PAUSE-SCD: Pan-Asia United States PrEvention of Sudden Cardiac Death Catheter Ablation Trial
Phase: NA
Conditions: Ventricular Tachycardia (VT)
Sponsor: University of Arizona

PAUSE-SCD Trial 
 
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STUDY PROTOCOL 
 
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Last updated: 21JULY2021 
 
 
 
Study Coordinating Site: 
 
University of Chicago 
Heart Rhythm Center 
5758 Maryland Ave 
Chicago, IL, 60637 
T: +1 773-702-5988 
 
 
 
 
 
 
 
Funding: St Jude Medical- Implantable Cardioverter Defibrillator for unfunded 
participants; Data Analysis, Statistical Analysis, Electroanatomic Core Lab 
 
 
 

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STUDY COORDINATING SITE CONTACT INFORMATION 
 
Hemal Nayak, MD 
5841 S Maryland Avenue MC9024 
Chicago, IL 60637 
University of Chicago Medical Center 
hnayak@bsd.uchicago.edu 
Tel: +1 773-702-5988 
Fax: +1 773-702-4666 
 
Yi (Dalise) Dai (Dalise Shatz) 
5841 S Maryland Avenue M559 MC9024 
Chicago, IL 60637 
University of Chicago Medical Center 
ydai1@medicine.bsd.uchicago.edu 
Tel: +1 773 834-5781 
Fax: +1 773 702-8577 
 
 
 
 
 

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PARTICIPATING CENTERS/PRINCIPAL INVESTIGATORS 
 
 
CHINA: 
 
Yao Yan, MD; Fuwai Cardiovascular Hospital; Beijing, China 
 
Minglong Chen, MD; The First Affiliated Hospital of Nanjing Medical University, 
Nanjing, China 
 
Shulin Wu, MD; Guangdong Provincial People's Hospital, Guangzhou, China 
 
Chenyang Jiang, MD; Sir Run Run Shaw Hospital, Hangzhou, China 
 
Jiang Jian, MD; West China Hospital, Chengdu, China 
 
SOUTH KOREA: 
 
Young Hoon Kim, MD PhD; Korea University, Seoul, South Korea 
 
JAPAN: 
 
Akihiko Nogami, MD PhD; Tsukuba University, Tsukuba, Japan 
 
Shiro Nakahara, MD PhD; Dokkyo Medical University, Saitama Medical Center, 
Saitama, Japan 
 
Akiko Ueda, MD PhD and Kyoko Soejima, MD; Department of Cardiology, Kyorin 
University Hospital, Tokyo, Japan 
 
Kazuhiro Satomi, MD, PhD; Tokyo Medical University, Tokyo, Japan 
 
TAIWAN: 
 
Shih-Ann Chen, MD;  Taipei Veterans General Hospital, Taipei, Taiwan 
 

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1. PROTOCOL SUMMARY 
2. INTRODUCTION 
 
2.1 BACKGROUND AND RATIONALE 
 
2.2 STUDY PURPOSE 
3. STUDY DESIGN 
 
3.1 STUDY OBJECTIVE 
 
3.2 STUDY ENDPOINTS 
 
3.3 CLINICAL CENTERS 
 
3.4 SUBJECT SELECTION 
 
 
3.4.1 INCLUSION CRITERIA 
 
 
3.4.2 EXCLUSION CRITERIA 
 
3.5 STUDY DESIGN OVERVIEW 
 
 
3.5.1 RANDOMIZATION 
 
3.6 STUDY POPULATION 
 
 
3.6.1 RANDOMIZED SUBJECTS 
 
 
3.6.2 REGISTRY SUBJECTS 
 
 
3.6.3 DISCONTINUED SUBJECTS 
4. STUDY PROCEDURES 
 
4.1 CENTER PERSONNEL 
 
4.2 SUBJECT SCREENING AND INFORMED CONSENT 
 
4.3 SCHEDULE OF VISITS AND PROCEDURES 
 
4.4 PRE-ABLATION 
 
4.5 ABLATION PROCEDURE (ABLATION ARM ONLY) 
 
 
4.5.1 MAPPING OF VENTRICULAR SUBSTRATE 
 
 
4.5.2 ABLATION APPROACH AND STRATEGY 
 
 
4.5.3 PROCEDURAL ENDPOINTS 
 
 
4.5.4 ICD PROGRAMMING 
 
 
4.5.5 DATA COLLECTION DURING ABLATION 
 
 
4.5.6 EPICARDIAL MAPPING AND ABLATION 
 
4.6 PRE-DISCHARGE 
 
 
4.6.1 PRE-DISCHARGE EVALUATION 

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4.6.2 CONCOMITANT MEDICAL THERAPY 
 
4.7 FOLLOW-UP 
 
 
4.7.1 SCHEDULED VISITS 
 
 
4.7.2 UNSCHEDULED VISITS 
 
4.8 DATA COLLECTION AND REPORTING 
 
4.9 SOURCE DOCUMENTATION REQUIREMENTS 
5. ADVERSE EVENTS 
 
5.1 DEFINITIONS 
 
 
5.1.1 ADVERSE EVENTS DEFINITION (AE) 
 
 
5.1.2 SERIOUS ADVERSE EVENTS DEFINITION (SAE) 
 
 
5.1.3 ANTICIPATED ADVERSE EVENTS 
 
 
5.1.4 UNANTICIPATED ADVERSE DEVICE EVENTS (UADE) 
 
5.2 HANDLING AND REPORTING OF ADVERSE EVENTS 
 
5.3 SUBJECT DEATH 
6. PROTOCOL DEVIATIONS 
7. EXPLANATIONS OF RISKS AND MITIGATION TO SUBJECTS 
 
7.1 RISKS 
 
7.2 MITIGATION OF RISKS 
 
7.3 POTENTIAL BENEFITS 
8. DATABASE AND CONFIDENTIALITY 
9. STATISTICAL ANALYSIS 
 
9.1 SAMPLE SIZE AND POWER CALCULATION 
 
9.2 PRIMARY ENDPOINT 
 
9.3 PRIMARY ENDPOINT ANALYSIS 
10. MONITORING 
11. INSTITUTIONAL REVIEW BOARD AND ETHICS COMMITTEE 
12. STATEMENT OF COMPLIANCE 
13. REFERENCES 
 

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1. PROTOCOL SUMMARY 
 
Title: 
Pan-Asia United States PrEvention of Sudden Cardiac Death 
Catheter Ablation Trial (PAUSE-SCD) 
 
Objective:  
1) To assess the incidence of sudden cardiac death and 
impact of ablation and ICD therapy vs. ICD therapy 
alone in Asia, which has not been studied in 
randomized trials except in the US and Europe. 
2) To explore the impact of preemptive VT ablation 
alone in patients at risk for sudden death 
(observational registry cohort). 
  
Sample Size: 
Pilot study sample size of 120 randomized patients (60 ICD 
and 60 ICD+ablation). Registry is reserved for patients who 
refuse randomization and received ablation only. 
 
Design: 
Prospective, multi-center randomized, controlled study.  
 
Clinical Sites: 
Approximately 8-12 ablation centers in Asia (China, Korea, 
Japan) will participate in the study.  Additional centers may 
be considered based on the discretion of the principal 
participating centers.  The anticipated enrollment duration is 
24 months for the initial pilot enrollment Additional 
associated centers may be used for referrals, clinically 
indicated ICD implantation, NIPS study, and ICD follow up. 
Due to the COVID19 global pandemic, China centers were 
shut down and complete access for patient follow-up will 
require an additional 6-12 months.  Therefore, we are 
requesting one extra year extension for follow up due to 
these unanticipated circumstances. No statistical review or 
analysis was performed, as follow-up remains incomplete as 
of April,28th , 2020.  
 
 
Inclusion Criteria: 
● Patient is receiving a new ICD or CRT-D implant, that 
has study required programing capabilities and is 
appropriate for remote monitoring. Patient who has 
received the ICD / CRT-D within 90 days of enrollment 
can also be enrolled.  
●  Patient who has a high risk of ICD shock as shown by 
documented Monomorphic VT (MMVT) by one or more of 
the following: 
o Spontaneous MMVT 
o Inducible MMVT during EP Study, 
o Inducible MMVT during NIPS Study 

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Inducible MMVT is defined as MMVT > 30 seconds or 
requiring electrical termination ( ATP or 
cardioversion)  
● Patient has EF < 50% or RV dysfunction 
● Patient has a cardiomyopathy with structural heart 
disease of any cause 
● 18 years of age or older 
● Patient has been informed of the nature of the study and 
has agreed to its provisions and provided written informed 
consent approved by the Institutional Review Board. 
 
Exclusion Criteria: 
 
• Any history of debilitating stroke with neurologic deficit  
• ST elevation MI or previous cardiac surgery within 60 days 
prior to enrollment 
• Patient is pregnant or nursing 
• Patient has chronic NYHA class IV heart failure 
• Patient has incessant VT necessitating immediate 
treatment 
• Patient has VT/VF thought to be from channelopathies 
• Limited life expectancy (less than one year) 
• Patient has current class IV angina 
• Recent CABG or PCI (< 45 days) 
• Patient is currently participating in another investigational 
drug or device study  
• Patient is unable or unwilling to cooperate with the study 
procedures 
• Known presence of intracardiac thrombi 
• Prosthetic mitral or aortic valve or mitral or aortic valvular 
heart disease requiring immediate surgical intervention 
• Major contraindication to anticoagulation therapy or 
coagulation disorder 
• Left Ventricular Ejection Fraction < 15% 
• Patient has had a previous ablation procedure for VT, 
excluding remote (> 3 months) outflow tract tachycardia 
• Patient has GFR < 30 mL/min/1.73m2 
• Patient has peripheral vascular disease that precludes 
LV access 
• Patient is thought to have idiopathic outflow VT as only 
VT 
• Patient has a PVC or VT induced cardiomyopathy that is 
expected to resolve with ablation and will not require an 
ICD 
• Patient has reversible cause of VT 
• Patient does not meet criteria for ICD or CRT-D 
 

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Intervention: 
 
1) ICD with medical management 
 
2) ICD with catheter ablation. Main strategy is scar-
based ablation with targeting of late potentials 
defined as low voltage potentials with fractionated, 
split, or delayed components  
 
3) Registry on non-randomized patients undergoing 
ablation only. 
 
Study Endpoint: 
 
The primary endpoint is defined as a composite of recurrent 
VT, 
cardiovascular 
rehospitalization, 
and 
death.  
Prespecified secondary endpoints include each of the 
individual 
components 
of 
the 
primary 
endpoint.  
Comparison of the ablation-only registry with the 
randomized patients will serve as an additional secondary 
outcome measure. 
 
Length of Study: 
 
The trial consists of a 2-3 year recruitment and 
randomization phase with a 2 year follow-up period.  
Due to the COVID19 global pandemic, China centers 
were shut down and complete access for patient follow-up 
will require an additional 6-12 months.  Therefore, we are 
requesting one extra year extension for follow up due to 
these unanticipated circumstances. No statistical review 
or analysis was performed, as follow-up remains 
incomplete as of April,28th , 2020.  
 
 
 

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2. INTRODUCTION 
 
 
2.1 Background and Rationale 
 
 
Sudden cardiac death (SCD) remains the leading cause of death in the United States, 
totally over 440,000 cases annually.  The incidence of SCD in Asia is unknown and the 
population potentially at risk is over four times the size of the Unites States.  ICD 
implantation remains the most effective abortive strategy to decrease mortality in the 
secondary and primary prevention setting.  However, the penetration and acceptance of 
ICD therapy into routine medical practice and guidelines in Asia is incomplete with 
significant unrealized potential.  In 2011, an estimated 800 ICDs were implanted in 
China, compared to half a million in the United States. 
 
The barriers to widespread adoption of ICD implantation across Asia are multifactorial, 
including financial, cultural, and scientific factors.  In China, the cost of the device is not 
covered by national insurance, making the technology cost- prohibitive for many 

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patients who are likely to derive benefit.  Cultural biases include aversion to surgery and 
implantation of devices, in addition to attitudes that reflect culture-specific disease 
progression.  Additionally, the vast majority of scientific evidence and randomized 
studies that support current ICD guidelines have been performed in US and Europe, 
outside of Asia.  The relative efficacy of ICD therapy in the Asian population has not 
been formally tested and lack of generalizable data is one factor that impedes 
widespread adoption among practicing physicians, which has a significant impact on 
how patients are counseled.  Continuity and clinical follow-up are challenges in such 
vast Asian countries, and the implantation of an ICD offers a potential means of 
improving upon these limitations.  In this current state, Asia serves as the ideal 
environment and setting to test the efficacy of both ICD therapy and catheter ablation in 
patients at risk for ventricular arrhythmias and sudden death.  Further, mortality impact 
from both ICD and ablation can be further studied as the majority of patients with 
structural heart disease referred for VT ablation in Asia do not have an ICD. 
 
ICD therapies have been strongly associated with increased hospitalization and all-
cause mortality.  As catheter ablation of VT has been demonstrated to decrease 
recurrent VT and ICD therapies, it is biologically plausible that ablation may have an 
impact on mortality.  A recent multicenter study of 2,061 patients by the International VT 
Ablation Center Collaboration demonstrated that recurrent VT after catheter ablation 
was associated with a 7-fold subsequent risk for mortality and across all stages of heart 
failure, patients that had successful ablation experienced improved survival.(1)  Only 
two randomized studies have been completed to date, SMASH VT (2)and VTACH(3), 
demonstrating that early preemptive ablation results in statistically significant reduction 
in subsequent ICD shocks.  A trend towards improved survival was seen in the ablation 
group in SMASH VT. 
 
 
2.2 Study Purpose 
 
The purpose of this study is to demonstrate that scar-based VT ablation in subjects who 
are clinically indicated for new ICD or CRT-D implantation and are at high risk of ICD 
shock with spontaneous monomorphic VT or inducible monomorphic VT during EP or 
NIPS study results in a superior clinical outcome compared to ICD with standard 
medical therapy.  Additionally, the registry arm which will enroll patients that refuse ICD 
will assess the efficacy of catheter ablation in the absence of background ICD therapy. 
 
Additionally, secondary goals of this study include: 
 
1) Increasing SCD awareness in Asia and improving clinical follow-up of patients at 
risk. 
2) Assessing whether SCD is less prevalent in Asia than US and Europe and 
prospectively determine the relative magnitude of benefit of both ICD and 
ablation.   
3) Determining the composition and etiology of patients referred for ICD and 
ablation in Asia.  Patients with ischemic cardiomyopathy represent a 

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disproportionately small proportion of patients referred for VT ablation, despite a 
high prevalence of coronary artery disease and myocardial infarction.  Biological 
and cultural differences in scar patterns may account for variations in 
arrhythmogenicity 
 
 
3. STUDY DESIGN 
 
 
3.1 Study Objective 
 
The study is a prospective, multi-center, randomized controlled trial evaluating the 
efficacy of ICD plus catheter ablation vs. ICD alone in preventing recurrent VT, 
cardiovascular rehospitalization, and death in patients with primary and secondary 
indications for ICD implantation. 
 
 
3.2 Study endpoints 
 
The primary efficacy endpoint is defined as freedom from recurrent VT, cardiovascular 
rehospitalization, and all-cause mortality through a period of 2 years after the procedure 
(ablation) or randomization (standard medical therapy).  Recurrent VT is defined as any 
appropriate ICD therapy (shock or ATP) or documented sustained monomorphic VT >30 
seconds. Cardiovascular rehospitalization is defined as a hospital admission after the 
randomized procedure for heart failure, procedure-associated complication, or 
arrhythmia-related causes during the follow-up period. 
 
 
3.3 Clinical Centers 
 
We anticipate enrollment of 120 patients for this pilot study at 8-12 institutions with 
extensive experience in complex ablation procedures.  As a conservative estimate, 
enrollment will occur over a 2 year period, with 60 patients per year (7-8 patients/year at 
each institution).  Additional centers may be considered based on clinical competency 
and experience. 
 
 
3.4 Subject Selection 
 
The Principal Investigator at each center has the responsibility of screening potential 
candidates to determine if they meet all the entry criteria. Subjects receiving new ICDs 
and at high-risk of ICD therapy are to be included. Those subjects receiving new ICDs 
(within 90 days of the study enrollment) for standard clinical reasons who also have 
documented MMVT will be considered for inclusion. MMVT may be evidenced using an 
EP study or Non-Invasive Programmed Stimulation study (NIPS) unless documented 

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spontaneous MMVT is available. Subjects who refuse ICD and undergo ablation will be 
included in a prospective registry arm. 
 
 
3.4.1 Inclusion Criteria 
 
● Patient is receiving a new ICD or CRT-D implant that has study required 
programing capabilities and is appropriate for remote monitoring. Patient who 
has received the ICD / CRT-D within 90 days of enrollment can also be enrolled.  
● Patient who has a high risk of ICD shock as shown by documented Monomorphic 
VT (MMVT) by one or more of the following: 
o Spontaneous MMVT 
o Inducible MMVT during EP Study, 
o Inducible MMVT during NIPS Study 
*Inducible MMVT is defined as MMVT > 30 seconds or requiring electrical 
termination (ATP or cardioversion)  
● Patient has EF < 50% or RV dysfunction 
● Patient has a cardiomyopathy with structural heart disease of any cause 
● 18 years of age or older 
● Patient has been informed of the nature of the study and has agreed to its 
provisions and provided written informed consent approved by the Institutional 
Review Board. 
 
 
3.4.2 Exclusion Criteria 
 
• Any history of debilitating stroke with neurologic deficit 
• ST elevation MI or previous cardiac surgery within 60 days prior to enrollment 
• Patient is pregnant or nursing 
• Patient has chronic NYHA class IV heart failure 
• Patient has incessant VT necessitating immediate treatment 
• Patient has VT/VF thought to be from channelopathies 
• Limited life expectancy (less than one year) 
• Patient has current class IV angina 
• Recent CABG or PCI (< 45 days) 
• Patient is currently participating in another investigational drug or device study  
• Patient is unable or unwilling to cooperate with the study procedures 
• Known presence of intracardiac thrombi 
• Prosthetic mitral or aortic valve or mitral or aortic valvular heart disease requiring 
immediate surgical intervention 
• Major contraindication to anticoagulation therapy or coagulation disorder 
• Left Ventricular Ejection Fraction < 15% 
• Patient has had a previous ablation procedure for VT, excluding remote (> 3 months) 
outflow tract tachycardia 
• Patient has GFR < 30 mL/min/1.73m2 

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• Patient has peripheral vascular disease that precludes LV access 
• Patient is thought to have idiopathic outflow VT as only VT 
• Patient has a PVC or VT induced cardiomyopathy that is expected to resolve with 
ablation and will not require an ICD 
• Patient has reversible cause of VT 
• Patient does not meet criteria for ICD or CRT-D 
 
 
3.5 Study Design Overview 
 
Based on assumptions from the SMASH VT trial and the AVID study, a 50% reduction 
in events from ablation is projected with a 50% event rate in the control arm at 2 years. 
120 patients are required to achieve 80% power to detect a true difference of this 
magnitude with a two-sided alpha error of 0.05.  The primary endpoint is a composite 
that includes cardiovascular rehospitalization and death, which will increase event rates 
at an estimated 10%/year, individually.(1,4) 
 
 
3.5.1 Randomization 
 
Subjects who meet inclusion/exclusion criteria will be entered into the randomized trial. 
Randomization will be 1:1 between control group and ablation group. Those randomized 
to the control group will receive ICD therapy and routine drug therapy (including 
antiarrhythmic drugs as indicated). Subjects randomized to the ablation group will 
receive ablation therapy plus ICD for ventricular tachycardia.  Patients that refuse ICD 
therapy and undergo ablation only will be enrolled in a prospective registry.  All primary 
statistical analyses will be performed on an intent-to-treat basis.  
 
Central randomization is conducted by the coordinating site. Prior to 10/12/16, the 
participating sites performed randomization using a table (block size of 4) provided by 
the coordinating site. After additional in-house statistical review of the protocol, 
electronic randomization from the coordinating site was advised. Central electronic 
randomization commenced on 10/12/2016. 25 patients were enrolled using the original 
randomization table schema. The remaining patients were randomized using electronic 
randomization. 
 
 
 
 
 
 
 
 
 
 
 

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3.6 Study Population 
 
 
 
 
3.6.1 Randomized Subjects 
 
The Intent to Treat (ITT) population includes all randomized subjects. These subjects 
can be included in the randomized trial if they meet all other entry criteria. 
 
 
3.6.2 Registry Subjects 
 
Patients that refuse ICD implantation will not be randomized and will be approached 
to sign consent for inclusion into a registry if they undergo catheter ablation without 
ICD.  Basic demographics and medical history will be collected from registry subjects 
upon enrollment.  Registry subjects will receive a phone contact and follow-up with 
clinic visits and device interrogation at 3, 6, 12, 18, 24, 30 and 36 months to check on 
their overall status. Due to the COVID19 global pandemic, China centers were shut 
down and complete access for patient follow-up will require an additional 6-12 
months.  Therefore, we are requesting one extra year extension for follow up due to 
these unanticipated circumstances. No statistical review or analysis was performed, 

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as follow-up remains incomplete as of April,28th , 2020. Registry subjects will receive 
a phone contact and follow-up with clinic visits 30 and 36 months to check on their 
overall status 
 
 
3.6.3 Discontinued Subjects 
 
• Lost to follow-up: subjects may be lost to follow-up despite exhaustive attempts 
to contact them. A minimum of two (2) attempts (by telephone or mail) to contact 
such subjects will be made and then a certified letter will be sent to the last 
known address. Attempts to contact the subject will be documented. 
• Subject/Family request: subjects may voluntarily decide to withdraw from the 
study with no penalty. If a subject chooses to discontinue participation in the 
study at the time of a study visit, the required assessments for that visit will be 
completed. If the subject notifies the clinical center by mail or phone, he/she may 
be requested to come in to have a final assessment. 
• Subject’s participation terminated by Investigator: a subject’s participation may 
be discontinued if the Investigator considers that it is in the subject’s best 
interest. 
• Subject’s participation terminated by site PI request. 
• Subject Death. 
 
If a patient is discontinued from the study, the reason for discontinuation will be 
documented and the data collected from this subject will be used in the final analysis 
and treated as censored subject. 
 
 
4. STUDY PROCEDURES 
 
 
4.1 Center Personnel 
 
Study investigators and support staff will be responsible for obtaining approval from 
their institutional IRB and ethics committee.  They will be responsible for completing 
case report forms and maintaining patient-level data throughout the duration of the 
study.  All EPs performing ablation procedures must have a minimum of 3 years 
experience in complex ablation. 
 
 
4.2 Subject Screening and Informed Consent 
 
All patients who are being considered for enrollment into the clinical trial must be 
screened by the site investigator or a member of the designated study staff for study 
eligibility. 
 

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Patients must sign the informed consent form prior to randomization or collection of any 
study data. Once randomized, they will be considered enrolled in the study.  The 
Investigator, Co-Investigator or Research Coordinator and if necessary, any witnesses 
should sign and date the consent as well.  Consented subjects who do not satisfy entry 
criteria are screen failures and will not be randomized. 
 
 
4.3 Schedule of Visits and Procedures 
 
All subjects participating in the study should follow the schedule of visits as outlined in 
the Table provided. 
 
 
4.4 Pre-Ablation 
 
Subjects shall undergo the items outlined for Pre-ablation / baseline in Table 2. 
• Informed Consent 
• Inclusion Exclusion Criteria 
• Medical History 
• TTE (Trans-thoracic echocardiogram). This can be obtained up to six months 
prior to the procedure to assess EF which is standard prior to ICD implant. An 
MRI or TEE can be performed in lieu of a TTE 
• TEE (Trans-esophageal echocardiogram) required if subject has history of LA or 
LV clot and recommended if subject has AF with a CHADS score >1 
• A CT or MRI is strongly recommended within 3 month prior to the ablation 
procedure to allow for anatomy fusion 
• 12-lead ECG within 6 months prior to the consent visit 
• Assessment of current AAD medication 
• Assessment of current anti-coagulation medication 
 
 
4.5 Ablation Procedure (Ablation Arm Only) 
 
 
4.5.1 Mapping of Ventricular Substrate  
 
High-density mapping will be performed with NAVX system (Ensite Velocity, St Jude 
Medical). Multipolar catheters such as duodecapolar multielecrode (Livewire 2-2-2 mm 
spacing) are strongly encouraged to facilitate high-density mapping.(5)  A minimum of 
500 points is strongly encouraged for each chamber mapped.  Epicardial mapping will 
be performed at the discretion of the treating physician but is encouraged for patients 
with ARVC and NICM. 
Scar will be defined as regions of low voltage <1.5 mV with dense scar as <0.5mV. 
 
 
4.5.2 Ablation Approach and Strategy 

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Irrigated-ablation technology will be used for mapping and ablation.  The choice of the 
catheter is up to the discretion of the physician performing the procedure.  The ablation 
technique will be targeting of late and abnormal electrograms within scar with 
prioritization of those with matching pacemaps, multiple exit sites pacemaps, or 
demonstrated diastolic activation during VT.  Slow conduction zones with isochronal 
crowding entering the latest zone of conduction should be targeted by using an 
isochronal activation timing display (Isochronal Late Activation Mapping).(6) Activation 
and entrainment mapping are encouraged if induced VTs are hemodynamically stable.  
If time allows, homogenization is the goal of the procedure, where all other local 
abnormal electrograms that demonstrate uncoupling are eliminated.(7) 
 
 
4.5.3 Procedural Endpoints 
 
Programmed stimulation is required before the ablation procedure with two cycle 
lengths (600ms and 400ms up to triple extrastimuli down to VERP or 200 ms).  This 
may be performed through the implanted ICD (NIPS). A VT is considered clinical if there 
is a morphologic match by 12-lead ECG or intracardiac EGM or has a similar 
tachycardia cycle length.   Left ventricular stimulation within scar should be performed if 
the patient is noninducible with RV stimulation.  Substrate-based ablation strategy 
targeting abnormal regions of slow conduction can be performed in the event of 
noninducibility. 
 
The acute procedural endpoint is noninducibility of the targeted clinical VT and 
elimination of abnormal electrograms within scar.  Programmed stimulation will be 
performed in the same fashion as prior to ablation.  Complete noninducibility is 
encouraged but not required. 
 
 
4.5.4 ICD Programming 
 
The ICD will be programmed to disable all therapies during mapping and ablation.  
 
In the Note section of the device, type the following message: 
 
PAUSE-SCD Trial subject. Please contact [physician or coordinator name] at [center 
name] at [center phone] before making any programming changes. 
 
Protocol-mandated programmed settings should be confirmed after the device is 
enabled at the conclusion of ablation.  VF zone of 230 bpm (ATP during charging) and 
VT zone 185 or 10 bpm slower than clinical VT (induced or spontaneous) with detection 
at 30/40 intervals. (ATPx3). 
 
 
4.5.5 Data Collection during Ablation 

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An ablation procedure form shall be completed by the operator, which includes patient 
demographics, number of VTs induced and targeted, predominant strategy, number of 
VT morphologies terminated during ablation, duration of radiofrequency applications, 
hemodynamic toleration during VT, and scar location and size. 
 
 
4.5.6 Epicardial Mapping and Ablation 
 
Epicardial access is encouraged in patients with ARVC and NICM substrate through the 
subxiphoid percutaneous approach, provided that surgical backup is present at the time 
of the ablation.  This can be performed as a combined strategy, where access is 
obtained prior to any systemic anticoagulation or after reversal of anticoagulation 
(documentation of ACT<150)  if VT remains inducible after endocardial ablation.  It is 
recommended to leave in an epicardial drain if >50 cc of bleeding is encountered.  
Coronary angiography is required prior to ablation to detail coronary artery proximity to 
ablation lesion set as well as high output pacing to assess for phrenic nerve location. 
 
 
4.6 Pre-Discharge 
 
 
4.6.1 Pre-Discharge Evaluation 
 
It is recommended that all patients have overnight observation after ablation.  In 
patients that undergo epicardial ablation, an echocardiogram should be performed in 
the following day.  
 
Subjects shall undergo the following at Pre-Discharge: 
• 12-lead ECG 
• Assessment of AAD medication 
• Assessment of anti-coagulation medication 
• Assessment of Adverse Events 
 
For ICD programming, the following steps will be followed: 
1) Program the device per guidelines outlined:  VF zone of 230 bpm (ATP during 
charging) and VT zone 185 or 10 bpm  slower than clinical VT (induced or 
spontaneous) with detection at 30/40 intervals. (ATPx3). 
 
2) If the device is not programmed according to the settings recommended and 
unless at discretion of the physician for subject’s benefit, a Deviation Form and 
any other applicable forms (i.e. Adverse Event or Hospitalization Form) must be 
completed if not previously submitted. 
 
3) Print out the following reports to be included with procedure form: 
i. Wrap-Up Overview 

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ii. Parameters Printout 
 
 
4.6.2 Concomitant Medical Therapy  
 
Subject cardiac medications will be documented and tracked over the duration of the 
study. All subjects with heart failure should have their heart failure medications 
optimized including use of beta-blockers and ACE inhibitors. A consult with a heart 
failure specialist is encouraged especially for optimization of drugs and for diuresis after 
ablation. Subjects in both the ablation and no ablation arm must be maintained on their 
pre-procedure anti-arrhythmic drug (AAD) unless clinical events dictate otherwise. Anti-
arrhythmic medications after ablation are at the discretion of the treating physician. 
 
Subjects who have significant LV endocardial ablation and have LV dysfunction should 
receive anticoagulation for four weeks post-procedure per current guidelines. Other 
subjects with LV endocardial ablation should be considered for ASA. Also any subject 
who requires anticoagulation for other reasons (e.g. AF) should be maintained on 
therapeutic anticoagulation. 
 
 
4.7 Follow-Up 
 
Follow-ups will be scheduled according to the Table provided: 
 
Study Activity 
Baseline 
Procedure 
3 
m 
6 
m 
12 
m 
18 
m 
24 
m 
30m 
36m 
Unscheduled 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
AAD/Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
TTE 
x 
 
 
x 
x 
 
x 
 
 
 
CT/MRI 
x 
 
 
 
 
 
 
 
 
 
12 lead ECG 
x 
 
 
 
 
 
 
 
 
 
Randomization 
x 
 
 
 
 
 
 
 
 
 
ICD implant 
 
x 
 
 
 
 
 
 
 
 
Ablation Procedure 
 
x 
 
 
 
 
 
 
 
 
ICD Interrogation 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
Death/Withdrawal 
 
 
 
 
 
 
 
x 
x 
 
Protocol Deviations 
 
 
 
 
 
 
 
 
 
 
Registry Subject 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
4.7.1 Scheduled Visits 
 
The following shall be evaluated at every visit: 
• Assessment of AAD medication 
• Assessment of anti-coagulation medication 

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• Assessment of Adverse Events 
• ICD Interrogation and event printout 
• An Echocardiogram will be performed at 6 months, 1 year, and 2 years if not 
already performed for routine clinical evaluation. 
 
 
 
4.7.2 Unscheduled Visits (as clinically warranted) 
 
The following shall be evaluated at unscheduled visits: 
• Assessment of AAD medication 
• Assessment of anti-coagulation medication 
• Assessment of Adverse Events 
• ICD Interrogation and event printout 
 
To accommodate subject referrals from remote hospitals, follow-up visits and device 
interrogations may be performed by the referring physician.  It is the investigators 
responsibility to obtain the completed Case Report Forms (CRF). 
 
 
4.8 Data Collection and Reporting 
 
All required data, including subject’s medical history for this trial are collected on 
standardized Case Report Forms (CRFs). CRFs were designed to balance the need for 
comprehensive data collection and to ease the process of data acquisition at the clinical 
center. The study coordinating site will provide each site with template CRFs to assist 
with data collection.  
 
Components of the CRF: 
• Subject selection criteria 
• Medical History 
• Medications 
• Preoperative baseline subject demographics 
• Ablation Procedure forms 
• Device Operation Form 
• ICD implantation information 
• Pre-discharge hospital summary (including post-procedural complications, etc.) 
• Assessment data at follow-up 
• Adverse event/ Serious adverse event 
• Unanticipated Adverse Device Effect 
• Report of Death 
• Subject Withdrawal 
• Protocol Deviations 
 
 

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4.9 Source Documentation Requirements 
 
Data recorded on CRFs must be verifiable by source documentation at the research 
center such as procedure reports, progress notes, discharge summaries, medication 
logs, and laboratory reports.  Each site is responsible for its own data monitoring. 
 
 
5. ADVERSE EVENTS 
 
Adverse events will be monitored and reported in the source documents and on the 
appropriate case report form, including seriousness, action taken and relationship to 
investigational system at every visit. If adverse events occur, the first concern will be the 
safety of the study participants. 
 
 
5.1 Definitions 
 
 
5.1.1 Adverse Events Definition (AE)  
 
An adverse event is any undesirable clinical occurrence or experience in a subject 
during the course of the study, whether or not it is related to the device or procedure. 
 
Each adverse event will be classified by the respective site investigator as serious or 
non-serious. This classification of the event determines the reporting procedures to be 
followed. The Investigator will also assess the possible relationship between the 
adverse event and the investigational device. Adverse events will be followed until they 
are adequately resolved or deemed unresolvable.  
 
 
5.1.2 Serious Adverse Events Definition (SAE)  
 
A serious adverse event is defined as an adverse event that results in: 
A. Death 
B. Serious deterioration in the health of the subject that: 
1) Results in a life-threatening illness or injury;  
2) Results in permanent impairment of a body structure or a body function;  
3) Requires inpatient hospitalization > 24 hours or prolongation of existing 
hospitalization;  
4) Results in medical or surgical intervention to prevent permanent impairment 
to body structure or a body function. 
 
 
5.1.3 Anticipated Adverse Events  
 
The anticipated adverse events provided in section 7.1 (Risks) are believed to represent 

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adverse events and complications experienced in either animal and/or clinical studies to 
date with ablation procedures reported in the literature. 
 
 
5.1.4 Unanticipated Adverse Device Effects (UADE) 
 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health 
or safety, any life-threatening problem or death caused by, or associated with, a device, 
if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in this Investigational Plan; or any other serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects. All UADE events 
should be reported to the coordinating center as soon as possible (within 24 hours), but 
in no event later than 10 days after the investigator first learns of the event. 
 
 
5.2 Handling and Reporting of Adverse Events 
 
Adverse events should be recorded in the source documents and on the Adverse 
Events Form. Non-serious adverse events will be reported to the IRB/EC as required by 
the respective site’s IRB/EC. 
 
If a serious adverse event or unanticipated adverse device effect occurs, the 
Investigator should do the following: 
1) Notify the coordinating center within 24 hours of awareness of death, within 48 
hours of awareness of a UADE and within 3 business days of awareness of an 
SAE. 
2) Obtain and maintain applicable medical records such as procedure summary, 
diagnostic procedure report, discharge summary, etc. in the treatment and follow-
up of the subject. 
3) Provide the coordinating center a complete case history along with the adverse 
event form. 
4) Inform the governing IRB/EC of the serious adverse event, in accordance with 
the IRB/EC’s reporting requirement. 
 
If the site investigator believes that a serious adverse effect is related to study 
procedures, the coordinating site should be notified within 10 days of the site 
investigator’s knowledge. While the coordinating site will not be responsible for safety 
conduct at the sites, the study team would like remain aware of any unexpected 
outcomes or risks. 
 
 
5.3 Subject Death 
 
Notification of death should include a detailed statement of the pertinent events and be 
signed by the site investigator in addition to the appropriate CRF(s). It is the site 
investigator’s responsibility to notify the appropriate IRB/EC, in accordance with the 

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IRB/EC’s reporting requirements. 
 
If the site investigator believes that the death is related to study procedures, the 
coordinating site should be notified within 24 hours of the site investigator’s knowledge. 
While the coordinating site will not be responsible for safety conduct at the sites, the 
study team would like remain aware of any unexpected outcomes or risks. 
Data communicated should include: 
• Date of death; 
• Primary cause (if known); 
• Temporal course of death (if known); 
• Any other circumstances surrounding the death; 
• Whether it was device or procedure related. 
• Autopsy report (if available) 
 
If available, also provide clinical notes and witness statements. Appropriate CRFs must 
also be completed. 
 
 
6. PROTOCOL DEVIATIONS 
 
A protocol deviation is defined as a study related activity that is not in compliance with 
the protocol or the Investigator Agreement.  Protocol deviations should be tracked and 
managed by each site, and reported according the site’s IRB/EC policies. 
 
Examples of deviations include but are not limited to: a required test not being done or 
not being done within the specified time-frame, a subject enrolled who did not meet the 
inclusion/exclusion criteria, a missed follow-up visit or missed visit window or enrollment 
of a subject without appropriate consent. 
 
 
7. EXPLANATIONS OF RISKS AND MITIGATIONS TO SUBJECTS 
 
 
7.1 Risks 
 
The following complications have been reported for commercially available ablation 
catheters or in published literature and are expected to be similar to those anticipated in 
this study. The list of complications includes but is not limited to: 
• Death 
• Cardiogenic shock 
• Complete Heart Block 
• New incessant VT/VF 
• Acute MI 
• Stroke 
• Pericarditis 
• Cardiac perforation causing pleural effusion or tamponade 

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• Adverse effects on implantable pacemakers, cardioverters, and defibrillators 
• Coronary artery occlusion 
• Heart Valve injury 
• Acute Pulmonary edema 
• Pulmonary embolism 
• Vascular access complications 
• Phrenic nerve injury 
• Arterial/venous thrombus: Clot formation in the artery or vein. 
• AV fistula: An abnormal passageway between an artery and a vein. 
• Catheter insertion site hematoma 
• Hemopneumothorax 
• Hypoxia 
• Infection: Localized or systemic 
• Peripheral venous thrombosis 
• Phrenic nerve damage 
• Pneumonia 
• Pseudoaneurysm 
• Radiation injury resulting in dermatitis 
• Respiratory failure 
• Radiation exposure during the fluoroscopic imaging of the catheters may slightly 
increase the lifetime risk of developing a fatal malignancy or a genetic defect in 
offspring 
• Fluid overload resulting in pulmonary edema and exacerbation of congestive 
heart failure (these risks are specific to open irrigated ablation catheters) 
 
Additional risks related to Epicardial Ablation: 
• RV puncture 
• Pericardial bleeding 
• Hemoperitoneum 
• Coronary Artery Damage 
• Phrenic Nerve Damage 
• Pleural Damage 
• Myocardial Infarction 
• Abdominal Bleeding 
• Pericarditis 
 
 
7.2 Mitigation of Risks 
 
Cardiac ablation procedure is performed by physicians thoroughly trained in the 
technique of VT mapping and radiofrequency catheter ablation, greater than 3 years out 
of fellowship, have complex ablation experience (typically >50 per year) and in a fully 
equipped electrophysiology lab. In addition operators and centers should have 
experience in epicardial ablation. Catheter advancement is carefully performed under 
fluoroscopic guidance in conjunction with internal electrograms and impedance 

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monitoring to minimize the risk of cardiac damage.  The physician take great care not to 
use excessive force to advance or withdraw the catheter when resistance is 
encountered.  Since pacemakers and implantable defibrillators can be affected by RF 
signals, temporary external sources of pacing and defibrillation are available during the 
ablation procedure.  The subject’s fluid balance and hemodynamic status is 
continuously monitored during ablation. Various displays and alarms are used as 
precautionary measures to warn the physician of the possibility of any undesirable event 
occurring. 
 
 
7.3 Potential Benefits 
 
The major benefit of undergoing treatment with ICD and catheter ablation is the 
reduction and possible elimination of ventricular arrhythmias that may result in death or 
ICD therapy and shocks.  The information gathered from the study will add to the 
understanding of the treatment options for subjects with ventricular tachycardia. This 
knowledge may advance medical science and have a benefit on other subjects with a 
similar arrhythmia. 
 
 
8. DATABASE AND CONFIDENTIALITY 
 
Conventional data management processing techniques will be used to by each center 
as they enter the data.  The coordinating site and all participating centers are dedicated 
to maintaining the confidentiality and privacy of subjects who volunteer to participate in 
the study.  Subject identifiers should be removed from any data that is shared with the 
coordinating site. Subject identifiers include, but are not limited to: subject’s name, 
social security number / unique identification number, and medical record number. 
Study documents will identify the subject by a subject study identification number. 
 
 
9. STATISTICAL ANALYSIS 
 
 
9.1 Sample size and power calculation 
 
Based on assumptions from the SMASH VT trial and the AVID study, a 50% reduction 
in events from ablation is projected with a 50% event rate in the control arm at 2 years. 
120 patients are required to achieve 80% power to detect a true difference of this 
magnitude with a two-sided alpha error of 0.05.  The primary endpoint is a composite 
that includes cardiovascular rehospitalization and death, which will increase event rates 
at an estimated 10%/year, individually. 
 
 
9.2 Primary Endpoint  
 

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The primary efficacy endpoint is defined as freedom from recurrent VT, cardiovascular 
rehospitalization, and all-cause mortality through a period of 2 years after the procedure 
(ablation) or randomization (standard medical therapy).  Recurrent VT is defined as any 
appropriate ICD therapy (shock or ATP) or documented sustained monomorphic VT >30 
seconds. Cardiovascular rehospitalization is defined as a hospital admission after the 
randomized procedure for heart failure, procedure-associated complication, or 
arrhythmia-related causes during the follow-up period. 
 
Prespecified secondary endpoints include each of the individual components of the 
primary endpoint.  Comparison of the ablation-only registry with the randomized patients 
will serve as an additional secondary outcome measure. 
Prespecified subgroup analysis will be performed for patients with RV cardiomyopathy. 
 
 
9.3 Primary Endpoint Analysis  
 
The primary endpoint analysis will be a time to event analysis and account for censored 
observations for all randomized subjects. Intention to treat analysis will be used for this 
endpoint; the analysis will be “analyzed as randomized” regardless of the actual 
treatment patients receive during the follow-up period. Kaplan-Meier (1958) estimates of 
the primary endpoint and overall survival will be generated along with 95% confidence 
intervals for the median time to event or death (Brookmeyer and Crowley, 1982).(8,9)  
Log-rank test will be used to compare the hazard functions between the two groups. 
Cox (1972) regression models will be fit to assess and adjust for baseline 
covariates.(10)  The median time to VT recurrence as well as the 95% confidence 
intervals will be reported for both groups. The event free survival probability as well as 
the 95% confidence intervals at the 24-month follow-up for both groups will be 
presented.  Adverse events will be tabulated by type and level of severity and compared 
between groups using chi-square or Fisher exact tests.   
 
Secondary analyses comparing outcomes in the ICD+ablation and ICD arms vs. the 
registry patients (ablation only) will be performed in a similar manner to those described 
above. 
 
Interim analyses will be generated by the coordinating center annually.  A Peto-Haybittle 
efficacy monitoring boundary will be used:  if the p-value for the difference between 
groups is <0.001, early stopping of the trial will be considered.  Using this monitoring 
bound, the p-value for statistical significance at the final analysis will remain at the 
nominal 0.05 level. 
 
 
10. MONITORING 
 
Each participating center is responsible for study execution, data collection and 
monitoring for protocol compliance and conduct.  The coordinating site may be 
consulted regarding any questions specific to protocol conduct. 

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The coordinating site will collect a copy of the IRB/EC approval letter for each site, as 
well as a copy of the final approved informed consent before randomization can begin. 
The coordinating site will collect a final complete data set from each site, and may work 
with the sites regarding any questions or outstanding data elements. 
 
Upon inspection of the final data set, the coordinating site may request to see source 
documentation, reports of protocol deviations or adverse events if needed to verify data 
elements. 
 
 
11. INSTITUTIONAL REVIEW BOARD AND ETHICS COMMITTEE 
 
The study protocol must be reviewed and approved by the appropriate Institutional 
Review Board/Ethics Committee before subject enrollment may begin. Proposed 
changes to the protocol must be reviewed by the coordinating site PI land significant 
changes must be approved in writing as well as the Institutional Review Board / Ethics 
Committee. A significant change is one which may increase risks or present a new risk 
to the subject, or which may adversely affect the scientific validity of the study. Each 
investigator must sign the protocol amendment before implementing the change at 
his/her center. 
 
IRB/EC approval is required for each institution participating in this investigation. Prior to 
enrollment, a signed copy of the Institutional Review Board approval letter addressed to 
the investigator must be submitted to the coordinating site certifying study approval. 
Investigators are responsible for obtaining and maintaining approval of the study by the 
IRB/EC. Annual review and approvals for continuation of the trial at each center must 
also be forwarded to the lead site where they will be submitted to coordinating site’s IRB 
at the time of continuing review, per IRB policy.  Correspondence with the IRB/EC 
should be retained at the center. Adverse events and protocol deviations must be 
reported per IRB/EC requirements. 
 
 
12. STATEMENT OF COMPLIANCE 
 
The clinical investigation shall be conducted in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki and ISO 14155.  
These principles protect the rights, safety, and well-being of human subjects, which are 
the most important considerations and shall prevail over interest of science and society. 
These principles shall be understood, observed, and applied at every step in the clinical 
investigation. 
 
Protocol required investigational activities shall not begin until the required approval, or 
favorable opinion from the Institutional Review Board (IRB) or Ethics Committee (EC) or 
regulatory authority has been obtained and any additional requirements imposed by the 
IRB or EC or regulatory authority shall be followed. 

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13. REFERENCES 
 
1. 
Tung R, Vaseghi M, Frankel DS et al. Freedom from recurrent ventricular 
tachycardia after catheter ablation is associated with improved survival in 
patients with structural heart disease: An International VT Ablation Center 
Collaborative Group study. Heart Rhythm 2015;12:1997-2007. 
2. 
Reddy VY, Reynolds MR, Neuzil P, Richardson AW, Taborsky M, Jongnarangsin 
K, Kralovec S, Sediva L, Ruskin JN, Josephson ME. Prophylactic catheter 
ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657-
65. 
3. 
Kuck KH, Schaumann A, Eckardt L, Willems S, Ventura R, Delacretaz E, 
Pitschner HF, Kautzner J, Schumacher B, Hansen PS. Catheter ablation of 
stable ventricular tachycardia before defibrillator implantation in patients with 
coronary heart disease (VTACH): a multicentre randomised controlled trial. 
Lancet 2010;375:31-40. 
4. 
Di Biase L, Burkhardt JD, Lakkireddy D et al. Ablation of Stable VTs Versus 
Substrate Ablation in Ischemic Cardiomyopathy: The VISTA Randomized 
Multicenter Trial. Journal of the American College of Cardiology 2015;66:2872-
82. 
5. 
Tung R, Nakahara S, Maccabelli G, Buch E, Wiener I, Boyle NG, Carbucicchio C, 
Bella PD, Shivkumar K. Ultra high-density multipolar mapping with double 
ventricular access: a novel technique for ablation of ventricular tachycardia. J 
Cardiovasc Electrophysiol 2011;22:49-56. 
6. 
Irie T, Yu R, Bradfield JS et al. Relationship between sinus rhythm late activation 
zones and critical sites for scar-related ventricular tachycardia: systematic 
analysis of isochronal late activation mapping. Circ Arrhythm Electrophysiol 
2015;8:390-9. 
7. 
Jais P, Maury P, Khairy P et al. Elimination of local abnormal ventricular 
activities: a new end point for substrate modification in patients with scar-related 
ventricular tachycardia. Circulation 2012;125:2184-96. 
8. 
Kaplan EL, Meier P (1958).  Nonparametric observations from incomplete 
observations.  J Am Stat Assoc 53:457-481 
9. 
Brookmeyer R, Crowley J (1982).  A confidence interval for the median survival 
time.  Biometrics 38:29-41. 
10. 
Cox DR (1972).  Regression models and life tables (with discussion).  J R Stat 
Soc B 30:187-220.