard 
deviation of time interval from ECG onset 
Q/onset R wave to maximum myocardial 
shortening in 16 LV segments. (From Haugaa et 
al, J Am Coll Cardiol Imaging 2010). 

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8.1.8 Cardiac Magnetic Resonance Imaging 
If not performed within the last 24 months prior to screening or if the participant has a pacemaker or 
an ICD, a comprehensive cardiac magnetic resonance imaging exam for study purposes must be 
performed prior to study drug administration and implantation of loop recorder. 
Cardiac magnetic resonance (CMR) done as a part of FLECAPRO will be performed using 1,5 or 3 Tesla 
scanner (Magnetom Vision Plus or Magnetom Sonata; Siemens, Erlangen, Germany) and a phased 
array body coil. The right and left ventricle will be covered by axial and sagittal breath-hold T1 
weighted turbo spin echo images, and by multiple short axis cine images using a breath-hold 
segmented balanced gradient echo sequence (fast imaging with steady-state free precession). Two-
chamber and four-chamber cine acquisitions will be obtained. Intravenous gadolinium-based 
contrast agents will be used, as late gadolinium enhancement has become the reference standard for 
noninvasive assessment of myocardial fibrosis 38-40. Post-processing analysis will be performed for 
calculation of myocardial function by ejection fraction, to assess extent and distribution of 
myocardial fibrosis, structural pathology in mitral valve apparatus and measurements of MAD 
distance. T1 mapping will be used according to current protocols. We will perform CMR according to 
Oslo University Hospital’s own safety procedures in participants with cardiac electronic devices prior 
to inclusion. 
In addition to CMR at baseline, we will perform CMR in 10 participants shortly after successful ILR 
implantation. This will be done in order to assess whether the ILR interferes with measurements of 
T1 times. We will also perform an additional CMR (after successful ILR removal) in participants 
randomized to receive the intervention arm as the last treatment period, in order to assess whether 
treatment with flecainide decrease markers of diffuse fibrosis. 
8.2 Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
8.2.1 Implantable Loop Recorder 
All enrolled participants will receive an ILR. Implantable loop recorder (ILR) is a small cardiac 
monitoring device implanted subcutaneously in the left parasternal precordial region, with 
approximately 4.5 years of battery capacity for LINQ II. The unit continuously monitors heart rhythm, 
and will store selected ECGs in the device memory according to a pre-programmed algorithm and/or 
by patient activation of the device. ILRs have been used for many years and is part of the established 
toolbox for evaluating patients with suspected paroxysmal cardiac arrhythmias, syncope and 
ventricular arrhythmias 26,41-43 28,44. The ILR is superior to conventional 24 hours Holter monitoring for 
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long time-intervals. The use of ILRs for detection of paroxysmal cardiac arrhythmias is rapidly 
increasing, much due to steadily decreasing size of device, development of easy and fast 
implantation procedures and high degree of safety 26,45. 
Prevalence of adverse events after ILR implantation is reported to be low26. Possible side-effects or 
complications include device rejection phenomena (local tissue reaction), device migration, local 
infection and erosion of the skin46. Recent studies have reported low prevalence of infection at 1%27. 
It is plausible that infection risk and overall complication risk today is even lower, given the small size 
of device, easy insertion technique and fast procedure of the LINQ II™. 
The ILRs implanted in FLECAPRO will be programmed towards primarily (but not exclusively) 
detecting ventricular arrhythmias. We will use the CE approved Medtronic LINQ II™ Insertable 
Cardiac Monitor. For specifications and device measures, see the Clinician Manual for LINQ II. The 
device can be interrogated remotely by the investigator via the mobile network or Wi-Fi. Patients will 
also be monitored remotely (Carelink™) without the need for physical visits to the outpatient clinic, 
with daily transmission of data. When the ILR battery is depleted, it will be explanted, usually about 
4.5 years post-implantation. The LINQ II™ is fully magnetic resonance imaging conditional. 
If consultations or interrogation of ILR reveals pathology in need of treatment or further 
investigation, this will be handled as in a normal clinical setting with proper patient information and 
referral to adequate investigations. 
At study completion, we will review all stored events for ventricular arrhythmias using the Carelink™ 
system. 
8.2.1.1 Implantation Procedure 
Implantation procedure will follow instructions from Medtronic’s Clinicians Manual. Skin is sterilized 
and patient prepared according to standard surgical procedures at Oslo University Hospital, 
Rikshospitalet. Local anesthetic is infiltrated in the area of interest, a small incision is made in the 
skin, and the device is inserted via a custom insertion tool (Figure 4). The incision is closed with 
surgical tape or 1-2 sutures. Normal procedure time including appliance of anesthetic is 10 minutes. 
Anticoagulant and antiplatelet therapy represents increased risk of local hemorrhage, and such 
treatment will be evaluated pre-operatively in concert with other risk factors for bleeding. 
Anticoagulant or antiplatelet medication will be dosage-adjusted or paused at the operating 
physician’s discretion if clinically safe. Local hematomas are generally easily controlled and treated 
and pose no risk of major bleeding because of location of operative site. 

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Figure 4. Insertion of implantable loop recorder. Medtronic LINQ II, Clinician’s Manual. 
8.2.1.2 LINQ II programming 
The LINQ II will be programmed towards optimal detection of ventricular tachycardias, with 
tachycardia interval length of 430 ms (equals 140 bpm), tachycardia duration of 3 events and “Tachy: 
Require Rapid Onset” feature turned on. The “Tachy: Require Rapid Onset” function will be used to 
distinguish sinus tachycardia from ventricular tachycardias, as ventricular tachycardias exhibits a 
sudden rate increase, while sinus tachycardia is characterized by a gradual increase in rate. The “PVC 
Detection Enable” feature will be turned on. This feature is designed to detect single PVCs between 
two normal sinus beats and does not count any beats that are part of a couplet or triplet PVC series. 
8.2.2 Holter Monitoring 
Holter monitor is a portable device for continuous recording of ECG for 24 hours, and must be 
performed in all patients. 
8.2.3 Health-related Quality of Life 
Self-reported, health-related quality of life will be gauged with the SF-36 and HADS questionnaires at 
baseline and after each study arm, for a total of three times. This assessment will be done at home 
via mobile phone app directly connected to the eCFR (ViedocMe©), which is an integrated part of 
the eCRF (Viedoc©), 1 week before the end of treatment visit. Participants will receive a reminder via 
the app 3 days before the visit. The day before the visit, participants will be reminded via SMS. At the 
end of treatment visit, participants will be directly questioned if they filled the questionnaires 
remotely. If not, the participants will be able to get help with login, or fill out the questionnaires by 
hand. The quality-of-life assessments at baseline will be performed prior to randomization, and we 
will allow participants to complete the questionnaires assessments before study procedures are 
performed. 
We will assess quality of life at baseline and after each study arm (see SoA) using validated 
questionnaires; Short Form 36 (SF-36) and Hospital Anxiety and Depression Scale (HADS) 
questionnaires. SF-36 is a self-reported measure of health and comprises of 36 questions covering 

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eight domains of health (limitations in physical and social activity, bodily pain, general mental health, 
limitation in usual role activities because of emotional and physical health problems, vitality and 
general health perceptions)22. These can also be combined to a “physical component summary” and 
“mental component summary”. The SF-36 has been extensively validated and assessed47. Score range 
from 0 to 100 and higher scores indicate better health status, and a 5-point change over time can be 
interpreted as clinically relevant47. 
HADS measures anxiety and depression symptoms using 14 items on a 4-point scale23. The score 
range for both anxiety and depressive symptoms is 0-21 with higher scores indicating greater anxiety 
or depression. It has been proven to be reliable and valid in several populations48. 
8.3 Safety Assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
8.3.1 Coronary Artery Disease Assessment 
All patients will be thoroughly evaluated clinically at baseline for coronary artery disease or coronary 
anomalies (see Medical History above). If not performed within the last 2 years prior to screening, we 
will perform a CT or invasive coronary angiography according to guidelines in force49. 
8.3.2 Visits and Telephone Contact 
We will conduct a physical visit to the study site at screening and after 1, 6 and 12 months during 
both treatment arms (see SoA). At these visits, we will perform 24-hour Holter monitoring and ECG. 
We will also review any signs of AE and SAE, assess compliance to study drug and measure plasma 
levels of flecainide. 
During the course of the study, participants will be able to contact our study nurse for questions. We 
will also contact patients by telephone if we detect ventricular tachycardia on the remote Carelink™ 
system to assess symptoms of the event (if any). 
8.3.4 Electrocardiogram 
12-lead ECG will be obtained as outlined in the SoA (see Section 1.2) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals. 
8.3.5 Exercise ECG 
Exercise ECG will be obtained as outlined in the SoA (see Section 1.2), which is an ECG that is 
recorded while participants are cycling on an exercise bike. 

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8.3.6 Pregnancy Testing 
Serum pregnancy testing will only be performed in WOCBP and at time points specified in the SoA. In 
addition, urine pregnancy tests will be provided free of charge to be used during the course of 
FLECAPRO. 
8.4 End of Treatment Visits 
An end of treatment visit will be conducted at the end of each treatment period. At this visit, we will 
assess compliance to study drug, perform ECG and physical examination, review any signs of AE and 
SAE, and perform a transthoracic echocardiography and exercise ECG. 
8.5 Clinical Events 
8.5.1 Ventricular Fibrillation 
Ventricular fibrillation is an ultrafast and disorganized heart rhythm leading to abrupt loss of heart 
function and breathing (cardiac arrest). The implantable loop recorders will automatically detect and 
record such an event with exact time and date (Figure 5). Ventricular fibrillation will be defined (as 
per ECG) as: 
- 
Chaotic irregular deflections of varying amplitude. 
- 
No identifiable P waves, QRS complexes or T waves. 
- 
Rate 150 to 500 per minute. 
- 
Amplitude decreases with duration. 
 
Figure 5. Ventricular fibrillation recorded by an implantable loop recorder in a patient with arrhythmic 
mitral valve prolapse. 
8.5.2 Ventricular Tachycardia 
The number of ventricular tachycardias will be assessed by implantable loop recorder (figure 6), 
electrocardiogram (ECG), Holter monitoring and stress ECG, and is defined as following: 
- Three or more consecutive ventricular beats (QRS duration >120 ms) with heart rate > 100 
beats/min. 
Ventricular tachycardia outcome definition: 

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- 
Sustained ventricular tachycardia: lasting >30 seconds or terminated earlier due to 
hemodynamic instability. 
- 
Non-sustained ventricular tachycardia with syncope: lasting <30 seconds, but leads to syncope 
(patient reported). 
- 
Non-sustained ventricular tachycardia: lasting <30 seconds. 
 
Figure 6. Non-sustained ventricular tachycardia recorded by an implantable loop recorder in a patient 
with arrhythmic mitral valve prolapse. 
8.5.3 Syncope  
Syncope is the medical term for fainting or passing out. It is caused by a temporary drop in blood 
flow to the brain due to a sudden drop in blood pressure, a drop in heart rate, or changes in the 
amount of blood in areas of the body. Ventricular tachycardias can cause syncope when the heart 
rate becomes so fast that it impairs the pump function of the heart. A syncope is defined as the 
following: 
- Transient loss of consciousness characterized by a rapid onset, short duration and 
spontaneous complete recovery. 
8.5.4 Ventricular fibrillation or ventricular tachycardia during flecainide treatment 
In case of ventricular fibrillation, polymorphic ventricular tachycardia or sustained ventricular 
tachycardia, flecainide concentration must be assessed concerning overdosing. The clinical personnel 
should contact a principal investigator and the clinical event will be discussed with expert 
electrophysiologists on a case-by-case basis. If considered safe, dose adjustment should be preferred 
over intervention discontinuation.  
8.6.5 Ventricular tachycardias detected by implantable loop recorder 
We expect to detect several ventricular tachycardias during the course of FLECAPRO. Due to the 
nature of continuous monitoring, we will likely identify asymptomatic ventricular tachycardias that 
otherwise would not have been detected, especially since most of the participants would not have a 
clinical indication for continuous monitoring outside of trial participation. Thus, continuous 
monitoring in trial participants may significantly influence care and management decisions. Detecting 
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modifying antiarrhythmic drug treatment or, if severe, considering ICD placement. In the lack of 
efficacious antiarrhythmic drugs in AMVP, patients with AMVP might be eligible for primary 
prophylactic ICD. However, the indication for primary prophylactic ICD in the context of AMVP is a 
matter of debate due to the lack of clinical trials. Consequently, participation in FLECAPRO may 
increase the likelihood of receiving a primary prophylactic ICD. To mitigate this risk, participants must 
meet specific criteria to be considered for ICD placement. The considerations and final decision on 
ICD placement will be discussed in a team including participants from the Steering Committee, a 
device specialist and electrophysiologist.  
ICD placement is warranted in case of: 
• 
ventricular fibrillation  
• 
VT (sustained or non-sustained) with hemodynamic instability 
ICD placement should be considered in case of: 
• 
sustained VT at any heart rate 
• 
polymorphic non-sustained VT at any heart rate if lasting more than 5 seconds 
• 
symptomatic non-sustained VT at any heart rate 
• 
asymptomatic non-sustained VT >180 bpm if lasting more than 5 seconds 
ICD placement is not warranted in case of: 
• 
asymptomatic non-sustained VTs outside of the above criteria. However, individual 
characteristics might impact this evaluation and the investigators are inclined to take 
individual participant characteristics into account. 
8.6 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The investigator and any qualified designees are responsible for the detection and documentation of 
events meeting the criteria and definition of an AE or SAE. Each patient will be instructed to contact 
the investigator immediately should they manifest any signs or symptoms they perceive as serious. 
When judging whether an AE or SAE is unexpected or not, the Summary of Product Characteristic 
(SmPC) for flecainide and metoprolol will be used as reference safety information. 
The methods for the collection of safety data are described below. 

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8.6.1 Definitions 
8.6.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered a medicinal product, which does 
not necessarily have a causal relationship with this treatment. An AE can therefore by any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. The term AE is used to 
include both serious and non-serious AEs. 
If an abnormal laboratory value/vital sign are associated with clinical signs and symptoms, the 
sign/symptom should be reported as an AE and the associated laboratory result/vital sign should be 
considered additional information that must be collected on the relevant eCRF. 
8.6.1.2 Adverse Event of Special Interest (AESI) 
In general, AESIs are AEs that occur in categories of special interest with regard to determining the 
benefit/risk profile and overall safety of a drug.  
Sustained ventricular tachycardia, polymorphic ventricular tachycardia or ventricular fibrillation is of 
special interest, since flecainide has a potential to cause reentry ventricular tachycardias, particularly 
in patients with myocardial fibrosis. Thus, these events could occur more frequently in the 
intervention arm. However, these events are typically associated with the disease under study, and 
they will not be reported according to the standard process for expedited reporting of SAEs even 
though the event may meet the definition of an SAE. These events are all included in the composite 
primary endpoint. However, if one of the following conditions applies, then the event must be 
recorded and reported as an AE/SAE: either the event is, in the investigator’s opinion, of greater 
intensity, frequency, or duration than expected for the participant; or the investigator considers that 
there is a reasonable possibility that the event was related to study intervention. 
8.6.1.3 Serious Adverse Event (SAE) 
An SAE is an AE that fulfils at least one of the following criteria: 
- 
Results in death 
- 
Is immediately life-threatening  
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent disability/incapacity 
- 
Is a congenital anomaly/birth defect 
- 
Is an important medical event that may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the other outcomes listed above. 

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Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations. This includes important medical events that may not be immediately life 
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the other outcomes listed above. These events, or 
in doubtful cases, should usually be considered serious and reported as SAEs using the important 
medical event criterion. Hospitalization for administrative reason (for observation or social reasons) 
is allowed at the discretion of the investigator and will not qualify as serious unless there is an 
associated adverse event warranting hospitalization. 
8.6.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Adverse Reaction: All untoward and unintended responses to an investigational product related to 
any dose administered. 
Unexpected Adverse Reaction: An adverse reaction, the nature of severity of which is not consistent 
with the applicable product information. This includes an increase in severity, specificity or 
frequency. 
Suspected Unexpected Serious Adverse Reaction: SAE that is unexpected and possibly related to the 
investigational products. When judging whether a possibly study drug related serious adverse event 
is unexpected or not, the flecainide or metoprolol SmPC will be used as reference safety information. 
8.6.1.5 Medical Device Deficiency (MDD) 
Implantable devices (ILRs) are being provided for use in this study. The investigator is responsible for 
the detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices, and will be reported according to standard procedures at Oslo 
University Hospital Rikshospitalet. 
A Medical Device Deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use errors and 
information supplied by the manufacturer. Deficiencies fulfilling the definition of an AE/SAE will 
follow the process outlined in section 8.4, and deficiencies not fulfilling the definition will be 
recorded as protocol deviations. 
8.6.2 Methods of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 

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8.6.3 Recording of AE 
If the patient has experienced adverse event(s), the investigator will record the following information 
in the eCRF: 
o The nature of the event(s) will be described by the investigator in precise standard 
medical terminology (i.e. not necessarily the exact words used by the patient). 
o The duration of the event will be described in terms of event onset date and event 
ended date. 
The investigator will assess intensity for each event reported during the trial and assign it to one of 
the following categories according to Common Terminology Criteria for Adverse Events version 4.0: 
o Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
o Moderate: Minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily life. 
o Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily life 
o Life-threatening consequences: Urgent intervention indicated.  
o Fatal 
The causal relationship of the event to the study medication will be assessed as one of the following: 
o Unlikely: The event is most likely related to etiology other than the investigational 
product. 
o Possible: A causal relationship is conceivable and cannot be dismissed. 
The outcome of the adverse event (resolved or still ongoing) will be registered. It is important to 
distinguish between seriousness and severity of AEs. Severity is a measure of intensity, whereas 
seriousness is defined by the criteria for SAE. An AE of severe intensity need not necessarily be 
considered serious. 
8.6.4 Reporting Procedure 
8.6.4.1 AE and SAE 
All AE and SAE that should be reported will be recorded in the patient’s eCRF. SAEs must be reported 
by the investigator to the Sponsor, Oslo University Hospital, within 24 hours after the site has gained 
knowledge of the SAE. The Serious Adverse Event Report Form must be completed, documented in 
the eCRF, signed and sent to the Medical Monitor. The initial report shall promptly be followed by 
detailed, written reports if necessary. The initial and follow-up reports shall identify the trial subjects 

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by unique trial code numbers assigned to the latter. The sponsor keeps detailed records of all SAEs 
reported by the investigators and performs an evaluation with respect to seriousness, causality and 
expectedness. 
8.6.4.2 SUSAR 
Suspected unexpected serious adverse reactions (SUSAR) will be reported to the Norwegian 
Medicines Agency. The following timelines should be followed: 
The sponsor will ensure that all relevant information about SUSARs that are fatal or life-threatening 
is recorded and reported as soon as possible to the Norwegian Medicines Agency in any case no 
later than seven (7) days after knowledge by the sponsor of such a case, and that relevant follow-up 
information is subsequently communicated within an additional eight (8) days. The sponsor shall 
ensure that other suspected adverse reactions that are serious and unexpected are reported to the 
Norwegian Medicines Agency and the Regional Committee for Medical Ethics within 15 days of the 
sponsor after knowledge of the event. The sponsor shall inform all investigators and involved 
clinicians of suspected adverse reactions that are serious and unexpected. An account of any 
interruption in treatment, the investigator’s assessment of the causal relationship, and 
consequences for further testing shall accompany the notification of suspected adverse reactions 
pursuant to the first and second paragraphs. 
8.6.5 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs and AESI will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up. 
8.6.6 Pregnancy and Contraceptives 
8.6.6.1 Definitions 
For the purpose of this protocol, a woman is considered of childbearing potential (WOCBP), i.e. 
fertile, following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. A pregnant woman is defined as WOCBP that have tested positive 
on a serum pregnancy test. 

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8.6.6.2 Mandatory contraceptive use 
Both flecainide and metoprolol are not recommended to be used during pregnancy. WOCBP will be 
informed at screening that we recommend to use contraception (preferably long-acting reversible 
contraceptives), and that participants should refrain from becoming pregnant, during the trial and 
until 3 days after discontinuation of study medications. The following contraceptives are accepted 
(according to Clinical Trials Facilitation and Coordination Group CTFG 21/09/2020 Version 1.1 
Recommendations related to contraception and pregnancy testing in clinical trials): 
Contraceptive methods considered as highly effective 
- 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
- 
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral 
injectable or implantable) 
- 
Intrauterine device 
- 
Intrauterine hormone-releasing system 
- 
Bilateral tubal occlusion 
- 
Vasectomised partner 
- 
Sexual abstinence 
Acceptable contraceptive methods not considered as highly effective 
- 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
- 
Male or female condom with or without spermicide 
- 
Cap, diaphragm or sponge with spermicide 
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female and male condom should not be used together. 
Participants will be provided with human chorionic gonadotropin (hCG) urine tests free of charge at 
inclusion and/or at study visits, and urged to confirm absence of pregnancy in case of delayed 
menstrual period (over one month between menstruations). This recommendation also applies to 
WOCBP with infrequent or irregular menstrual cycles. Any female participant who becomes pregnant 
while participating in the study will discontinue study intervention. In case of study drug 
discontinuation, the patient will still be enrolled in the study.  

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8.6.6.3 Pregnancy reporting 
Pregnancies will be reported by the principal investigator to the sponsor as outlined in section 
8.6.4.1. The outcome of the pregnancy will be reported, and information will be collected until three 
months after delivery, if possible. If a pregnancy has an adverse outcome (i.e. for the mother and/or 
the baby), an SAE report will be completed. Information about the baby can only be collected upon 
consent from the parents.  
8.7 Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of flecainide as specified 
in the SoA (section 1.2). A maximum of 2 samples may be collected at additional time points during 
the course of FLECAPRO if warranted and agreed upon between the investigator and the sponsor. 
The actual date and time of each sample will be recorded. Participant confidentiality will be 
maintained. 
8.8 Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 Genetics 
Genetic analyses are not planned in this study. 
8.10 Biomarkers 
Blood samples will be collected for baseline characteristics and adequate safety during the course of 
FLECAPRO. Biomarkers will include Hb, white blood cell count, platelet count, K, Na, glucose, HbA1c, 
creatinine, eGFR, ALT, AST, bilirubin, albumin, INR, NT-proBNP and troponin T. Samples will be 
collected according to the schedule described in the SoA.  
Extra blood samples will be taken, appropriately labeled and stored in a study specific biobank at 
Oslo University Hospital. FLECAPRO study personnel will have access to the samples, as well as the 
respective analysis units. Samples will be marked with trial specific code, and only FLECAPRO study 
personnel have access to the code list. Sponsor will within 2 years after end of trial (defined as last 
patient last visit, expected to occur December 31 2025) submit and receive approval for further use 
of the samples (general biobank with a separate consent form), and if not, the samples in the study 
specific biobank will be destroyed within 2 years after end of trial.  
8.11 Immunogenicity Assessments 
Not applicable. 

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8.12 Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
9.0 Statistical Considerations 
A separate detailed Statistics Analysis Plan (SAP) will be developed in collaboration with the 
dedicated study statistician employed by the Clinical Trial Unit at Oslo University Hospital before data 
lock. 
The first main statistical analysis is planned when the last patient has completed the end-of-study 
visit 26 months after randomization. The number and severity of adverse events will be assessed 
consecutively. Deviation from the original statistical plan will be described and justified in the Clinical 
Study Report. Amendments to plan can be done until the day of database lock. 
9.1 Statistical Hypothesis 
The primary objective is to demonstrate that flecainide and metoprolol is superior to metoprolol 
alone in achieving a reduced number of ventricular tachyarrhythmias at 12 months. 
The null hypothesis of no difference in number of ventricular tachyarrhythmias between flecainide 
and metoprolol, and metoprolol alone, will be tested: 
• 
H0: There is no difference in number of ventricular tachyarrhythmias between flecainide and 
metoprolol, and metoprolol alone. 
• 
H1: There is a non-zero difference in number of ventricular tachyarrhythmias between 
flecainide and metoprolol, and metoprolol alone. 
The null hypothesis will be tested for superiority, with two-sided tests and confidence level equal to 
0.05. 
9.2 Population for Analysis 
The following populations will be considered for the analyses: 
- 
Intention-to-treat (ITT) population: All randomized participants, regardless of protocol 
adherence. 
o This population will be used to assess superiority for the primary endpoint and key 
secondary endpoints. 
- 
Safety population: All patients who have been enrolled in the trial, and who have received at 
least one dose of flecainide. 

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o This population will be used to assess the secondary safety endpoints 
- 
Per-protocol population: All participants who have completed 26 months of treatment and 
taken study drug according to the protocol. 
o This population will be used for sensitivity analyses of the primary endpoint. 
9.3 Statistical Analysis 
The Statistical Analysis Plan will be finalized prior to completion of the study and will include a more 
technical and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary and 
key secondary endpoints. 
Dedicated study statistician will be employed via the Clinical Trial Unit at Oslo University Hospital for 
the entire study period.  
9.3.1 Primary Endpoint 
We will test superiority for the primary endpoint in the intention-to-treat population using a 
generalized linear mixed model with Poisson regression at the 0.05 significance level. Random effects 
for the patient ID will be used to account for repeated measurements given by the crossover design. 
Based on the preliminary data, we expect some patients to have zero primary endpoints in the 
intervention arm, which could lead to challenges when using Poisson regression. Thus, zero-inflated 
models or negative binomial regression would be needed, or a binary outcome in case most patients 
have no endpoints during the intervention arm (for details see SAP). 
9.3.2 Pre-defined subgroup analyses 
Certain characteristics are associated with higher incidence of ventricular arrhythmia. We trust the 
randomization and crossover study design for balanced allocation in sequencing of study arms. 
However, interaction effects in subgroups of interest will be assessed in the study: 
o Females or males 
o Normal or reduced left ventricular ejection fraction at baseline 
▪ 
Cut off 55% 
o Normal or abnormal left ventricular end-diastolic diameter 
▪ 
Cutoff 58 mm for males and 52 mm for females 
o No/trivial or moderate/severe mitral regurgitation 
o Presence or absence of mitral regurgitation 
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o Presence or absence of mitral annular disjunction 
o Presence or absence of late gadolinium enhancement 
o Monofocal or multifocal premature ventricular complexes 
o Presence or absence of connective tissue disease 
o BMI ≥30 or BMI <30. 
o ICD vs no ICD at inclusion 
o Presence or absence of prior aborted cardiac arrest 
o Presence or absence of T-wave inversions on ECG 
9.3.3 Key Secondary Endpoints 
The rates of the predefined key secondary endpoints will be tested in a hierarchical order, meaning 
that hypothesis testing stops at the first non-significant endpoint (p≥0.05). 
 Generalized linear models will be used for the secondary endpoints, specifically linear models for 
continuous variables, logistic models for binary variables, Poisson for count variables. Random effects 
for the patient ID will be used to account for repeated measurements. 
9.3.4 Secondary Safety Endpoints 
Safety analyses will include tabulation of type and frequency of all adverse events. Any serious 
adverse events will be reported with comprehensive narratives. Any value of safety laboratory 
parameters outside normal ranges will be identified. 
9.3.5 Exploratory Secondary Endpoints 
The secondary endpoints defined as “exploratory” in the protocol will be tested and interpreted as 
hypothesis generating. 
9.3.6 Missing Data 
Every reasonable effort will be made to minimize missing data. Some data may be missing 
completely at random (MCAR) and missing at random (MAR). However, some instances of data 
missing not at random (MNAR) may occur: 
- 
Availability for analysis 
o If either the intervention (flecainide and metoprolol) increases likelihood of being 
available for analysis by decreasing incidence of ventricular tachycardia, or decreases 
the likelihood of being available for analysis by increasing incidence of Safety Composite.  
- 
Allocation to treatment sequence 
o If study intervention increases quality-of-life as hypothesized, increased dropout may 
occur in participants sequenced to be treated with intervention first and control second. 

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This is especially true if participants experienced AEs on metoprolol or other beta 
blockers prior to enrollment. 
o Similarly, increased dropout may occur in participants sequenced to be treated with 
control first and intervention second, as participants have to wait for 13 months to start 
potential effective treatment. 
- 
Missing cardiac magnetic imaging data 
o Participants in FLECAPRO are likely to have a high burden of premature ventricular 
complexes that might interfere with CMR image acquisition causing missing CMR data. 
Additionally, some participants might have unconditional cardiac devices prior to 
inclusion and thus a contraindication to CMR. 
Because of this, we will take conservative and simplistic measures to handle missing data. The mixed 
model framework generally accounts for missing data that are MAR, but given the above, we will also 
perform sensitivity analysis imputing the missing data with methods that do not rely on the 
assumption of “missing-at-random”, such as “last-observation-carried-forward” and “worst-case” 
imputation.  
In particular, missing data on the primary endpoint analyses will be replaced using multiple 
imputation models (for details see Statistical Analysis Plan). In case of missing data on Holter 
monitoring or questionnaires (whole questionnaire or single questions), a baseline observation 
carried forward single imputation will be used.  
Sensitivity analysis for the primary endpoints will be performed on the complete-case data and on 
the worst-case imputation data. Additional post-hoc sensitivity analyses will be performed if 
unexpected patterns of missing data are observed. 
9.4 Interim Analysis 
Interim analysis has not been planned. 
9.5 Sample Size Determination 
Sample size estimates are calculated based on limited previous data from the same population. For 
an individual patient, the primary endpoint can be expected to occur at least 3 times during the 
control arm based on a previous case series21. On the contrary, there is limited data on the 
occurrence of the primary endpoint in the intervention arm. Because of the potential proarrhythmic 
effect of flecainide, side effects and relatively soft primary endpoint, we consider a 60% reduction in 
the primary endpoint clinically relevant. A 60% reduction is a realistic effect size based on our 
previous data on flecainide use in the same population21.  

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There is no standard method to calculate sample size for a count based endpoint in a crossover 
setting. However, to obtain 80% power with a two-sided 0.05 alpha for a 60% reduction in the 
primary endpoint in the intervention group, these two sample size calculations have been used: 
- 
14 patients should complete the study when using simulation without excess zeros. 
- 
22 patients should complete the study when using simulations with excess zeros.  
Both methods have their limitations. Firstly, the simulations are based on data from a limited case 
series21. There is larger heterogeneity in the patient population included in FLECAPRO, and, 
consequently, a possibility that subgroups of patients do not show the same efficacy seen in the case 
series. Thus, using strict sample size estimates from these simulations could lead to a clinically 
underpowered study. Secondly, if the hypothesis of FLECAPRO holds true, we expect the primary 
endpoint not to occur in some patients during the intervention arm. Because of this, statistical 
methods that do not account for excess zeros could prove inadequate. For further details see SAP.  
Because of these limitations, we plan for a conservative approach to sample size calculation and will 
plan for 40 patients to complete the study. Based on the simulations, this number will not lead to a 
mathematically underpowered study, while also taking into account a larger heterogeneity in the 
patient population. We expect 25% dropout, and thus, we will enroll a maximum of 50 participants 
such that approximately 40 evaluable participants complete the study. 
A 25% dropout rate is high, but we believe this to be relevant. Firstly, if the hypothesis of FLECAPRO 
holds true, the crossover study design may cause patient randomized to intervention arm first to 
drop out during the control arm if developing side effects. Secondly, severe ventricular 
tachyarrhythmias may occur in both study arms during the course of FLECAPRO, potentially leading 
to treatment discontinuation. 
10.0 Supporting Documentation and Operational Considerations 
10.1 Regulatory and Ethical and Study Oversight Considerations 
This study will be conducted in accordance with the protocol and with the following: 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable national laws and regulations 
Registration of patient data will be carried out in accordance with national personal data laws. 

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10.1.1 Ethical Considerations for Participants 
If the hypothesis of the study is correct, participants will receive superior treatment during half of the 
study period. This constitutes a significant benefit. 
Individuals who consent to the study will commit to additional visits at the academic institution, with 
travel cost and risk. They will also contribute with personal information, and thereby trust the 
sponsor to treat their data appropriately. 
The active protocol will include a study-specific invasive procedure with implantation of a loop 
recorder and possibly invasive coronary angiography (the latter only if participants have symptoms 
and risk factors for coronary artery disease at screening). The CT coronary angiography and cardiac 
magnetic resonance imaging will expose the participants to a contrast agent and a radiation dose 
(radiation only for the former) over the regular clinical course. However, the contrast dose is low and 
overt renal damage is very uncommon after contrast-enhanced CT or cardiac MRI. 
10.1.2 Ethics Committee Approval 
The regional ethics committee must approve the study protocol, including the patient information 
and informed consent form to be used, before enrollment begins. The investigator is responsible for 
informing the regional ethics committee of any major amendments to the protocol as per national 
requirements. 
10.1.3 Financial Disclosure 
FLECAPRO is an investigator-sponsored study. The trial is funded by the South-Eastern Norway 
Regional Health Authority through a grant (#2024024), and by ProCardio Center for Innovation, Oslo 
University Hospital, through the Research Council of Norway. We will not apply for funding from 
industry outside of providing implantable loop recorders (Medtronic). The authors have no 
commercial interest or economic disclosure related to the project. The investigators take sole 
responsibility for the integrity of the data, the writing of the manuscript and the dissemination of the 
results. Medtronic will have neither influence on the data collection or analyses, nor writing of the 
manuscript. 
10.1.4 Informed Consent Procedure 
The investigator or his/her representative will explain the nature of the study to the participant and 
answer all questions regarding the study. Participants will be informed that their participation is 
voluntary and that the participant is allowed to refuse further participation in the protocol whenever 
he/she wants for any reason. This will not prejudice the patient’s subsequent care. Participants will 
be required to sign a statement of informed consent before enrollment in the study. This will be 
done in accordance with the national and local regulatory requirements. A copy of the informed 

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consent will be provided to the participant. The signed and dated consent forms will be filed in the 
Investigator Site File binder.  
Participants who are rescreened are required to sign a new informed if rescreening occurs after 3 
months of the previous informed consent signature date. 
10.1.5 Recruitment Procedure 
The population available for screening in FLECAPRO will be: 
- 
All consecutive patients with symptomatic arrhythmic mitral valve prolapse at scheduled follow-
up at the Outpatient Clinic at Department of Cardiology, Oslo University Hospital, Rikshospitalet. 
- 
All patients with mitral valve prolapse admitted to the Department of Cardiology at Oslo 
University Hospital, Rikshospitalet, due to symptomatic ventricular arrhythmias. 
Cardiologists at surrounding hospitals will be informed about the trial and the possibility to refer 
patients to our outpatient clinic for evaluation and possible participation. 
A principal investigator or study nurse will approach the participant to give additional information 
and obtain informed consent. A principal investigator could have a prior clinical relationship with the 
potential participant. Potential participants will get written and oral information about the trial at a 
physical visit at Department of Cardiology, Oslo University Hospital, Rikshospitalet. They will be 
given as much time as needed to decide whether to participate in FLECAPRO. 
10.1.6 Data Protection 
All clinical trial information will be recorded, processed, handled, and stored by the Sponsor in such a 
way that it can be accurately reported, interpreted and verified while the confidentiality of records 
and the personal data of the participants remain protected in accordance with the given permissions 
by the Ethics Committee and Personal Data Officer at Oslo University Hospital and applicable law on 
personal data protection (Regulation (EU) 2016/679, General Data Protection Regulation, GDPR). 
Appropriate technical and organizational measures will be implemented to protect information and 
personal data processed against unauthorized or unlawful access, disclosure, dissemination, 
alteration, or destruction or accidental loss, in particular where the processing involves the 
transmission over a network. The data will not be used for economic benefit nor be made available 
for commercial actors. Patients will be informed that his/her medical records may be reviewed for 
trial purposes by authorized individuals other than their treating physician. 
10.1.6.1 Electronic Case Report Forms (eCRF) 
FLECAPRO will use an online electronic Case Report Form (eCRF) on the Viedoc® platform. The 
designated investigator staff will enter the data required by the protocol into the eCRF. The Principal 

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Investigator is responsible for assuring that data entered into the eCRF are complete, accurate, and 
that entry is performed in a timely manner. If any assessments are omitted, the reason for such 
omissions will be noted in the eCRFs. Corrections, along with the reason for the corrections, will also 
be recorded. After database lock, the investigator will receive a digital copy of the subject data for 
archiving at the investigational site. 
10.1.6.2 Source Data 
Some data will be recorded directly into the eCRF, which together with the patient electronic medical 
record, is to be considered the source data. All data important for patient safety and continued care 
must be duplicated in the patient’s medical record as described below. Study-specific imaging data, 
ILR data and blood analyses are independent source data. 
The medical records of each patient should clearly describe at least: 
- 
That the patient is participating in the study 
- 
Date when the informed consent was obtained from the patient 
- 
Results of all assessments confirming a patient’s eligibility for the study 
- 
Disease (past and current; both the disease studied and others, as relevant) 
- 
Relevant allergy or intolerance 
- 
Surgical history, as relevant 
- 
Treatments withdrawn/withheld due to participation in the study  
- 
Results of assessments performed during the study 
- 
Treatment provided, changes in treatments during the study and the time points for the changes 
- 
Visits to the clinic/telephone contacts during the study, including those for study purposes only 
- 
Adverse Events and Serious Adverse Events (if any) including causality assessments 
- 
Date of, and reason for, discontinuation from the study treatment 
- 
Date of, and reason for, withdrawal from the study 
- 
Date of death and cause of death if available 
10.1.6.3 Database Management 
Data will be entered into the eCRF without delay and stored in the dedicated and secure online 
platform (Viedoc®). Data will be extracted from Viedoc® for analysis, and the extracted data will be 
stored in dedicated, secure areas. Data will be stored in a pseudonymised manner, where each study 
participant is recognizable by his/her unique trial subject number. The data will be stored until 31st of 
November 2050 in compliance with local regulations, or until the patient requires that his/her data 
are deleted. Data in the eCRF will be handled according to GCP. Only the personnel authorized to 
enter and/or analyze data (i.e. investigators) will have access to the database. 

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10.1.6.4 Data Sharing 
In agreement with good research ethics, we will share anonymized data sets with the medical 
community via the medical journal upon submitting the manuscript. 
10.1.8 Study Monitoring 
The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check that 
the study is conducted as approved by the Ethics Committee and adhere to Good Clinical Practice 
(GCP) guidelines. 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed 
access to source data for source data verification in which case a review of those parts of the hospital 
records relevant to the study may be required. 
Study monitoring will be performed by the Clinical Trial Unit, Oslo University Hospital. 
10.1.9 Data Monitoring Committee and Safety Data Review 
Participant safety will be continuously monitored by the Data Monitoring Committee, which includes 
safety signal detection at any time during the study. The Data Monitoring Committee is independent 
from the Sponsor and will be composed of individuals with no competing interest and regard to the 
study investigational products or study outcome. The committee consists of two independent 
clinicians and a statistician. It will receive written reports summarizing patient recruitment, the 
number of AEs/SAEs and the registered occurrence of the primary endpoint and secondary safety 
endpoint (safety composite) after the first 5 patients have been randomized, and once every 6 
months thereafter. They will be encouraged to assess signals of safety without hypothesis testing. 
The committee will have access to the randomization code, and can perform an interim analysis 
regarding the number of adverse events and serious adverse events if they find it necessary. The 
Data Monitoring Committee will receive additional information on demand and can advise 
temporary or permanent stop in patient enrollment. In case there is worry of a pattern of worse 
ventricular arrhythmia outcome, a recommendation to abort the study will be given to the Sponsor.  
If moderate or severe AEs are consistently observed across participants by the medical monitor, the 
dose escalation will be temporarily halted and no further participants will be dosed until a full safety 
review of the study has taken place. The same is true if unacceptable pharmacological effects 
reasonably attributable to flecainide or metoprolol in the opinion of the investigator are observed in 
several of the participants. The number of such effects will be at the discretion of the Data 
Monitoring Committee. Relevant reporting and discussion with the Medical Monitor and Data 
Monitoring Committee will take place before resumption of dosing. 

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If severe ventricular tachyarrhythmias occur during treatment with flecainide, the Investigator will 
consult the Data Monitoring Committee before deciding to discontinue flecainide. 
10.1.10 Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. 
Patient files shall be kept for the maximum period permitted by each hospital. The study 
documentation (eCRFs, etc.) shall be retained and stored during the study and for 25 years after last 
patient visit. All information concerning the study will be stored in a safe place inaccessible to 
unauthorized personnel, in accordance to local regulations. 
10.1.11 Trial Registration 
The Clinical Trial Information System (CTIS) will be the primary registry of the trial.  
10.1.12 Trial insurance 
The Principal Investigator has insurance coverage for this study through the Norwegian 
Pasientskadeloven. Insurance for the intervention will be obtained from Legemiddelforsikringen. 
10.1.13 Cost-benefit Consideration 
The project will need considerable funding for thorough and precise execution. Any unforeseen 
events may also impose a cost to the public hospital system. The cost of medication is not negligible. 
On the other side, the potential economic benefits from reducing ventricular arrhythmic burden, 
frequent hospital visits and patient symptoms are substantial. Therefore, our general consideration is 
that this project holds great potential for improved cost-benefit in the long-term. 
10.1.14 Publication Policy 
The results of this study will be submitted for publication and posted in a publicly assessable 
database of clinical study results. We will allow for a separate publication of study design, rationale 
and baseline characteristics once all subjects have been enrolled.  
The results of this study will also be submitted to the Competent Authorities and the Regional Ethics 
Committees according to EU and national regulations. All personnel who have contributed 
significantly with the planning and performance of the study (Vancouver convention 1988) may be 
included in the list of authors. The principal investigator will be first or last author. The funding 
sources have had no role in the conception of the study. Neither will the funding sources participate 
in the implementation of the study, in the analyses of the results, or in the decision to publish. 
All manuscript authors of the main analysis and spin-off projects must be according to ICMJE 
recommendations and must be approved by the Steering Committee. 

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10.1.15 Cost 
Participants will receive a refunded prescription of metoprolol and flecainide based on the current 
approved treatment indication. 
All patients enrolled in the study will receive implantable loop recorder. A loop recorder (LINQ II) will 
cost approximately 15.000 NOK for the study duration for one patient. The total cost of loop 
recorders in FLECAPRO will be approximately 750.000 NOK. The Sponsor will provide the loop 
recorders, in collaboration with Medtronic (Minneapolis, USA) via a research consortium (ProCardio 
Center for Innovation). 
All patients enrolled in the study will undergo cardiac magnetic resonance (CMR) at baseline if not 
contraindicated (e.g. due to non-compatible ICD) or done within the last 2 years prior to inclusion. 
We will perform CMR in all patients randomized to receive the intervention arm as the last treatment 
period. Additionally, we will perform CMR in 10 patients without prior ICD shortly after ILR 
implantation. A CMR will cost approximately 3.000 NOK for one examination of one patient. The total 
cost of CMR in FLECAPRO will be approximately 255 000 NOK. 
10.2 Spin-offs 
Spin-off projects are analyses planned around the primary inclusion database. Projects that are not 
pre-defined must be approved by the Steering Committee and Partners after written project 
proposal. Spin-off projects will have a dedicated supplementary protocol. 
Planned spin-off analyses: 
o Assessment of left ventricular reverse remodeling following flecainide therapy. 
▪ 
In addition to performing echocardiography after each treatment period, we 
will perform an additional CMR in patients randomized to the intervention 
arm as the last treatment period (after ILR has been removed). The CMR will 
be performed to assess whether markers of diffuse fibrosis decreases after 
suppression of ventricular arrhythmias. 
o The implication of ILR on measurement of T1-times. 
▪ 
We will ask 10 participants to undergo an additional CMR exam shortly after 
implantation of ILR to assess whether ILR affects the magnetic field in a way 
that markers of diffuse fibrosis cannot be measured reliably.  
o Association between change in health-related quality of life (SF-36 and HADS) and 
arrhythmic burden by Holter or LINQII. 
o Association between PVC count on Holter monitoring and LINQ II. 

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▪ 
Participants will be assessed by Holter monitoring 6 times during the course 
of FLECAPRO (300 in total 50 participants). We will assess the validity of the 
PVC algorithm of LINQ II compared to Holter monitoring. 
10.3 Partners 
Partners are collaborating units with their associated contact person. They have key roles in the main 
study and can propose subsequent spin-off studies. 
10.3.1 Section for Outpatient Clinic, Oslo University Hospital, Rikshospitalet 
The section for outpatient clinic at Department of Cardiology is a large outpatient clinic treating and 
following patients with genetic cardiac disease, survivors of cardiac arrest and other arrhythmic 
disorders. The section treats 2500 outpatients every year, and is the only center in Norway having 
clinical experience with arrhythmic mitral valve prolapse. Qualified and dedicated cardiologists 
contribute to screening, inclusion and follow-up. 
- Kristina H Haugaa, MD PhD, Head of Section 
10.3.2 ProCardio Center for Innovation, Oslo University Hospital, Rikshospitalet 
ProCardio Center for Innovation is a newly established Center for Research-based Innovation funded 
through the Research Council of Norway. At ProCardio, researchers and industrial partners work 
together to ensure that ideas become products that benefit patients, which is led by internationally 
renowned researchers including fields of cardiogenetics, sudden cardiac death and arrhythmic mitral 
valve prolapse. The ILRs provided by Medtronic is through this research consortium. 
 
- Kristina H Haugaa, MD PhD, Center Director 
10.3.3 Section for Electrophysiology, Oslo University Hospital, Rikshospitalet 
The section for electrophysiology at the Department of Cardiology is the largest electrophysiological 
laboratory in Norway. More than 1600 electrophysiological exams and ablations are performed every 
year, as well as 350 cardiac device implantations every year. The section has experience in 
management and follow-up of patients with arrhythmic mitral valve prolapse. Qualified and 
dedicated electrophysiologists contribute with study planning, endpoint assessment and 
implantation of cardiac devices. 
- Erik Kongsgård, MD PhD, Head of Section 
10.3.4 Section for Echocardiography, Oslo University Hospital, Rikshospitalet 
The section for echocardiography at the Department of Cardiology is the largest echocardiographic 
laboratory in Norway and has international accreditation. More than 10.000 echocardiographic 

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exams are performed every year, including on many patients with mitral valve prolapse. Qualified 
and dedicated echocardiographers and technicians contribute with acquisitions and interpretations 
of optimal quality. 
 
- Helge Skulstad, MD PhD, Head of Section 
10.3.5 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Rikshospitalet 
The Department of Radiology and Nuclear Medicine at Oslo University Hospital has state-of-the-art 
modern CT and MRI scanners. They have good accessibility for high-end CMR and will perform and 
evaluate all CT and CMR data. The Department will also conduct planned spin-offs. 
 
- Einar Hopp, MD PhD, Head of Department 
10.4 Study Committee Structure and Contact Details 
- 
Principal Investigator: 
o Dr. Eivind W Aabel, Oslo University Hospital 
▪ 
+4741243148 // e.w.aabel@medisin.uio.no 
- 
Steering Committee: 
o Prof. Kristina H Haugaa, Oslo University Hospital 
▪ 
kristina.haugaa@medisin.uio.no 
o Dr. Erik Kongsgård, Oslo University Hospital 
▪ 
ekongsga@ous-hf.no 
o Dr. Erik Lyseggen, Oslo University Hospital 
▪ 
elysegge@ous-hf.no 
o Dr. Øyvind H Lie, Oslo University Hospital 
▪ 
oyvlie@gmail.com 
o Dr. Nina E Hasselberg, Oslo University Hospital 
▪ 
nihass@ous-hf.no 
- 
Medical Monitor: 
o Dr. Erik Lyseggen, Oslo University Hospital 
▪ 
+4748603200 // elysegge@ous-hf.no 
- 
Endpoint Adjudication Committee: 
o  Dr. Ane Cecilie Dale, cardiologist, St. Olavs Hospital, Trondheim, Norway 
▪ 
ane.cecilie.dale@stolav.no 
o Dr. Brage H Amundsen, cardiologist, St. Olavs Hospital, Trondheim, Norway 
▪ 
brage.hoyem.amundsen@stolav.no 
o Dr. Stian Ross, cardiologist, Oslo University Hospital, Oslo, Norway 

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▪ 
stross@ous-hf.no  
- 
Study Statistician: 
o Nina Gunnes, statistician, Oslo University Hospital, Oslo, Norway 
▪ 
ninagu@ous-hf.no 
- 
Data Monitoring Committee: 
o Prof. Torbjørn Omland, cardiologist, Akershus University Hospital, Nordbyhagen, 
Norway 
▪ 
torbjorn.omland@medisin.uio.no 
o Prof. Jan Pål Loennechen, cardiologist, St. Olavs Hospital, Trondheim, Norway 
▪ 
jan.pal.loennechen@stolav.no 
o Inge Christoffer Olsen, external statistician, Oslo University Hospital, Oslo, Norway 
▪ 
inge.christoffer.olsen@gmail.com 
 
 

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Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a 
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Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of 
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2019;41(3):407-477. DOI: 10.1093/eurheartj/ehz425. 
 

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12.0 Signature Page 
I hereby declare that I will conduct the study in compliance with this protocol and the applicable 
regulations: 
Name 
Title 
Role 
Date 
Signature 
Eivind W Aabel  
MD, PhD 
Principal Investigator 
 
 
Erik Lyseggen 
MD, PhD 
Medical Monitor 
 
 
Christian Five 
MD 
Sub-investigator 
 
 
Cecilie Bugge 
MD 
Sub-investigator 
 
 
Thea Dalen 
RN 
Study Nurse 
 
 
Emilie 
RN 
Study Nurse