Ablation in Brugada Syndrome for the prevention of VF Episodes (BRAVE study):
A prospective, multicenter, randomized non-blinded clinical study

Research Protocol

Ablation in Brugada Syndrome for the prevention of VF Episodes:

BRAVE Study

Principal Investigator: Koonlawee Nademanee, MD

Host Institution: Bumrungrad International Hospital, Bangkok Thailand

Chulalongkorn University, Bangkok, Thailand

Project Duration 36 months

Protocol Summary

Thus, risk stratification in this population is extremely vexing as less than 80% of the affected even have symptoms and many times, the patient is diagnosed only after surviving an episode, if indeed they survive. The current mode of treatment for high risk BrS patients is to undergo an implantable defibrillator (ICD) implant, however, the ICD does not provide an overall solution as the patient will then be subjected to unplanned therapy delivered by the ICD, and moreover, a continuous need for device replacement as the amount of therapy delivered in this subject class is extremely high and results in rapid battery depletion. The patient is then subjected to the risks associated with device changeout at a frequency of every 5 years, on average. In addition, the occurrence of BrS in Southeast Asia increases as the poverty line lowers making routine device changeouts almost an impossibility. And the psychological trauma the patient is subjected to once exposed to unplanned therapy, and even planned therapy, is often overlooked.

The aim of our study is to prove that ICD alone is not the sole solution in this patient subset and that catheter ablation of the ventricular fibrillation (VF) substrate is most effective treatment in the diagnosed BrS patient.

Title: Ablation in Brugada Syndrome for the prevention of VF Episodes (BRAVE study)

Design: A prospective, multicenter, randomized non-blinded clinical study

Objective: The purpose of this study is to demonstrate the effectiveness and safety of ablation therapy in patients with Brugada syndrome to prevent ventricular fibrillation episodes

Hypothesis: Ablation of arrhythmogenic substrate on the epicardial surface of the right ventricular outflow track leads to normalization of the Brugada pattern and prevents spontaneous VT/VF episodes when compared to standard therapy

Enrollment: 200 patients to be randomized in a 1:1 fashion to ablation versus standard therapy

Clinical Sites: Multicenter study

Patient Population: Patients, ages 18 to 60, with symptomatic Brugada syndrome with a recent (less than 2 years) implantable cardiac defibrillator (ICD). Eligible patients will be randomized in a 1:1 fashion to catheter ablation of the arrhythmogenic substrate or close monitoring as per standard treatment.

Primary Endpoint: Freedom from VT/VF episodes in patients receiving ablation therapy.

Risks: The risks of the ablation include bleeding, stroke, blood clot, vascular trauma, heart perforation, and side effects of conscious sedation.

Additional risks: Because the ablation patients will require pericardial access, complications related to this type of access will have to be taken into consideration. Possible complications include life threatening right ventricular perforation, coronary artery ablation leading to ischemia that could require further intervention, persistent pericardial effusion and/or tamponade.

Protected Classes: Study subjects will not include prisoners, any person experiencing diminished mental capacity or patients who are pregnant. Minors under 18 may be considered if there is a significant family history of genetic mutation.

Potential Benefits: The direct benefit for patients undergoing ablation is the potential elimination of VT and VF episodes. It is furthermore expected that quality of life will improve since fewer to none ICD shocks or interventions will be needed. Whether further morbidity is prevented will be subject to discussion. The information gained from this study may benefit patients with Brugada Syndrome by improving future treatment modalities and could provide an alternative therapy to ICD

Abbreviations:

AE Adverse Event

Abl Ablation

AR Adverse Reaction

BrS Brugada Syndrome

CI Chief Investigator

CFR Code of Federal Regulations

CRF Case Report Form

DSMB Data Safety Monitoring Board

ECG electrocardiogram

FISMA Federal information security Management Act

GCP Good Clinical Practice

HIPAA Health insurance portability and accountability act

HRA Health Research Authority

ICD Implantable Cardiac Defibrillator

ICF Informed Consent Form

IS Inappropriate shocks

ISF Investigator Site File

JREO Joint Research & Enterprise Office

LP Late potentials

MS mili-seconds

NHS National Health Service

PI Principal Investigator

PIS Participant Information Sheet

QA Quality Assurance

QC Quality Control

RCT Randomised Control Trial

REC Research Ethics Committee

RV Right Ventricle

RVOT Right ventricular outflow tract

SAE Serious Adverse Event

SDV Source Document Verification

SOP Standard Operating Procedure

SSA Site Specific Assessment

TMG Trial Management Group

TSC Trial Steering Committee

VF Ventricular Fibrillation

VT Ventricular Tachycardia

Table of Contents

Objectives. 7

2.1 Hypothesis. 7

2.2 Primary endpoints: VT/VF Death. 8

2.3 Secondary endpoints: 8

Study Design.. 8

3.1 Randomization and treatment. 8

3.2 Electrophysiological study and ablation protocol. 9

Study Population.. 10

4.1 Patient Selection – Inclusion Criteria. 10

4.2 Patient Selection – Exclusion criteria. 10

4.3 Cross over: 11

4.4 Study Follow up: 11

4.5 Discontinuation/withdrawal of participants and stopping rules. 11

4.6 Adverse Events. 11

5 Statistics. 12

5.1 Statistical considerations: 12

5.2 Statistical Analysis: 12

Citations. 14
Appendix 1. Uniform Tachycardia Detection & Tachycardia Programming Recommendations. 16
Appendix II DSMB, Core Labs, Event Adjudication.. 19
Appendix III Event Schedule. 20

Introduction

Brugada syndrome (BrS) is an autosomal inherited disease with variable transmission associated with ST-segment elevation of the right precordial ECG leads. It is associated with an increased risk of ventricular fibrillation (VF) and sudden death in patients with otherwise structurally normal hearts. The mean age of patients with BrS is 41±15 years old and it is predominantly observed in males [1]. Because of its association with premature death, patients with BrS are often prescribed an implantable cardiac defibrillator (ICD) [8]. An ICD is the only proven effective treatment for symptomatic patients who have experienced aborted sudden cardiac death [14].

However, ICD guided therapy has many drawbacks and disadvantages in this relatively young patient population. For example, a recent study enrolling 378 patients with BrS who were initially treated with an ICD (mean age 46 ± 13 years) showed that device related complications occurred in 36% of them during a follow-up of 77 ± 42 months. At 10 years, rates of inappropriate shocks (IS) and lead failure were 37% and 29%, respectively. IS occurred in 91 patients (24%, 4 ±4 shocks/patient) because of lead failure (n=38), supraventricular tachycardia (n=20), T-wave oversensing (n=14), or sinus tachycardia (n=12). One patient died due to IS. Other serious complications reported included infection, needing lead extraction, (2.3%) and severe depression (1.3%), which led to suicide in 2 patients, demonstrating a heavy psychological burden of ICD on patients [10].

We must also consider that recurrent VF episodes and even appropriate shocks by an ICD are associated with a lower quality of life. The annual rate of recurrent arrhythmic events is estimated to be 7-10.2 % in cases with a prior (documented) VF presentation and 0.6-2 % in patients with syncope [4, 9, 10]. To suppress VF and prevent ICD shocks, isoproterenol is used in the acute phase, and oral quinidine, denopamine or cilostazol are used as secondary prevention [2, 3, 5, 7]. These antiarrhythmic drugs seem to be effective in treating symptomatic BrS patients, however, discontinuation of antiarrhythmic drug therapy is often required due to side effects. For example, quinidine treated patients may develop gastrointestinal symptoms, liver dysfunction, thrombocytopenia, sick sinus syndrome or QT prolongation [2, 3, 5]. Quinidine is also not available in many countries as the pharmaceutical companies have ceased its production due to low profitability [13]. Such a therapeutic limitation is of great significant in clinical practice and demands other options to help these patients.

Recently, Nademanee et al. demonstrated epicardial catheter ablation as an effective therapy for patients with BrS and recurrent VF [6]. In this study, the authors demonstrated that ablation of fragmented electrograms, located on the epicardial right ventricular outflow tract (RVOT), results in normalization of the Brugada pattern and prevents VT/VF during the subsequent electrophysiology study as well as spontaneous recurrent VT/VF episodes in patients with BrS [6]. While this hypothesis forming study only included 9 patients, the number of patients treated in such fashion currently stands at 30 subjects with similar results (unpublished data). Other centers around the world do have some preliminary experience as well.

Therefore, epicardial ablation targeting abnormal low voltage signals and fractioned late potentials in BrS patients appears to be a promising therapeutic option. The selection of patients, the safety of ablation and its effectiveness needs to be better established. To answer these questions, we are proposing a study that aims to prospectively evaluate the effectiveness of ablation therapy in BrS patients who have been implanted with a defibrillator.

1. Objectives

2.1 Hypothesis

The objective of this multicentre study is to demonstrate the effectiveness and safety of epicardial ablation therapy in BrS patients.

2.2 Primary endpoints: VT/VF Death

The primary end point is the time from the date of randomization to VT/VF episodes as detected by ICD interrogation or death whichever occur first.

2.3 Secondary endpoints:

Include time to resolution of Brugada pattern, time to VT/VF therapy, complications from epicardial approach.

3. Study Design

This is a multicentre, randomized, non-blinded, prospective, two-arm trial, which compares the effectiveness of the epicardial ablation therapy in BrS in the patients initially treated with an ICD. Since epicardial ablation is a more difficult procedure compared to endocardial approach [11], participating sites will be highly experienced centers with surgical backup. All sites will be expected to submit the protocol to their respective Institutional Review Board, Medical Ethics Committee or equivalent.

3.1 Randomization and treatment

Patients are randomized 1:1 to either 1) ablation or 2) control (no ablation) group (Figure 1).

The randomizations will be blocked and stratified by participating centers to avoid major imbalances between treatment and control at any particular site. Epicardial ablation will be performed under routine protocols. Ablation end points is 1) elimination of all fragmented electrograms in the epicardial RVOT after infusion of one of the following sodium channel blockers:(ajmaline, pilsicainide, flecainide or procainamide).

3.2 Electrophysiological study and ablation protocol

In the electrophysiological lab, catheters will at least be placed in right ventricle (RV) and the His-bundle area. Femoral arterial pressure will be continuously monitored. Pericardial access will be obtained using the technique described by Sosa et al [12].

During sinus rhythm, electroanatomic mapping of the RV is performed. Detailed endocardial and epicardial mapping of arrhythmogenic substrate of the RV is performed. Abnormal electrograms are defined as electrograms that have (1) low voltage (≤1 mV), (2) split electrograms or fractionated electrograms with multiple potentials with ≥ 2 distinct components, with >20 ms isoelectric segments between peaks of individual components and (3) long duration (>80 ms) or late potentials (LPs), with distinct potentials extending beyond the end of the QRS complex. The interval from the end of the QRS complex to the end of the local electrogram was measured to determine the magnitude of LPs. Subsequently, programmed stimulation is performed for VT/VF induction (3 cycle lengths [600, 500, and 400 ms] up to triple stimuli via a quadripolar catheter in the RV apex or RVOT. When VT/VF becomes sustained and hemodynamically unstable, cardioversion / defibrillation is settled to restore sinus rhythm. Repeat epicardial electroanatomic mapping will be performed after the infusion of one of the following sodium channel blockers: (ajmaline, pilsicanide, flecainide or procainamide).

Radiofrequency ablation will be then performed to eliminate all of the abnormal signals described above.

4. Study Population

4.1 Patient Selection – Inclusion Criteria

Patients are diagnosed as BrS according to the recent consensus statement by HRS/EHRA/APHRS [8]. Symptomatic BrS patients are included in this study. Symptomatic BrS is defined as patients presenting with the type1 BrS ECG under/without a sodium channel blocker with 1) aborted cardiac arrest cases, 2) documented VF episodes, 3) agonal respiration during sleep with difficulty to arouse, 4) syncope of unknown origin, or 5) seizure suspected of arrhythmic origin. Other inclusion criteria are 1) diagnosed symptomatic BrS with an implanted ICD within the last 5 years ,2) diagnosed symptomatic BrS with an implanted ICD longer than 5 years but has at least 1 appropriate shock within the last 5 years, 3) patients who give an informed consent and undergo randomization, and 4) no structural heart disease or concomitant medical illness.

4.2 Patient Selection – Exclusion criteria

1) Patients under 16 years or over 70 years of age, 2) combined BrS and long QT syndrome, and 3) medical or mental conditions precluding a long-term follow-up.

4.3 Cross over:

Patients who have recurrent frequent ICD discharges in the control arm could be treated by ablation. Quinidine could be used in case of recurrent ICD discharges in either group.

4.4 Study Follow up:

All ablation patients will be follow up within one month after the ablation procedure and Control Arm patients will be followed every 3 months following Randomization. Both groups will be followed 3 months thereafter for ICD interrogation and assessment of VT/VF episodes. ICD programming for Tachycardia detection and therapy must be uniform for all sites as per guideline by 2016 HRS/EHRA/APHRS/SOLAECE expert consensus statement (Appendix 1). The follow-up period would be at the minimum of 1 year for each patient. Ajmaline or procainamide challenge will be performed at 3 months after ablation All non-ablation patients will be follow up every 3 months to have their symptoms assessed and their ICD interrogated. All patients will have an ECG with leads V1-V3 in the 4^th, 3^rd and 2^nd intercostal spaces respectively.

4.5 Discontinuation/withdrawal of participants and stopping rules

Withdrawn participants will return to their standard of care and routine clinical follow-ups. Participants who are screen failures (pre-randomization) will be replaced. Patients who are lost to followup post randomization will not be replaced. The trial may be terminated early based upon undisputable benefits of the catheter ablation subset or if there is sufficient evidence that continuation of the study would jeopardize participant health or safety.

4.6 Adverse Events

The AE reporting is exclusive to intervention related; stop defined as 3 months post procedure except for pericarditis, which is reportable for 6 months post ablation.

5 Statistics

5.1 Statistical considerations:

This clinical study is powered for the composite primary end point of death and VT/VF episodes interrogated by ICD at a median follow-up of 24 months. The total sample size of 200 patients (100 patients for the ablation group and 100 patients for the control group) has been determined to provide a high degree of confidence (power 80%) and control of a type I error rate of 0.05 for the defined primary end point. Sample size calculations are based on an expected annual event rate of 10% for the control group while assuming that the annual event rate would be reduced 10-fold (i.e., to 1%) in the ablation group. There will be one interim analysis when 50 patients are enrolled in each group and all patients have a follow up period of at least 1 year. The interim analysis will provide early stopping rules for futility and efficacy comparing ablation vs. control group.

5.2 Statistical Analysis:

For the intent-to-treat analysis, the randomized groups will be compared for differences in baseline characteristics using standard parametric and nonparametric procedures. Factors found to be significantly different between groups will be used as covariates in subsequent analyses. The intent-to-treat analysis contrasts event rates between the two treatment arms and use a) Kaplan-Meier methods for calculating survival curves, b) logrank method for comparing survival curves, and c) Cox regression methods for comparing survival curves adjusting for covariates found to be different between treatment arms. For a patient who has not experienced VT/VF episode and is last known to be alive, time to composite VF/VT or death will be censored at the last ICD assessment date.

There will be one interim analysis with early stopping rules for futility and efficacy comparing ablation vs. control group using a group sequential design. The endpoint of the interim analysis will be based on the annual event rates in ablation and control groups. The decision rule for the interim analysis is derived based on the following assumptions:

Annual event rate for control group: 10%
Annual event rate for ablation group: 1%
Type I error = 5%; power = 80%
The probability of early termination is approximately 6% (68% chance to claim efficacy and 32% chance to stop for futility)
At final analysis, approximately 85% chance to claim efficacy.

6. Citations

Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D et al. (2005). Brugada syndrome: report of the second consensus conference. Heart Rhythm., 2(4), 429-440.
Belhassen B, Glick A & Viskin S. (2004). Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation, 110(13), 1731-1737.
Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P et al. (2004). Hydroquinidine therapy in Brugada syndrome. J.Am.Coll.Cardiol., 43(10), 1853-1860.
Kamakura S, Ohe T, Nakazawa K, Aizawa Y, Shimizu A, Horie M et al. (2009). Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1-V3. Circ.Arrhythm.Electrophysiol., 2(5), 495-503.
Mizusawa Y, Sakurada H, Nishizaki M & Hiraoka M. (2006). Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment. J.Cardiovasc.Pharmacol., 47(3), 359-364.
Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K et al. (2011). Prevention of ventricular fibrillation episodes in brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation, 123(12), 1270-1279.
Ohgo T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T et al. (2007). Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm., 4(6), 695-700.
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C et al. (2013). HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia SyndromesExpert Consensus Statement on Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm., e75-e106.
Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL et al. (2010). Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation, 121(5), 635-643.
Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y et al. (2013). Outcome after implantation of a cardioverter-defibrillator in patients with brugada syndrome: a multicenter study-part 2. Circulation, 128(16), 1739-1747.
Sacher F, Roberts-Thomson K, Maury P, Tedrow U, Nault I, Steven D et al. (2010). Epicardial ventricular tachycardia ablation a multicenter safety study. J.Am.Coll.Cardiol., 55(21), 2366-2372.
Sosa E, Scanavacca M, d’Avila A & Pilleggi F. (1996). A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc.Electrophysiol., 7(6), 531-536.
Viskin S, Antzelevitch C, Marquez MF & Belhassen B. (2007). Quinidine: a valuable medication joins the list of ‘endangered species’. Europace., 9(12), 1105-1106.

Nademanee K, Veerakul G, Mower M, Likittanasombat K, Krit- tayapong R, Bhuripanyo K, Sitthisook S, Chaothawee L, Lai MY, Azen SP. Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial. Circulation. 2003; 107:2221–2226.

7. Appendix 1. Uniform Tachycardia Detection & Tachycardia Programming Recommendations

Modified from Wikof et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm, February 2016

Tachyarrhythmia detection duration criteria must be programmed

to require the tachycardia to continue for at least 6–12 seconds or for 30 intervals before

completing detection, to reduce total therapies.

The slowest tachycardia therapy zone limit should be programmed

at 190 bpm to reduce total therapies.

Discrimination algorithms to distinguish SVT from VT should be programmed to include rhythms with rates faster than 200 bpm and potentially up to 230 bpm (unless contraindicated to reduce inappropriate therapies.

Dual-chamber discriminators that misclassify VT as SVT if the atrial lead dislodges are discouraged in the perioperative period. Dual-chamber discriminators are contraindicated in patients with known atrial lead dislodgment, atrial under sensing or oversensing of far field R waves, and in those with permanent AF. It is recommended to activate lead-failure alerts to detect potential lead problems.

Higher minimum rates for detection might be appropriate for young patients or for those in whom SVT-VT discriminators cannot reliably distinguish SVT from VT, provided there is no clinical VT below this rate.

It can be useful to program more than one tachycardia detection zone to allow effective use of tiered therapy and/or SVT-VT discriminators and allow for a shorter delay in time-based detection programming for faster arrhythmias.

When a morphology discriminator is activated, it is reasonable to reacquire the morphology template when the morphology match is unsatisfactory, to improve the accuracy of the morphology discriminator.

It may be reasonable to activate lead “noise” algorithms that withhold shocks when detected VT/VF is not confirmed on a shock or other far-field channel to avoid therapies for nonphysiologic signals.

It may be reasonable to activate T-wave oversensing algorithms, to reduce inappropriate therapies.

It may be reasonable to program the sensing vector from bipolar to integrated-bipolar in true-bipolar leads at risk for failure of the cable to the ring electrode to reduce inappropriate therapies.

ATP-capable ICD therapy devices that ATP therapy be programmed to deliver at least 1 ATP attempt with a minimum of 8 stimuli and a cycle length of 84%–88% of the tachycardia cycle length for ventricular tachyarrhythmias to reduce total shocks, except when ATP is documented to be ineffective or proarrhythmic. It is indicated to program burst ATP therapy in preference to ramp ATP therapy, to improve the termination rate of treated ventricular tachyarrhythmias. Burst ATP therapy is preferred to ramp ATP therapy, to improve the termination rate of treated ventricular tachyarrhythmias.

8. Appendix II DSMB, Core Labs, Event Adjudication

Data and Safety Monitoring Board:

David Haines, MD

Professor, Cardiovascular Medicine, OUWB School of Medicine

Director, Heart Rhythm Center, Beaumont Health

Royal Oak, MI 48073

Peng Chen, MD (Chair)

Medtronic Zipes Chair in Cardiology

Director, Krannert Institute of Cardiology

Chief, Division of Cardiology, Department of Medicine

Indiana University School of Medicine

Teo Wee Siong, MBBS, FAMS, FRCP, MRCP, FACC, FHRS

Mount Elizabeth Medical Centre

Singapore

ECG Core Lab – Academic Medical Center, Amsterdam Netherlands

Arthur A. M. Wilde, MD PhD

Pieter G. Postema, MD PhD

ICD Core Lab/Events Adjudication

Antony Chu, M.D., F.A.C.C., F.A.H.A., F.H.R.S., F.A.C.P.

Director of Cardiac Electrophysiology, Interim

Director of Complex Ablation – Arrhythmia Services Section

Clinical Cardiac Electrophysiology Fellowship Program Director

Division of Cardiology at the Rhode Island and Miriam Hospital

Warren Alpert School of Medicine, Brown University, Rhode Island Hospital

9. Appendix III Event Schedule

Group I Ablation

Group II Control