Comparison of (R) and (S) Propafenone for Prevention of Atrial Fibrillation Induction
Phase: PHASE1
Conditions: Atrial Fibrillation
Sponsor: Vanderbilt University

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Protocol Title:  
Comparison of (R) and (S) Propafenone for 
Prevention of Atrial Fibrillation Induction 
Protocol Date: 
10/3/2019 
NCT #: 
NCT02710669

 
 
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Comparison of (R) and (S) Propafenone for Prevention 
of Atrial Fibrillation Induction 
 
 
 
Principal Investigator: 
 
Bjorn Knollmann, M.D., Ph.D.  
Professor of Medicine and Pharmacology 
Division of Clinical Pharmacology 
Vanderbilt University 
 
 
Nashville, TN 
 
 
 

 
 
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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 
Statistical Considerations 
11.0 
Privacy/Confidentiality Issues 
12.0 
Follow-up and Record Retention 
 
Appendices 
Appendix A Study Procedure Calendar 

 
 
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1.0 
BACKGROUND 
 
1A. The need for more mechanism-based therapy for atrial fibrillation: AF is the most common sustained 
cardiac arrhythmia affecting 2-5 million adults in the U.S. at an estimated cost of over 26 million dollars per 
day. With the aging of the population, the projected number of people affected with AF is estimated to be 12 
million by 2050. The AF epidemic is further complicated by the lack of effective therapies. Despite recent 
advances in catheter-based and surgical treatments for AF, antiarrhythmic drugs (AAD) remain the mainstay of 
treatment for most patients with symptomatic AF. However, response in an individual patient is highly variable 
and carries risks of proarrhythmia and extracardiac toxicity. The poor efficacy of AAD is due to the poor 
understanding of the underlying pathophysiology and failure to target therapy to underlying mechanisms. The 
current strategy for a trial of AAD therapy focuses primarily not on efficacy, but on the side-effect profile of 
available membrane active drugs. There is little evidence-based data to assist the physician in selecting the 
most appropriate AAD for a particular patient. Over the last decade, genetic studies have provided important 
insights into the molecular mechanisms of AF, and our data suggest that genetic factors also contribute to 
variable drug actions. Given that the current success rate for AADs in AF is ~50% over a 6-12 month period, 
continued research aimed at refining AAD therapy such that underlying mechanisms are targeted is a major 
research priority in this field and our study will contribute to achieving this goal. 
 
1B. Role of “leaky” RyR2 Ca release channels in AF pathophysiology: To better understand the molecular 
pathophysiology of AF, it is important to place it in the context of common arrhythmia mechanisms such as 
focal ectopic activity and reentry. Ectopic activity can be triggered by early afterdepolarizations (EADs), 
delayed afterdepolarizations (DADs), or enhanced automaticity. Rapid focal activity in the pulmonary veins 
(PVs) can not only initiate AF but sustain it. High frequency firing drivers or rotors or a single localized reentrant 
circuit can also give rise to the irregular atrial discharge that is typical for AF. Atrial fibrillatory activity may also 
be caused by multiple fixed and functional circuits that are time and space dependent. While the cellular 
mechanisms causing paroxysmal AF in humans are clearly multifactorial, experimental evidence from our 
group as well as others suggest that in mouse models Ca leak mediated by RyR2 Ca release channels is one 
important mechanism responsible for triggering of this form of the arrhythmia. Since Ca leak has been 
demonstrated in atrial tissue from patients with persistent and paroxysmal AF, but the causal relationship to 
human AF remains controversial, the overarching goal of this application is to test the hypothesis that leaky 
RyR2 channels confer increased susceptibility to paroxysmal AF that can be targeted therapeutically. 
 
1C. Are “leaky” RyR2 channels a common downstream consequence of genetic AF risk variants? 
Recent insight into underlying AF mechanisms has been advanced by the identification of common and rare 
genetic variants associated with AF. Linkage analyses and candidate gene approaches have identified 
mutations in a variety of genes encoding cardiac ion channels, gap junction proteins, and signaling molecules. 
In contrast, genome-wide association studies (GWAS) have identified and validated 9 common AF 
susceptibility alleles, with several loci on chromosome (chr) 4q25 having the strongest association with AF 
(relative risk 1.39-1.72). Although the mechanism for this association remains uncertain, the locus is adjacent 
to the paired-like homeodomain transcription factor 2 (PITX2) gene which is critical for cardiac development, 
and reduced Pitx2 expression generates AF risk in mice. Given how commonly leaky RyR2 channels are found 
in studies of human AF, and that individuals carrying 4q25 risk alleles respond better to Class IC drugs 
flecainide and propafenone, both of which also inhibit RyR2 channels, this raises the hypothesis that PITX2 
variants and possibly other rare AF-linked variants may initiate a cascade of cellular signaling events that 
ultimately leads to deranged RyR2 gating, which then contributes to AF by increasing Ca leak, generation of 
DADs and triggered activity. Hence, such derangement of Ca handling may constitute a common 
electrophysiological mechanism by which common genetic variants increase susceptibility to paroxysmal AF. 
To investigate this hypothesis, we will conduct a proof-of-concept clinical trial whereby the role of Ca leak for 
paroxysmal AF will be tested in humans by comparing AF suppression in the clinical EP laboratory. (R)- and 
(S)-propafenone have varying degrees of RyR2 channel inhibition and will therefore be used as tools to 
provide the first evaluation of whether RyR2 Ca leak contributes to AF inducibility in humans. 
 
2.0 
Rationale and Specific Aims 
 

 
 
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The overarching aim of our study is to test the hypothesis that RyR2 blockade is beneficial for preventing AF 
induction in humans with paroxysmal AF. We have received an NIH R01 award to evaluate the efficacy of 
RyR2 channel blockade to prevent inducible AF or atrial flutter (AFL) in patients undergoing an AF ablation. 
We will test the role of RyR2 channel blockade by comparing drugs with variable RyR2 action: (R)-
propafenone, (a combined RyR2 and Na channel blocker), and (S)-propafenone (largely devoid of RyR2 
inhibition).  
 
Specific Aim: To test the hypothesis that (R)-propafenone is superior to (S)-propafenone in 
suppressing induction of AF/AFL by a rapid atrial pacing protocol. 
 
Rationale: Recent human studies have shown that paroxysmal forms of AF are associated with increased Ca 
leak from intracellular Ca stores and RyR2 dysfunction. But, it remains controversial if this abnormal Ca 
leakiness is mechanistically important for AF risk in humans. In mice, enhanced diastolic Ca release mediated 
by loss of the Ca-binding protein Casq2 can cause AF by promoting regional Ca elevations and DADs. 
Furthermore, inhibition of spontaneous Ca release with (R)-propafenone prevented AF by reducing the rate of 
DADs and triggered atrial activity, whereas Na channel blockers without RyR2 blocking properties (S-
propafenone and lidocaine) were much less effective. These data suggest that RyR2 blocking properties are 
important for therapeutic efficacy against AF caused by leaky RyR2. The general approach for this study will 
utilize a rapid atrial pacing protocol to induce AF in subjects undergoing AF ablation. Subjects referred for AF 
ablation will be randomized to either (R)-propafenone, (S)-propafenone, or placebo (vehicle) in a double blind, 
randomized fashion. A single 10-minute infusion of intravenous (R)- or (S)-propafenone or placebo (vehicle) 
will be given at the start of the ablation procedure before a rapid atrial pacing protocol is performed to test 
inducibility of AF.  
 
3.0 
Animal Studies and Previous Human Studies 
 
3.1: (R)-propafenone is the most potent inhibitor of spontaneous Ca release among clinically-approved AADs. 
We recently screened clinically available AAD for activity against spontaneous Ca release due to leaky RyR2 
channels using permeabilized ventricular myocytes from Casq2-/- mice. In this assay, cell membrane 
permeabilization excludes any confounding drug effects on cell membrane ion channels (i.e., Na channels) on 
Ca storage and release. We found that (R)-propafenone was the most potent inhibitor of spontaneous Ca 
waves (Fig. 1). The (S)-enantiomer of propafenone, which has significantly less activity against RyR2 
channels, was essentially ineffective against Ca waves (Fig. 1). This is an intriguing finding, because (R)-
propafenone inhibits the metabolism and elimination of (S)- propafenone, leading to much higher levels of (S)-
propafenone compared to (R)-propafenone during chronic administration in patients, which may limit the 
efficacy of racemic propafenone currently used to treat AF patients.  
 
3.2: (R)- and (S)-propafenone as tools to determine the role of RyR2 channel block for preventing AF 
induction. If leaky RyR2 channels render atria susceptible to AF induction, as suggested by mouse models with 
mutant RyR2 or loss of Casq2, then agents with RyR2 channel blocking properties should have superior 
efficacy compared to agents that do not. Consistent 
with its higher potency suppressing Ca release in vitro 
(Fig. 1), we recently reported that (R)-propafenone 
exhibited 
superior 
efficacy 
compared 
to 
(S)-
propafenone 
and 
lidocaine 
for 
suppressing 
spontaneous Ca release, DADs and pacing-induced 
AF in Casq2-/- mice (Fig. 2). Furthermore, (R)-
propafenone was significantly more effective than Na 
channel blockers without RyR2 blocking properties 
(lidocaine, S-propafenone) in preventing CPVT in 
Casq2-/- mice, and in suppressing spontaneous Ca 
elevations and DADs in Langendorff-perfused rabbit 
ventricles. Unlike other experimental RyR2 blockers, 
(R)- and (S)-propafenone are already in clinical use as 
Figure 1: Suppression of Ca wave activity by AADs. 

 
 
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the racemic, and therefore will be used to test our 
hypothesis that leaky RyR2 channels confer AF 
risk that can be targeted therapeutically in 
humans. 
 
3.3 Increased AF risk due to chr4q25 SNPs near 
PITX2. While the link between 4q25 SNPs and 
altered PITX2 expression in humans remains 
controversial, mouse models support a causal 
role of reduced Pitx2 expression for increased AF 
susceptibility. The initial report by the Martin lab 
attributed 
increased 
AF 
susceptibility 
in 
heterozygous Pitx2+/- mice to failure to suppress 
a left-sided pacemaker. Pitx2c, the major cardiac 
isoform, 
suppresses 
sinoatrial 
node 
(SAN) 
specific gene expression in the left atrium (LA) by 
binding to and repressing Shox2. Shox2 is 
essential for SAN development, and Pitx2+/- mice show increased expression in the LA. This is intriguing; 
because in mice and humans Pitx2c is expressed after birth only in the LA and in the PVs. Together with a 
recent study demonstrating that Pitx2 regulates expression of ion channels (including RyR2) in the adult 
mouse LA, these data suggest that Pitx2 plays a role beyond regulating SAN gene expression in the adult LA. 
However, published studies have not investigated whether RyR2 Ca leak contributes to AF in Pitx2 mice. 
Furthermore, due to restricted expression of Pitx2, an effect on the RyR may be localized to LA and PV region 
and we therefore will determine the origin of AF in this model as shown in Fig. 3. 
 
Chromosome 4q25 SNPs modulate differential response to AADs in patients with AF. Here, we examined 
whether symptomatic response to AAD is modulated by the three common AF risk loci on chr4q25 (near 
PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3). We studied 478 (discovery cohort) and 198 (validation 
cohort), age and gender matched Caucasian patients with AF. Clinical variables such as age, hypertension, 
and lone AF failed to predict response to AADs. However, a 4q25 WT SNP was associated with successful 
symptom control (OR 2.97, 95% CI 1.42-6.21, P=0.003). Furthermore, individuals who carried a variant 4q25 
SNP responded better to class I (flecainide or propafenone) than class III (>95% sotalol) AADs in both the 
discovery and validation cohorts (Table 1). These findings provide additional rationale for our study as they 
suggest that common AF risk variants predict differential response to AAD.  
 
Figure 2: Effect of R-propafenone (R-Prop), S-propafenone (S-
Prop) and lidocaine on spontaneous Ca elevations (A, B), QRS 
(C) and AF induction (D) in intact Casq2-/- hearts. 
Figure 3: Posterior atrial activation mapping during AF. Right panel: Anatomical origin of focal AF in Casq2-/- (n=7) 

 
 
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 3.3 (R)-propafenone prevents AF induction in Pitx2+/- 
heterozygous mice. Pitx2+/- mice were kindly provided by Dr. 
James Martin, Baylor Univ. Consistent with literature reports, 
AF inducibility at baseline was 67% in Pitx2+/- mice using atrial 
burst pacing (Fig. 3). Administration of (R)-propafenone (5 
mg/kg i.p.) completely prevented AF in Pitx2+/- mice (Fig. 4).  
 
3.4 The Vanderbilt AF Ablation Registry (VAFAR). To 
demonstrate the feasibility of performing a clinical trial in 
patients undergoing AF ablation, we present data from a 
clinical 
and 
genetic 
bio-repository 
(VAFAR) 
that 
was 
established by Dr. M. Benjamin Shoemaker (Co-investigator) 
in 2011. VAFAR has prospectively enrolled over 900 patients undergoing AF ablation. Uniform protocols for 
enrollment, blood collection, storage, DNA extraction, intra-procedural electrophysiologic data collection, and 
clinical follow-up are in place. 
 
3.5 VAFAR demonstrates that 4q25 risk allele 
carriers have impaired response to AF ablation. In 
2013, 
we 
examined 
atrial 
tachyarrhythmia 
recurrence (AF/AFL, or atrial tachycardia [AT]) 
following 378 catheter-based AF ablations in 
VAFAR). The final cohort consisted of 311 patients 
(median age 60 years [IQR 52-66]; 47% 
paroxysmal; 10% lone AF). The overall recurrence 
rate over 18-months follow-up was 53%. Using an 
additive genetic model, a graded gene-dose 
response was detected based on the number of 4q25 risk alleles (P=0.037) such that heterozygous risk allele 
carriers suffered a 21% earlier recurrence of AT/AF (survival time ratio 0.79 [95% CI: 0.62-0.99]), and 
homozygous risk allele carriers a 39% earlier recurrence (survival time ratio 0.61 [0.37-1.0]). These findings 
suggest that common 4q25 AF risk alleles modulate response to ablation therapy in patients with 
predominantly paroxysmal AF.  
 
4.0 
Inclusion/Exclusion Criteria 
 
Table 2: Eligibility Criteria 
Inclusion 
Exclusion 
atrial fibrillation 
long-standing persistent AF  
≥ 18 years of age 
presents in AF/AFL the morning of the ablation procedure 
undergoing AF ablation 
the presence of any of the following in a patient without a permanent pacemaker or ICD:  
a) sick sinus syndrome indicated by the inability to previously tolerate an 
antiarrhythmic drug  due to bradycardia 
b) sinus bradycardia with HR <50 bpm at the time of study drug administration 
c) right bundle branch block, left bundle branch block, or bifascicular block 
d) PR > 280 ms, or history of 2nd or 3rd degree AV block 
 
 
 
concomitant use of CYP3A4 inhibitors and CYP2D6 inhibitors 
 
previous surgical or catheter ablation for AF or MAZE procedure  
 
amiodarone use within 3 months prior to enrollment 
 
AAD (other than amiodarone) within 5 half-lives prior to AF ablation 
 
expected life span < 1 year 
 
creatinine clearance <30 ml/min 
 
reversible cause of AF (ie. thyrotoxicosis) 
 
unrevascularized coronary artery disease 
 
Canadian Class IV angina  
 
left ventricular ejection fraction <40% 
 
New York Heart Association Class III or IV symptoms 
Table 1. Differential response to AADs based on 
4q25 SNP genotype.
52 
Discovery Cohort 
Drug class 
Wild type 
(n=309) 
Minor allele 
carriers (n=90) 
P- 
value 
Class I 
87 (28%) 
37 (41%) 
0.02 
Class III 
222 (72%) 
53 (59%) 
0.02 
Validation Cohort 
Drug class 
Wild type 
(n=97 ) 
Minor allele 
carriers (n=46) 
P 
Class I 
37 (39%) 
30 (67%) 
0.01 
Class III 
60 (61%) 
16 (34%) 
0.02 
 
 
 
 
Figure 4: R-propafenone prevents AF induction in Pitx2+/- mice. 

 
 
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previous heart transplantation  
 
planned heart transplantation or ventricular assist device 
 
cardiac/thoracic surgery ≤ 6 months prior to enrollment 
 
severe asthma or COPD 
 
Breastfeeding 
 
5.0 
Enrollment/Randomization 
 
Recruitment and informed consent: Eligible subjects will be identified through StarPanel. A member of the 
study team will request an introduction from the clinical staff, if the patient agrees. Following the introduction, 
the team member will approach the patient prior to AF ablation. Information describing the study, why the 
research is being done and what will be learned will be provided. The risks as described above will be 
delineated. The benefits will be described as general scientific knowledge, along with potential treatment 
advances. No direct immediate benefit to the subjects is anticipated. Informed consent will be documented with 
the subject’s signature using an IRB-approved consent form for this protocol. 
 
Randomization: This will be a double-blind, randomized study. Eligible subjects will be randomized according 
to a permuted block scheme with a block size of balancing interval, varying randomly according to the outcome 
of a computer-generated random number. This ensures that the cumulative number of assignments to each 
treatment (R-propafenone, S-propafenone, or placebo/vehicle) will be in balance after each block of 
assignments had been made. A statistician will design the randomization table and enable the randomization 
tool within REDCap. After a patient enrolls for the study, the study nurse will determine the treatment 
assignment using the randomization tool in REDCap. The day prior to the ablation procedure, the study nurse 
will notify IDS to prepare the study drug. The morning of the AF ablation procedure, the study nurse will pick up 
the study drug from the IDS. 
An initial set of 6 patients received (R)- or (S)-propafenone at a rate of 1mg/kg to establish subject safety. This 
was open-label and not randomized. The data was reviewed with the DSMB on Dec 1, 2016. The DSMB 
recommended continuing the study with the 1mg/kg dose. 
 
The study drug will be administered via a peripheral i.v. at a rate of 1mg/kg (maximum of 100mg) over 10 
minutes. This will occur following induction of general anesthesia at the start of the procedure (Table 3).  Dr. 
Shoemaker will remain blinded to the treatment assignment as he is responsible for performing the study 
pacing protocol, electrogram interpretation, and interval measurement. 
 
 

 
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6.0 
Study Procedures 
 
Encounter 1: Enrollment and Informed Consent 
• 
Performed by study nurse in VU outpatient clinic or inpatient setting 
Encounter 2: Day of AF Ablation  
• 
Ablation will be scheduled by the patient’s physician according to clinical availability and is often offset by 
1-60+ days from time of enrollment. The scheduling of the AF ablation procedure and post-procedure care 
are determined by the availability of the operator and patient according to standard of care practices.  
• 
AF ablation will be performed according to standard of care practice by the patient’s physician. Table 3 
summarizes an estimated time frame for the clinical activities and simultaneous performance of the study 
protocol  
• 
After the patient arrives in the operating room, they will be undergo standard of care preparation for surgery 
including sterile drape and administration of general anesthesia using endotracheal intubation and 
mechanical ventilation.  
• 
A transesophageal echocardiogram (TEE) is performed as standard clinical practice by the cardiac 
anesthesiolgy attending physician immediately following intubation. This is performed to exclude the 
presence of a left atrial appendage thrombus and to document the presence of any pericardial fluid at 
baseline. The TEE is then used later in the procedure to assist in visualization of the interatrial septum for 
transseptal puncture. As part of the research protocol TEE pictures of the LV will be recorded to allow for 
offline measurement of LV contractility.  
• 
“Time out” will be performed at the start of the case by the primary operator. Immediately following time-
out, the study drug infusion will be started (1 mg/kg over 10 minutes; maximum dose 100 mg).  
• 
15 minutes following completion of the study drug infusion, blood will be collected from central venous 
sheaths that are placed at the beginning of the case. Blood will be drawn from the sheaths immediately 
before the AF induction protocol. This will be to enable measurement of serum propafenone levels at the 
time of AF induction testing. Blood will be delivered to the core laboratory for Cardiovascular Translational 
and Clinical Research for DNA extraction and serum/plasma storage. 
• 
Next, repeat TEE recordings of the LV will be performed.  
• 
The AF ablation procedure will be performed as per standard of care by the primary operator and clinical 
team. Dr. Shoemaker and a study nurse will perform the study protocol. 
• 
A standard electrophysiologic (EP) study will be performed at the start of the case after intracardiac 
catheter placement (including a decapolar CS catheter). The standard clinical EP study includes 

 
 
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measurement of AV block cycle length, AV node effective refractory period (ERP), atrial ERP, and 
ventricular block cycle length. Diastolic pacing threshold will be determined, and AERP will be tested at a 
pacing output of 2 times the diastolic threshold at 2 ms (standard of care). Following measurement of these 
conduction intervals, the pacing protocol to test for AF inducibility will be performed as follows:  
• 
Stimulation Protocol #1: 
o A standardized protocol will be used to induce AF or atrial flutter (AFL). 
o This protocol is similar to common clinically used protocols to induce supraventricular 
tachyarrhythmias during performance of clinical EP studies. 
o The LA will be paced from the most distal CS electrode that can consistently capture the atrium. 
The CS catheter will be placed in standard clinical position. 
o 15 beat bursts of 20mA amplitude and pulse width of 2 msec will be used 
o We will wait 10 seconds between bursts and decrement by 10msec for each burst 
o Step 1: starting cycle length will be 250 msec and decrement down to 180 msec or loss of 1:1 atrial 
capture (AERP). If there is no 1:1 capture at 250ms, the starting cycle length will be 10ms greater 
than the coupling interval of the atrial ERP at a drive train of 600 ms. 
o Step 2 will be used if there is no sustained AF/AFL during Step 1, and it will consist of 5 atrial 
pacing bursts of 15 seconds at the lowest cycle length of which 1:1 atrial capture was achieved.  
o The parameters for this AF induction pacing protocol can be programmed into the cardiac stimulator 
system (EP-4 Cardiac Stimulator, St. Jude Medical Inc., St. Paul, MN) and performed automatically. 
The time required to perform Step 1 of the research pacing protocol is ≤ 96 seconds, and 
Step 2 (conditional on step 1 being non-inducible) is ≤ 125 seconds. 
o Sustained AF/AFL will be defined by a duration of >30 seconds. 
o Patients who develop sustained AF/AFL will either: 1) spontaneously convert prior to ablation; 2) 
convert during the ablation procedure (majority of patients); or 3) undergo direct current 
cardioversion (DCCV) at the end of the case. DCCV during AF ablation procedures is common and 
will be performed according to standard clinical practice at the discretion of the attending physician. 
o Some patients will develop AF/AFL during the standard clinical EP study. If it sustains >30 seconds 
it will be counted toward the primary endpoint, and the research AF induction pacing protocol will 
not be performed.  
 
• 
Standard-of-care monitoring following an AF ablation is inpatient 23-hour continuous cardiac telemetry 
observation with specialized cardiac-trained nursing care. Cardiac-trained nurse practioners remain in 
the hospital overnight and communicate with the electrophysiology fellow on call at night for any patient 
care issues. Intravenous access is maintained post-procedure during their hospitalization. 
 
7.0 
Risks 
 
Patients undergoing AF ablation are at risk for complications by nature of the procedure. These risks 
are inherent to the patient population studied here. The risks of obtaining blood samples from existing venous 
lines and determination of serum propafenone levels are minimal. There are risks associated with inducing 
atrial fibrillation and D/C cardioversion, however these are commonplace during AF ablation and add little to 
the risk inherent to this study population. There are risks associated with propafenone which include: new or 
worsened arrhythmias, unmasking Brugada syndrome, new or worsened congestive heart failure, conduction 
disturbances, altered pacemaker thresholds, agranulocytosis, exacerbation of myasthenia gravis, elevated 
ANA titers, and impaired spermatogenesis. Proarrhythmic effects may be more pronounced in patients with 
patients with liver or kidney disease, or patients taking other QT-prolonging drugs or inhibitors of CYP2D6, 
CYP3A4, and CYP1A2 isoenzymes. The majority of these risks are associated with chronic use, and are less 
applicable to the single dose regimen used for this study. Furthermore, the potential arrhythmic adverse effects 
are easily treated in the setting of the EP lab. There may be unknown risks of R- and S- propafenone, although 
these specific enantiomers have been previously used in clinical studies, both orally and as a single IV dose as 
we propose. 
Major side effects of propafenone include bradycardia and proarrhythmia. We will monitor for these side 
effects with continuous cardiac telemetry. Patients are admitted for 23-hour observation following atrial 
fibrillation ablation. Propafenone will no longer be biologically active prior to discharge in the majority of 

 
 
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patients. In a small subset of patients who are poor metabolizers, duration of action may extend to 32 hours, 
however the peak effect will have been observed prior to discharge. At the discretion of the attending cardiac 
electrophysiologist, the decision will be made to withhold discharge in the case of unresolved symptomatic 
bradycardia or ventricular ectopy believed to compromise patient safety. 
One risk of donating samples for genetic research may be the release of information that could link the 
patient to the stored samples and/or the results of the tests run on those samples. The release of this 
information could cause problems with insurance or future employment. We have mechanisms in place to 
protect against such risks.  
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
 
Data and Safety Monitoring Plan 
 
Oversight of the data and safety monitoring plan will be provided by a Data and Safety Monitoring Board 
(DSMB). The DSMB will meet at least twice a year and review data on adverse events, adverse drug reactions, 
data quality, and study recruitment. DSMB reports will be sent to the IRB at least yearly.  
 
, who will serve as Chair, is Professor of Pediatrics and has over 20 years of experience in 
clinical research. The remainder of the DSMB is comprised of 
 (University of 
Maryland), 
 (University of Calgary), 
 (Vanderbilt, Department of Bioethics), and 
 an Associate Professor in the Department of Biostatistics and will serve as the statistical 
member of the DSMB. He is Assistant Director 
 
. He has also served on the DSMB of 8 clinical 
trials since 2004. 
 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others: 
 
Definitions of adverse events: an adverse event (AE) is "any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment". 
 
Adverse events include: 
o Worsening (change in nature, severity or frequency) of conditions present at the onset of the trial 
o Patient / subject deterioration due to the primary illness 
o Intercurrent illnesses 
o Drug interactions 
o Events related or possibly related to concomitant medications 
o Abnormal laboratory values or changes of vital signs, as well as significant shifts from baseline within 
the range of normal, which the Investigator considers clinically significant. 
 
Unexpected Adverse Drug Reaction: an unexpected Adverse Drug Reaction is “an adverse reaction, the 
nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s 
Brochure for an unapproved investigational medicinal product)”. Definitions of serious adverse events or 
serious adverse drug reaction: during clinical investigations, adverse events may occur which, if suspected to 
be drug-related (adverse drug reactions), must be significant enough to lead to important changes in the way 
the medicinal product is developed (e.g., change in dose, population, needed monitoring, consent forms). This 
is particularly true for reactions, which, in their most severe forms, threaten life or function.  
 
A serious adverse event/experience (SAE) or reaction is any untoward medical occurrence that at any dose: 
 
1. results in death 
2. is life-threatening 
3. requires inpatient hospitalization or prolongation of existing hospitalization 
4. results in persistent or significant disability/ incapacity (as per reporter’s opinion) 

 
 
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5. is a congenital anomaly/birth defect 
6. is another medically important condition 
7. The term "life-threatening" in the definition of "serious" refers to an event in which the patient is at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
 
Important medical conditions that may not result in death, be life-threatening, or require hospitalization may be 
considered as SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.  
 
Definition of severity of adverse events: 
 
Mild: 
 
Causing no limitation of usual activities; the subject / patient may experience slight discomfort. 
 
Moderate:  
Causing some limitation of usual activities; the subject / patient may experience annoying 
discomfort. 
 
Severe:  
Causing inability to carry out usual activities; the subject / patient may experience intolerable 
comfort or pain. 
 
Definition of adverse event causality: 
 
The Investigator will determine causality of each adverse event by using the classification criteria: unlikely, 
likely, or not assessable. 
 
Unlikely: 
The AE is considered by the Investigator to be due to a pre-existing condition, a known 
manifestation of the target disease, a recurrent condition, or is likely explained by environmental 
or diagnostic therapeutic factors or was pre-existing and did not deteriorate. 
 
Likely: 
The AE occurred during or after administration of the study treatment or a pre-existing event 
worsened within an appropriate period of time, and at least one of the following criteria is 
applicable:  
o the event could not be explained by the clinical condition or history of the subject, 
environmental or toxic factors, or other diagnostic or therapeutic measure; 
o was an expected ADR associated with study treatment or a class-labeled drug effect; 
o AE subsided or disappeared after withdrawal or dose reduction of study treatment; or 
o AE recurred after re-exposure to study treatment. 
 
Not assessable: There is insufficient or conflicting evidence for classifying the causality of the AE as likely or 
unlikely. Lack of information may apply for this situation. 
 
Note: AEs with causality 'likely' or 'not assessable' are considered to be 'possibly drug-related.' 
 
 
 
Adverse event reporting 
 
Any adverse events (AEs) will be reported to the PI within 72 hours of notification of the event. The PI will 
notify the DSMB of any major adverse events. Any unanticipated problems involving risk to the participants or 
others will be discussed with the PI and DSMB. Non-serious AEs and incidences of noncompliance with the 
protocol will be reported to the IRB at the time of annual review. 
 

 
 
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Serious Adverse Events (SAEs) will be reported according to the following procedure: 
 
The occurrence of serious adverse events will be reported to the Investigator within 24 hours after notification 
of their occurrence. The Investigator will report SAEs to the DSMB and Vanderbilt Institutional Review Board 
within 7 days of the Investigator’s notification of the event. 
 
In an unanticipated event of prolonged side effect, requiring prolongation of hospital stay, patients will be 
retained in the hospital until side effects have resolved. For minor side effects, where inpatient care is deemed 
unnecessary, follow- up will be maintained via phone or as outpatient if necessary. Patient and their families 
will be given the PI’s contact number for reporting any other effects of medication following discharge. 
 
Any newly discovered information which may affect the subject or their caregiver’s decision to continue to 
participate in the study will be passed on to them as soon as possible. This may also result in a change to the 
consent form and review by the IRB. 
 
 
 
9.0 
Study Withdrawal/Discontinuation 
 
Participants may withdraw from the study at any time by informing the study staff verbally or in writing. If an 
individual withdraws their consent, we will withdraw the participant. Contact information for the PI and study 
staff will be made available to the participant upon enrollment in the consent document.  Any remaining 
biological samples and data will be destroyed. Any data or biological samples that have been used for 
research prior to their withdrawal request will not be withdrawn and destroyed. 
A participant may be withdrawn from the study by the PI if any of the following occurs: 
i. A procedural complication occurs prior to completion of the study protocol that requires the AF ablation 
procedure to be aborted, or precludes collection of study data. 
ii. The patient becomes hemodynamically unstable for any other reason that requires the AF ablation 
procedure to be cancelled prior to completion of the study protocol, or precludes the collection of study 
data 
iii. The primary operator determines it is in the patient’s best interest to forego completion of the study 
protocol  
iv. The patient spontaneously converts to AF or atrial tachycardia/flutter prior to completion of study protocol 
 
10.0 
Statistical Considerations 
 
We will test the hypothesis that (R)-propafenone is superior to (S)-propafenone and (S)-propafenone is 
superior to (P)-placebo at suppressing AF in patients undergoing an AF ablation. Our primary analysis will use 
multivariable regression to test whether our primary determinant (R-propafenone versus S-propafenone) and 
(S-propafenone versus placebo) significantly reduces the primary endpoint of inducibility of AF after study drug 
infusion (yes/no). Inducibility of AF will expressed as an ordinal variable based on the stage of the induction 
protocol that AF was induced (Stage 0, Stage 1, Stage 2). Patients who had only AFL induced will not be 
included in the primary analysis, but will be included in a secondary analysis. Adjustment will be made for age, 
sex, and other established AF risk factors. To avoid over-fitting of multivariable regression, a 10:1 ratio for 
degrees of freedom per the less frequent outcome event will be used in our modeling. The sample size of 243 
(108 for R-propafenone, 108 for S-propafenone, and 27 for placebo), was selected to power an exploratory 
pharmacogenomics aims that analyzes common variants at the 4q25 AF risk allele. A blinded interim analysis 
reviewed by the DSMB in March 2019, demonstrated a difference was emerging between the treatment groups 
for the new primary ordinal endpoint with a P-value of 0.075, thus continued enrollment was recommended.  
 
11.0 
Privacy/Confidentiality Issues 

 
 
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The conduct of genetic studies raises specific issues with respect to protection of human subjects. We 
describe here mechanisms in place at Vanderbilt through IRB policy to protect against such risks; these apply 
to all studies described below.  All records are retained on password-protected computers accessible only to 
members of the study team. Computers containing these records are only connected to networks if they 
include appropriate firewalls and security measures. Deidentified records and DNA samples may be shared 
with other investigators who have IRB-approved protocols and who agree to comply with the protections 
provided at this institution. These research materials are transferred only by secure methods. The identity of 
any individuals and their families are not to be revealed in any publication without their written informed 
consent. 
 
12.0 
Follow-up and Record Retention 
 
The expected duration of this study is estimated to be 4 years. The study results will be retained for at least six 
years after the study is completed. At that time, the research information, with the exception of genetic 
information, not already in the medical record will be destroyed. Genetic information will be kept for an 
undetermined period of time for future gene research.