FAST RCT: Prospective Randomized Clinical Trial of Fetal Atrial Flutter & Supraventricular Tachycardia Therapy
Phase: PHASE3
Conditions: Fetal Atrial Flutter Without Hydrops, Fetal Supraventricular Tachycardia Without Hydrops, Fetal Supraventricular Tachycardia With Hydrops
Sponsor: Edgar Jaeggi

 
1 
 
 
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FAST RCT PROTOCOLS  
Prospective Randomized Clinical Trial of Fetal Atrial Flutter & 
Supraventricular Tachycardia Therapy 
 
 
  
 
 
 
 
 
 
 
 
Study Sponsor: 
Edgar Jaeggi, MD, FRCP(C) 
Head, Fetal Cardiac Program 
The Hospital for Sick Children 
555 University Avenue, Toronto, ON, Canada M5G 1X8  
Tel: +1-416-813-6142 ext.2
 
FAST Therapy Trial communication: FAST.trial@sickkids.ca 
Study Funded by: The Canadian Institutes of Health Research (CIHR) 
 

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PROTOCOL AGREEMENT 
I have read the protocol specified below. In my capacity as Qualified or Principal Investigator (QI/PI), my duties 
include ensuring the safety of the study subjects enrolled in Randomized Clinical Trials under my supervision and 
providing the Sponsor Dr. Edgar Jaeggi at The Hospital for Sick Children, Toronto, Canada, with complete and 
timely information, as outlined in the protocol.  Furthermore, on behalf of the study staff and myself, I agree to 
maintain the procedures required to carry out the study in accordance with accepted Good Clinical Practice (GCP) 
principles and to abide by the terms of this protocol. 
REB number(s) at your site:   
 
 
 
 
 
 
 
 
 
Protocol Title:  FAST Therapy Trial  
(indicate which study or studies) 
□ RCT Sub-study A: Fetal Atrial Flutter without Hydrops   
□ RCT Sub-study B: Supraventricular Tachycardia without Hydrops  
□ RCT Sub-study C: Supraventricular Tachycardia with Hydrops 
Protocol Version/Date:   
 
 
 
 
 
 
 
 
 
 
 
Site/Study PI Signature  
 
Date 
 
Name and Title (Print) 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 
E-mail 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
 
AE: Adverse event 
AF: Atrial flutter 
AET: Atrial ectopic tachycardia 
AV: Atrioventricular 
AVRT: AV reentrant tachycardia 
BID: Twice a day 
BP: Blood pressure 
Bpm: Beats per minute 
CRFs: Case report forms 
DSMB: Data & Safety Monitoring Board 
ECG: Electrocardiogram 
ECHO: Echocardiography 
F/M: Fetal/maternal 
HR: Heart rate 
IUD: Intrauterine demise 
NND: Neonatal death 
PJRT: Permanent junctional reciprocating tachycardiaRCT: Randomized Clinical Trial 
REB: Research Ethics Board 
SAE: Serious adverse event 
SAR: Serious adverse reaction 
SUADR: Serious Unexpected Adverse Drug Reaction 
SVA: Supraventricular tachyarrhythmia  
SVT: Supraventricular tachycardia 
TID: Three times a day 
WPW syndrome: Wolff-Parkinson-White syndrome 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1.  
INTRODUCTION ............................................................................................................................................ 6 
2.  
STUDY BACKGROUND AND RATIONALE .............................................................................................. 6 
2.1 
CLINICAL RELEVANCE OF SVA ................................................................................................................... 6 
2.2 
MECHANISMS OF SVA ................................................................................................................................... 7 
2.3 
MANAGEMENT AND OUTCOME OF FETAL SVA ...................................................................................... 7 
2.4 
TRANSPLACENTAL THERAPY OF SVA ...................................................................................................... 8 
2.5 
EFFICACY OF TRANSPLACENTAL THERAPY ........................................................................................... 9 
2.6 
SAFETY OF TRANSPLACENTAL THERAPY ............................................................................................. 11 
3.  
STUDY FEASIBILITY .................................................................................................................................. 12 
3.1 
SURVEYS ........................................................................................................................................................ 12 
3.2 
SAMPLE SIZE CALCULATIONS .................................................................................................................. 13 
4.  
STUDY DESIGN ............................................................................................................................................ 14 
4.1 
TRIAL COMPONENTS ................................................................................................................................... 14 
4.2 
RANDOMIZED TRIAL. .................................................................................................................................. 14 
4.3 
STUDY WITHDRAWAL ................................................................................................................................ 15 
4.4 
PARTICIPANT REPLACEMENT. ................................................................................................................. 15 
4.5 
NON-PARTICIPATION. ................................................................................................................................. 15 
5.  
STUDY SAFETY ............................................................................................................................................ 15 
5.1 
SAFETY PROCEDURES................................................................................................................................. 15 
5.2 
ADVERSE EVENT ASSESSMENT AND DOCUMENTATION ................................................................... 16 
     5.2.1 
ASSESSMENTS OF COMMON PREGNANCY BIRTH AND NEONATAL EVENTS .................................................... 18 
5.3 
ADVERSE EVENT REPORTING ................................................................................................................... 18 
5.4 
EARLY STOPPING RULE. ............................................................................................................................. 19 
6.  
STUDY MANAGEMENT & RESPONSIBILITIES ................................................................................... 19 
6.1  
MEDICAL OVERSIGHT. ............................................................................................................................. 19 
6.2 
TRIAL OVERSIGHT ....................................................................................................................................... 19 
6.3 
DATA MANAGEMENT .................................................................................................................................. 20 
6.4 
DATA & SAFETY MONITORING BOARD (DSMB) .................................................................................... 20 
6.5 
STEERING COMMITTEE MEMBERS .......................................................................................................... 20 
6.6 
NATIONAL COORDINATORS ...................................................................................................................... 20 
7.  
CONDUCT OF THE RANDOMIZED CLINICAL TRIALS ..................................................................... 21 
7.1  
PATIENT IDENTIFICATION ......................................................................................................................... 22 
7.2 
ELIGIBILITY CRITERIA ................................................................................................................................ 22 
7.3 
INFORMED CONSENT (IC) ........................................................................................................................... 23 
7.4 
PATIENT DATA ENTRY ................................................................................................................................ 23 
7.5 
DATA REVIEW ............................................................................................................................................... 24 
7.6 
RANDOMIZATION TO FIRST LINE THERAPY .......................................................................................... 24 

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     7.6.1 
CONCOMITANT MEDICATIONS ......................................................................................................................... 27 
7.7   
STUDY CONDUCT ......................................................................................................................................... 27 
7.8  
PROCEDURES OUTSIDE OF STANDARD CARE ....................................................................................... 28 
7.9   
RCT CENTERS & DURATION ...................................................................................................................... 30 
7.10 
OUTCOME MEASURES................................................................................................................................. 31 
7.11  
STATISTICAL ANALYSES ........................................................................................................................... 32 
7.12  
QUALITY AND ETHICAL STANDARDS ..................................................................................................... 33 
7.13  
AGREEMENTS AND POLICIES .................................................................................................................... 34 
 
 
8  
DISSEMINATION OF RESULTS AND PUBLICATION GUIDELINES ............................................... 35 
9 
REFERENCES ............................................................................................................................................... 36 
 
 
 
 
  
 
 
 
 

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1.  INTRODUCTION 
Although fetal supraventricular tachyarrhythmias (SVAs), including atrial flutter (AF) and other forms of 
supraventricular tachycardia (SVT), are the most common causes of intended in-utero fetal therapy, none of the 
drugs used has ever been evaluated for their effects on the mother and her child in a Randomized Clinical Trial 
(RCT). In the absence of such evidence, there is no consensus for the optimal management. The Fetal Atrial 
Flutter and Supraventricular Tachycardia (FAST) Therapy Trial is a prospective multi-centered trial that 
addresses this knowledge gap to guide future fetal SVA therapy to the best of care.  
Study components of the FAST Therapy Trial include:  
 Three prospective RCT sub-studies (FAST RCT) to determine the efficacy and safety of specific 
transplacental drug regimens in suppressing fetal AF without hydrops, SVT without hydrops, and SVT with 
hydrops. Additional information on the RCT sub-studies is available at ClinicalTrials.gov under listing 
#NCT02624765. Participation in the regulated FAST RCTs is currently restricted to pre-selected centers.   
 
A prospective observational cohort study (FAST Registry) is a non-regulated Registry which seeks to establish 
an international database of fetal SVA management done to date, to be used to publish information on the results 
of current prenatal care and to evaluate the need for additional FAST RCTs. Participation in FAST Registry 
requires site REB approval and an executed legal contract with the Hospital for Sick Children, Toronto (REB 
Number# 1000048953).  
  
This protocol applies to centers that are participating in the RCT sub-studies. 
The primary outcome of the FAST RCT  will be the proportion of term deliveries of live-born children with a 
normal cardiac rhythm. Term delivery is defined as birth 37 0/7 weeks gestation or later.3, 4 Secondary outcomes 
will determine the efficacy of 1st line, 2nd line, 3rd line, and maintenance drug therapy in controlling the different 
arrhythmias prior to birth and patient safety. We expect faster cardioversion to be significantly associated with 
higher rates of normal term deliveries and less perinatal mortality, morbidity and resource utilization due to 
shorter hospitalization.  
 
2.  STUDY BACKGROUND AND RATIONALE  
2.1 CLINICAL RELEVANCE OF SVA. SVA is the most common cause of fetal tachycardia ≥180 bpm, affecting 
1/4,000 pregnancies. Despite its relative rarity, it is a leading cause of fetal heart failure, prematurity and 
perinatal death. The development of fetal hydrops (defined by >1 of these symptoms: abdominal, pleural, 
pericardial effusion(s); skin edema) is associated with perinatal mortality as high as 35%. The risk of hydrops 
increases if SVA presents at a younger gestational age and is rapid and enduring, but even intermittent SVA may 

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have serious consequences.5, 6 In the largest retrospective study to date on fetal SVA by Jaeggi et al, 40% of 114 
fetuses with SVT presented with hydrops, which was associated with a perinatal mortality rate of 21%.1 In 
another study by Simpson et al, fetal hydrops occurred in 41% of 127 SVA cases and was associated with 27% 
mortality.5 In the absence of fetal hydrops, the risk of SVA-related perinatal mortality is much lower (0%-4%).1, 5  
2.2 MECHANISMS OF SVA. The main mechanisms of fetal SVA, AF and SVT, may be distinguished by 
echocardiography.7, 8 Their prenatal differentiation is clinically relevant since AF is associated with a lower 
conversion rate to sinus rhythm in response to antiarrhythmic drug therapy compared with SVT.1 AF is sustained 
by a circular macro-reentrant pathway within the atrial wall and the AV node is not part of the reentry circuit.9 
Typical atrial rates range between 400 and 500 bpm, which is most commonly associated with 2:1 AV conduction 
and ventricular rates between 200-250 bpm. The atrial rate in SVT is almost always <300 bpm. Fetal SVT itself is 
produced by 3 main mechanisms: 1) AV reentrant tachycardia (AVRT), involving the AV node for antegrade 
(AV) conduction and a fast retrograde (VA) conducting accessory pathway; 2) permanent junctional reciprocating 
tachycardia (PJRT), like AVRT but with slow retrograde pathway conduction; and 3) atrial ectopic tachycardia 
(AET) due to an atrial focus with enhanced automaticity. The differentiation of AVRT, PJRT or AET by fetal 
echocardiography can be difficult and will not be required for the RCT since there is no evidence that it affects the 
result of therapy. In addition, AVRT (60%) and AF (30%) account for 90% of all fetal SVA cases.1 Rare cases 
with SVT and AF will be classified in FAST according to the main mechanism at the 1st exam.9  
2.3 MANAGEMENT AND OUTCOME OF FETAL SVA. Management options upon a new diagnosis of fetal SVA 
include observation, drug therapy, and delivery with postnatal cardioversion. Care decisions are largely influenced 
by SVA characteristics, gestational age, fetal-maternal health, and willingness of the mother to undergo treatment. 
Close observation without drug therapy is usually a safe approach for the fetus with infrequent, brief SVA 
episodes, as heart failure will rarely develop. Conversely, fetuses with incessant SVA tend to develop fetal 
hydrops if left in tachycardia. Prior to 37 weeks, transplacental pharmacological treatment to obtain a normal 
rhythm is the preferred option because the hazard associated with preterm delivery outweighs the risks of drug 
therapy. After 37 0/7 weeks, primary delivery by caesarean section is often elected. Cardioversion prior to birth 
will also facilitate vaginal delivery by allowing the interpretation of the fetal heart rate tracings during labor. In 
the study by Jaeggi1, 15% of mothers did not receive prenatal treatment because the arrhythmia was considered 
insignificant, 15% were immediately delivered for postnatal cardioversion, and 70% received transplacental drug 
therapy. Still, preterm delivery was a frequent outcome of treated cases (37%) due to failure of the elected drug to 
rapidly control the fetal SVA. Newborns with SVT typically receive antiarrhythmic drug therapy during the 1st 
year, while AF is expected to not recur.9    
Optimizing the management to improve outcomes of fetal SVA is a major research focus of the FAST Therapy 
Trial. Unnecessary interventions and complications could be prevented with the primary use of the most efficient 
therapy for fetal SVA. Based on published data, the preterm birth rate should be no higher than 7.6%.10, 11 With an 
incidence of 37% preterm deliveries in Jaeggi’s study,1 fetal SVA was associated with 5-fold increased odds of 
prematurity. Preterm infants are at substantially greater risks for mortality and morbidity than term infants due to 
immaturity-related complications, including respiratory distress syndromes (7.5 fold increased risk e.g. at 37 vs. 
>38 weeks).12 The neonatal need of intensive care and length of hospital stay are inversely related to the 

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gestational age at birth.11, 13 Neonatal mortality in babies born between 34-38 weeks is 4.6 times higher than in 
term infants.14 In addition, compared with term babies, delivery <38 weeks is associated with poorer 
developmental and educational outcomes, and increased burden of later disease.11, 15, 16 Finally, delivery by 
caesarean section is associated with a substantial list of maternal risks, with correlations that typically favor 
vaginal delivery, including shorter hospital stays, less maternal morbidity, lower costs, and lower risks for adverse 
obstetric and perinatal outcomes for next births.11, 17  
2.4 TRANSPLACENTAL THERAPY OF SVA. The rationale to offer transplacental drug therapy to mothers with fetal 
SVA is to achieve rapid and lasting cardioversion, to prevent or treat fetal heart failure, and to allow the 
pregnancy to continue to term with the delivery of a healthy child. Transplacental fetal therapy generally occurs 
with one of three 1st line agents, digoxin, flecainide, and sotalol, which all have been used for decades to treat 
fetal SVA. Amiodarone or direct fetal drug administration are mainly reserved for therapy-resistant SVA because 
of increased risks of maternal and fetal adverse events (AEs).5-9, 18-31  Detailed descriptions of drug actions and 
possible AEs related to the use of the study drugs are provided in the Monographs. In brief: 
 DIGOXIN actions include parasympathetic slowing of sinus node and prolongation of the AV nodal 
refractoriness. In the absence of hydrops, oral digoxin is well absorbed and transferred to the fetus, to reach 
fetal serum concentrations that are close to those in maternal serum (F/M ratio 0.8-1) within 3-5 days.2 No 
serious AEs (SAEs) have been reported, but nausea, anorexia, headache, visual disturbances and dizziness are 
among the more common patient complaints.1   
 
 FLECAINIDE inhibits Na+ channels, slowing conduction and increasing refractoriness of all cardiac tissues. 
Flecainide is well-absorbed and transferred to the fetus to reach therapeutic levels within 3 days (F/M ratio 
0.7-0.9).2, 32 At maternal serum concentrations >1 mcg/ml, the QRS interval may prolong and the risk of 
proarrhythmia increase. Infrequent maternal AEs include blurred vision, nausea, constipation, dizziness, and 
headache. Maternal SAEs have not been reported but there is one case of unexplained in-utero demise of a 
non-hydropic fetus 23 years ago.6 
 
 SOTALOL is both an iKr channel and β-blocker, with β-blockade as the main effect at doses <160 mg/day. The 
combined effects decrease heart rate, and prolong action potential duration and tissue refractoriness throughout 
the heart.33, 34 Sotalol is well absorbed and transferred to reach a fetal steady state level similar to maternal 
plasma level (F/M ratio 0.7-2.1).2, 22 The agent is usually well-tolerated and maternal SAEs have not been 
reported. Maternal sotalol up to 480 mg/day did not cause significant prolongation of neonatal QTc.35 
Symptoms related to β-blockade may include fetal or maternal bradycardia.1 There is a single case of 
unexplained fetal death in the absence of fetal hydrops in the literature.21  
In summary, antiarrhythmics act on one or several ion channels and/or the autonomous system. Drug-specific 
differences in actions and pharmacokinetics likely predetermine the potential of a compound in terminating and, 
once achieved, in suppressing SVA recurrence.36 AVRT involves myocardium, the AV node and accessory 
pathway(s) in the reentrant circuit. Alteration of the conduction and refractoriness properties of any of these 
tissues may terminate AVRT. Digoxin prolongs AV nodal refractoriness. If the prolongation is sufficient, reentry 
will terminate because the AV node becomes refractory to premature depolarization. Flecainide delays the 

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myocardial conduction and disproportionally prolongs refractoriness of the myocardium and the conduction 
system at faster rates. Sotalol delays AV nodal conduction and prolongs the refractory period to electrical 
stimulation of the myocardial and conduction tissues. Suppression of arrhythmias confined to atrial tissue (AET; 
AF) is possible by flecainide and sotalol that directly act on atrial cells. Digoxin has probably no such direct 
effects on atrial cells but slows tachycardia rates, owing to improved ventricular filling with lower atrial pressure 
and distension. The hemodynamic changes may alter electrical tissue properties and indirectly suppress AF.37 
2.5 EFFICACY OF TRANSPLACENTAL THERAPY.  
PROSPECTIVE STUDY. There are no other prospective randomized studies of fetal SVA therapy to date.  
RETROSPECTIVE STUDIES. Retrospective studies report inconsistent success rates for all 1st line agents in 
treating fetal SVA.2 In studies (total n=226) using oral digoxin monotherapy, in-utero cardioversion has been 
reported in 50% to 100% of SVA without hydrops, but in <20% of SVA with hydrops.5, 8, 9, 18, 24, 30 Flecainide 
(n=70) has resulted in sinus rhythm in 58% to 100% of SVA cases without hydrops and in 43% to 58% of those 
with hydrops.6, 18, 24, 26, 29, 31 Sotalol (n=56) has been successful in 40% to 100% of SVA without hydrops, and in 
50% with hydrops.21, 22, 29 While the studies confirm that there is no single medication that can convert all fetal 
SVAs to a normal rhythm, direct comparisons of study results is impossible as study cohorts varied in disease 
severities, definitions of treatment success, drug doses, schedules, and many other factors. Data on the impact of 
the same agents as 2nd line monotherapy or in combination to treat therapy-resistant SVA is largely unavailable.2  
DRUG COMPARISONS. The only study to directly compare transplacental drug therapies by Jaeggi et al., an 
initiator of the FAST Therapy Trial, represented the experience of 3 sites, each using a different 1st line agent.1 An 
adverse primary outcome, defined as a) preterm delivery, b) perinatal death, or c) persistent SVA to birth, was 
documented in 45% of 75 treated SVT cases (outcome a) 32%; b) 8%; c) 5%) and 58% of 36 treated AF cases (a) 
50%; b) 3%; c) 6%), and was mainly related to incomplete SVA control at the time of the event. However, Jaeggi’s 
study also demonstrated that the fetal response to treatment independently depended on the SVA pattern, fetal 
state and the choice of 1st line therapy. AF [Fig. 1] and fetal hydrops [Fig. 2] were independently associated with  
Fig. 1. Freedom from termination of fetal 
SVT vs. AF despite drug treatment (n=111). 
AF responded more slowly to drug therapy than 
SVT (HR=2; p=0.005). Cardioversion at 5 and 
10 days was achieved in 50% and 63% of 
fetuses with SVT and in 25% and 41% of cases 
with AF. 
Fig. 2. Freedom from termination of fetal SVT 
with and without hydrops (n=75). Treatment 
failure was also more likely if SVT was associated 
with fetal hydrops (HR=1.8; p=0.04) at the time of 
diagnosis. It took more than twice as long (9 vs. 4 
days) for conversion of 50% of SVT cases to a 
normal rhythm if fetuses were hydropic. 21% of the 
hydropic cases died. 

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lower cardioversion rates. On the other hand, 1st line monotherapy with sotalol resulted in faster/higher AF 
termination rates [Fig. 3] while flecainide or digoxin was superior in terminating SVT [Fig. 4] and in lowering 
tachycardia rates if SVA persisted [Fig. 5].  None of the agents as 2nd line therapy was associated with a greater 
rate of SVA termination although sotalol tended to be superior for AF. Once fetal SVA was converted to sinus 
rhythm, chronic drug therapy to birth with the drug(s) that successfully terminated the SVA was used to prevent 
recurrences. Recurrence of SVT and AF was documented in 8% and 15% of cases during the first month of 
maintenance treatment.1 
 
 
 
 
 
Fig. 4. Freedom from termination of fetal SVT 
(n=75): For patients with SVT, in multivariate models 
adjusted for hydrops and SVT pattern, the use of 
flecainide (HR: 2.9; p=0.01) or digoxin (HR: 2.1; 
p=0.02) as 1st therapy were associated with increased 
likelihood of SVT termination compared to sotalol. The 
median time to conversion of 50% of cases was 3 days 
with digoxin, 4 days with flecainide but 12 days with 
sotalol. 
Fig. 3. Freedom from termination of fetal AF 
(n=36): For patients with AF, in multivariate models 
adjusted for arrhythmia pattern, 1st line sotalol was 
associated with a greater likelihood of AF termination 
compared with digoxin (HR: 5.4; p=0.05) or flecainide 
(HR: 7.4; p=0.03). Time to conversion of 50% was 12 
days with sotalol, but not achieved with the other drugs 
before delivery. 
Fig. 5. Effects of 1st line treatment on tachycardia 
rates. When incessant SVT (n=23) or AF (n=22) 
persisted to day 5 of treatment, ventricular rates were 
lowered more with flecainide and digoxin than with 
sotalol (p<0.001). This suggests that flecainide and 
digoxin are similarly effective in reducing the 
tachycardia to better tolerated rates while sotalol has no 
or only modest heart rate slowing effects. 

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In summary, our previous study results support the concept that successful transplacental drug therapy and the 
outcome of the pregnancy significantly depend on any of these three variables: 
 The underlying SVA mechanism (AF vs. SVT)  
 The fetal state (fetal hydrops vs. non-hydrops), and 
 The primary choice of antiarrhythmic therapy 
The optimal choice of therapy at the time of a new SVA diagnosis is of critical importance as it is the only 
variable that may be directly influenced by the treating physician’s decisions. 
While the study by Jaeggi provided new data on the potentials and limitations of prenatal drug therapy and in 
selecting agents for the FAST Therapy Trial, several limitations inherent to the retrospective study design may 
limit the validity of some study findings. This includes: a) relatively small case numbers due to the relative rarity 
of SVA (111 treated cases; 3 therapy arms); b) differences in disease severity among patient cohorts; and c) 
insufficient data to address AEs and 2nd line therapy. One important study conclusion nonetheless was that 1st line 
therapy initiation with only one antiarrhythmic is probably safe unless fetal heart failure is present (21% perinatal 
mortality), leading to this proposal to start with single drug therapy in the absence of hydrops (RCT Sub-study A 
and B) and dual therapy with hydrops (RCT Sub-study C). This approach is also supported by latest clinical data 
that showed no mortality with the primary use of digoxin and flecainide in fetal SVT with hydrops.38 
2.6 SAFETY OF TRANSPLACENTAL THERAPY There is extensive retrospective data on the safe use of digoxin, 
sotalol, and flecainide, either alone or when used in combinations for this indication, with the limitation that AEs 
were most likely inconsistently documented and thus underreported in retrospective studies. Although minor 
drug-related AEs are not infrequent patient complaints based on our own retrospective experience1 and drug 
monographs, life-threatening AEs owing to the use of fetal antiarrhythmic drug therapy in predominantly healthy 
mothers have not been reported.2, 36 However, virtually all antiarrhythmic agents may have the potential to 
provoke new or to exacerbate existing arrhythmias. This risk increases with toxic drug levels, maternal heart 
disease, ventricular arrhythmia, and hypokalemia.39-41 Previously reported mortality rates of treated fetuses with 
SVA without hydrops were between 0% and 5%, whereas about 20% of fetuses with SVA with hydrops had died, 
usually due to treatment-resistant SVA.2, 5 In our large experience, we never observed unexpected SAEs, 
irrespective whether single or multiple drug therapy was used.1 
To minimize risks of SAEs a) only mothers without serious health and pregnancy concerns other than fetal SVA 
are eligible for participation in the RCTs (see Section 7.2); b) the primary physician and participant both are 
informed about the assigned drug therapy from the time of randomization to study end (open label trial); c) drug 
dosages will be used that are considered to be safe and effective (see 7.6), thus avoiding toxic levels (digoxin) and 
excessive QTc prolongation >0.5 (sotalol); and d) initiation of therapy is recommended in-hospital to monitor 
maternal/fetal heart rates and wellbeing, followed by serial outpatient encounter once arrhythmia control is 
achieved (see 7.7).   
 
 
 

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3.  
STUDY FEASIBILITY 
3.1 SURVEYS. To determine feasibility of the FAST Therapy Trial, we conducted two large surveys.  
In Survey I, of which 87 tertiary maternal-fetal (47%) and fetal cardiology (61%) sites replied, we determined:   
a) caregivers responsible for the management of fetal SVA at each site; b) average numbers of treated cases/year 
and site; c) the willingness to participate in a prospective RCT (94% support) and/or a prospective registry (90% 
support); d) current 1st line drug choices [Fig. 6] and e) drug preferences for hypothetical RCTs [Fig. 7]. 
In Survey II, we obtained (89 potential study sites, 23 countries): a) numbers of treated SVA cases based on 
institutional reviews of 2011-2012 [Fig. 8], b) expected maternal consent/recruitment rates at each center (mean: 
81%), and assessed c) participation rates in the AF/no hydrops RCT (n=75; 86%), SVT/no hydrops RCT (n=76; 
87%), SVT/hydrops RCT (n=78; 90%), and/or the registry (n=69; 79%). Of 87 centers willing to participate in at 
least one RCT, three RCTs were elected by 66 (76%), 2 RCTs by 12 (14%), and 1 RCT by 7 (8%) centers. We 
also obtained >80 letters of collaboration from major fetal-maternal centers that wish to participate in the FAST 
Therapy Trial, incl. 10 Canadian sites. All study goals are achievable within <5 years with <50 average sized 
centers. 
Fig. 6. Current 1st line drug choices (Survey I; n=87)   
Digoxin was most commonly quoted as 1st choice agent to 
treat SVT and AF without hydrops. If there was fetal 
hydrops, flecainide for SVT and sotalol for AF were 
slightly preferred over digoxin. Less than 20% currently 
use 1st line therapy with more than one agent to treat 
SVA/hydrops despite the slow cardioversion rates to drug 
monotherapy (Fig. 2) and the high risk of adverse 
outcome. 
 
 
 
 
Fig. 7. Elected 1st line drug comparisons in potential 2-
arms RCTs (Survey I; n=81)  
 SVT without hydrops: digoxin vs. flecainide 
 AF without hydrops: digoxin vs. sotalol 
 SVT or AF with hydrops: digoxin plus flecainide vs.     
    digoxin plus sotalol.  
Potential 2-arm comparisons selected in the survey are in 
agreement with the study results of Jaeggi et al1, 
eliminating the agent that was associated with the weakest 
cardioversion rate for SVT (sotalol) and AF (flecainide) 
in the comparisons (Fig. 3-4) 
 

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3.2 SAMPLE SIZE CALCULATIONS. Based on our survey results and the retrospective study by Jaeggi et al, we 
expect 70% of SVA cases to be SVT (50% no hydrops; 20% hydrops) and 30% AF (25% no hydrops; 5% 
hydrops).1 Survey II suggests that an average of 2.3 SVT/no hydrops, 1.21 AF/no hydrops and 1.03 treated 
SVT/hydrops cases/year/center will be eligible for RCT enrolment, with average consent rates of 81%. Sample 
size calculation for 2-arm treatment comparisons was performed using PASS (Power and Sample Size) v12 
(NCSS, LLC, Kaysville, Utah, USA). To calculate sample size requirements for this study we expected the 
proportion of patients with normal primary outcome to be 55% with SVT without hydrops, 30% with AF without 
hydrops, and 30% of SVT with hydrops with the inferior treatment arm (i.e. the null hypothesis). We aim to detect 
an improvement of +20% in the proportion of patients with a normal primary outcome with the superior RCT arm 
(i.e. 75% for SVT without hydrops; 50% for AF without hydrops and SVT with hydrops; i.e. the alternative 
hypothesis). The test statistic used is the two-sided Likelihood Ratio test which is equivalent to the Wald chi-
square for logistic regression models which will be used to analyze our primary outcome. The significance level 
of the test of significance was targeted at 0.05, with a power of 80%. Assuming those metrics, we will need 550 
RCT participants, with a minimum number of patients in each of the three RCTs of: 
AF without hydrops (RCT A):  186 (93/arm) treated cases ← 232 approached cases with 80% consent rate 
SVT without hydrops (RCT B): 178 (89/arm) treated cases ← 222 approached cases with 80% consent rate 
SVT with hydrops (RCT C):    186 (93/arm) treated cases ← 232 approached cases with 80% consent rate 
 
With 50 average sized sites, we anticipate 225 treated patients/year (mean: 4.5) to be approached during the study 
period which should be sufficient to recruit the required number of patients with SVT without hydrops (RCT B) in 
1.9 years, AF without hydrops (RCT A) in 3.8 years and SVT without hydrops (RCT C) in 4.4 years. In contrast, 
we do not expect sufficient cases for a separate AF with hydrops RCT (0.27 cases/year and site). Study completion 
<5 years would require a minimum of 20 average sized centers in RCT B (4.7 years), 40 centers in RCT A (4.7 
years), and 45 centers in RCT C (4.9 years). The site investigator will be responsible for recruiting participants 
and conducting the study at the participating center. There is no data on consent rates for a prospective fetal SVA 
trial. Survey II suggests average consent rates of 81%. Consent rates are available from other fetal-maternal 
RCTs. Despite the more invasive nature of these studies, consent was obtained in 71.4% of eligible mothers to 
study the impact of serial amnioreduction vs. selective fetoscopic laser photocoagulation to treat fetal twin-twin 
Fig. 8. Average number of treated cases per year of 
centers that plan to participate in at least one RCT 
(Survey II; n=87/89 centers). Data represent the 30 
largest centers (blue), the 50 largest centers (red) and 
all participating centers (black) in the SVT RCT 
(76/87), AF RCT (75/87) and SVT/hydrops RCT 
(78/87). SVT, AF and SVT/hydrops account for 50%, 
25% and 20% of SVA cases. Sample size calculations 
(2.11) are based on data of “qualified centers.” No 
AF/hydrops RCT is planned (5% of SVA cases). 

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transfusion syndrome in a US-based study;42 in 86% of mothers to compare prenatal with postnatal repair of fetal 
myelomengocele;43 and in 86% of mothers to study the impact of fetal endoscopic tracheal occlusion with 
standard postnatal care for congenital diaphragmatic hernia.44 As we will not compare experimental but standard 
therapy, we would expect equal or higher maternal consent rates.      
IN SUMMARY, most sites contacted in our Surveys agreed that there is a need for prospective studies, and would be 
willing to participate in sufficient numbers to complete all components of the FAST Therapy Trial with <5 years. 
Other research collaborations already exist with and among many potential study sites (e.g. TTTS laser 
interventions; PIAF study; Fetal Intervention Registries; retrospective multi-institutional collaborations (SVA, 
CHB, Ebstein, etc.). Potential 2-arm comparisons [Fig. 7] are in agreement with our previous study findings1 that 
suggested better results with 1st line flecainide or digoxin for SVT [Fig. 4] and with sotalol for AF [Fig. 3]. Health 
Canada has issued letters of no objection for the RCTs.  
 
4.  STUDY DESIGN 
4.1 TRIAL COMPONENTS. The FAST Therapy Trial is a prospective trial of patients with a new diagnosis of fetal 
SVA. The study aims to compare the impact of different perinatal treatment strategies from the time of SVA 
diagnosis to 30 days after birth or death. Research components as shown in Figure 9 include: 
 
 
 
 
 
 
 
4.2 RANDOMIZED TRIAL. (See 7 for conduct details). The FAST RCT Sub-studies A, B and C are open label 
phase III trials of standard 1st line therapy, which either is started as monotherapy (no hydrops) or as dual therapy 
(hydrops). To participate as a patient in an RCT sub-study, all maternal and fetal inclusion criteria and none of the 
exclusion criteria must be fulfilled (see below). Differentiation between “AF vs. SVT” and “hydrops vs. non-
hydrops” is required for randomization into the appropriate sub-study (Fig. 9). The site investigator will be 
responsible for diagnosis, eligibility assessment and randomization in the appropriate RCT arm. Each participant 
will be assigned a unique study identifier to protect privacy and to be used for communication with the site 
investigator. The Echo Core Lab at SickKids will review as soon as possible, but not prior to randomization or 
treatment initiation, all uploaded baseline data and will ensure diagnostic accuracy by reviewing de-identified 
 Three prospective RCT sub-studies to determine the 
efficacy and safety of specific transplacental drug 
regimens in suppressing: A) fetal AF without hydrops 
(RCT A); B) SVT without hydrops (RCT B); and C) 
SVT with hydrops (RCT C). 
  
A prospective observational cohort study (FAST Registry) 
to document the outcome of patients because randomization 
is not offered or not possible, non-study 1st line medication 
is used, or observation without treatment is elected (REB 
Number# 1000048953). 
 

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baseline fetal SVA tracings and abdomen/chest images, as well as ECG and clinical data of each participant. Once 
started on 1st line therapy, the treating physician will at any time be free to modify and/or change treatment for the 
remainder of gestation. Patient care maps for the different treatment arms are provided that may help and be used 
to guide most perinatal management decisions to birth. Maternal questionnaire and, if applicable, case report 
forms (CRFs) will be used to assess for maternal and fetal AEs and specified outcomes (5.2.1) at each participant 
encounter.  
With 50 centers and 80% consent rates per RCT, actual study periods are expected to take 1.9 years (RCT B: SVT 
without hydrops), 3.8 years (RCT A: AF without hydrops), and 4.4 years (RCT C: SVT with hydrops), 
respectively. This will allow postnatal follow-up to a minimum of 30 days after birth of all study participants. 
Recruitment for the RCT sub-studies will be competitive and once a predetermined number of participants are 
enrolled, new patients will be considered for the registry only. 
4.3 REGISTRY. Registry data will be used to determine the outcome of the non-randomized (treated), and 
untreated SVA study population to examine the impact and outcome of alternative treatment approaches. This 
includes fetal AF with hydrops, which is not studied by a separate RCT due to the rarity of the association. 
4.4 STUDY WITHDRAWAL. A subject is free to withdraw from participation in the trial at any time, for any 
reason, specified or unspecified, and without prejudice. The reason for the subject’s withdrawal from the study (if 
given) will be documented in the Study Completion/Exit Form.  If the subject withdraws, data that has already 
been collected up to that point in time will be kept (as indicated in the patient informed consent).  
4.5 PARTICIPANT REPLACEMENT. Study participants withdrawing from the trial will be replaced 1:1 to obtain 
the target number of evaluable participants per RCT arm.  
4.6 NONPARTICIPATION. If an eligible patient has been approached for the RCT but elects to not participate the 
screening information should still be documented in REDCap, including the patient’s decision to not participate. 
Collection of basic screening information by the sponsor is important as it will allow an analysis of patient 
willingness to participate, of excluded cases and an estimation of the number of total SVA cases. Moreover, 
information on the rate of non-participation will be essential for future publications.  
5.  STUDY SAFETY 
5.1 SAFETY PROCEDURES. The FAST RCTs will assess standard prenatal treatment that has been used for 
decades because the fetus suffers from a life-threatening yet treatable cardiac condition and other management 
options including direct treatment or premature delivery are considered more invasive, more harmful, or both. 
Perinatal demise is not an unusual outcome of hydropic fetuses with SVA, irrespective of the choice of treatment.  
Health Canada, FDA (US) and MHRA (UK) have approved all three RCT sub-studies. There is extensive data on 
the safe use of the study agents for this indication. Minor drug-related maternal AEs are not infrequent 
[monographs],1 but maternal SAEs owing to fetal antiarrhythmic drug therapy have not been reported.2, 36 
However, virtually all antiarrhythmics have proarrhythmic potentials to provoke new or exacerbate existing 

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arrhythmias. This risk increases with toxic drug levels, maternal heart disease, preexisting ventricular arrhythmia, 
and hypokalemia.  
Procedures for study participants to minimize the risk of SAEs include:  
 
only mothers without serious health and pregnancy concerns other than fetal SVA are eligible for 
participation in RCT sub-studies (see 7);  
 
the primary physician and participant both are informed about the assigned drug therapy from the time of 
randomization to study end (open label trial);  
 
drug dosages will be used that are considered to be safe and effective, thus avoiding toxic levels (digoxin) 
and excessive QTc prolongation >0.5 (sotalol); d) concomitant medication (7.6.2) that may interact with a 
study drug are not to be used or, if no alternative exists, used with caution during the trial; and  
 
initiation of therapy is recommended in-hospital to monitor maternal/fetal heart rates and wellbeing, 
followed by serial outpatient encounter once arrhythmia control is achieved.   
5.2 ADVERSE EVENT ASSESSMENT AND DOCUMENTATION. A main objective of FAST RCTs is patient safety. 
This is accomplished by the systematic recording of AEs.  
Adverse Event (AE): is defined as any untoward medical occurrence of a symptom that may or may not 
have a causal relationship with the treatment used. Examples include a rash noted during a physical exam, 
abnormal lab results, or a change from a baseline condition.  
Failure of the drug does not constitute an AE. Sources of information will include observation (physical exam; 
ECG; echo; lab result), patient statement, patient charts, and serial assessment at each encounter by questionnaire 
for changes from baseline (↑ severity/frequency of pre-existing symptom(s)) or new AEs).  
It will be the responsibility of the primary physician to identify, and to classify the seriousness, severity, causality 
and expectedness of an AE as follows:  
a) Assessment if event qualifies as serious: 
Serious Adverse Event (SAE): A SAE is any untoward medical occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity  
 
Results in congenital abnormalities or birth defect 
Other events may be treated as SAEs if the Principal Investigator considers it to be an important medical event 
that may jeopardize the participant or require intervention to prevent one of the other outcomes listed above. 
 

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b) Severity assessment: 
Mild 
Events are considered MILD if signs/symptoms are mild, clinical relevance is marginal, 
laboratory findings are asymptomatic and no specific medical intervention is required.  
Moderate 
Events are considered MODERATE if they require minimal, local, or non-invasive 
intervention only. 
Severe 
Events are considered SEVERE if they interrupt the participant’s normal daily activities 
and generally require systemic drug therapy or other treatment; they are usually 
incapacitating. 
 
c) Causality assessment: 
Definitely related 
There is a certainty that the event is related to the study drug(s). 
Probably related 
There is high likelihood that the event is related to the study drug(s).  
Possibly related 
There is a likelihood that the study drug(s) is the cause of the event, but other causes 
cannot be ruled out.  
Unlikely related 
It is not likely that the event is related to the study drug(s), and other more likely causes 
are present. 
Unrelated  
Evidence exists that the event is related to something other than a study drug.  
 
d) Expectedness assessment: 
An event is considered unexpected if the nature, severity or frequency is not consistent with the risk 
information listed in the Product Monograph. 
Pregnancy- and treatment-related AEs will be documented by the site investigator. Prior to the start of drug 
therapy (pretreatment forms), a thorough medical history should be obtained to document all preexisting maternal 
symptoms, complaints and health concerns. As many pregnancy related symptoms are intermittent in nature, a 
thorough history including variations in severity and frequency should be taken. AEs should be reassessed at each 
participant encounter. If signs or symptoms remain similar to baseline or are less in severity, frequency, or both, 
they will be considered within the usual range and do not need to be documented as AEs. In contrast, signs and 
symptoms that are new or, if preexisting, are more frequent/severe, need to be documented, assessed for severity 
and causality, and followed up until resolution.  
 
 

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5.2.1 
ASSESSMENTS OF COMMON PREGNANCY, BIRTH AND NEONATAL EVENTS  
The following common pregnancy, delivery, and neonatal events should be recorded in source documents (clinic 
notes or CRFs) if they occur and are only requested be recorded on AE worksheets if the PI or MD delegate feel 
that the event may be drug related and/or determine that a full assessment is required.
Prenatal Maternal Events: 
 
Accidents or injuries 
 
Anaemia 
 
Back pain 
 
Bacterial or viral infections  
 
Contractions 
 
Diabetes and associated complications  
 
Gestational hypertension/ worsening of 
hypertension 
 
Heartburn 
 
Hemorrhoids; varicosis 
 
Hospitalization for obstetrical reasons 
 
Hypoglycemia requiring treatment  
 
Leg muscle cramps 
 
Ligament pail 
 
Pre-eclampsia and eclampsia 
 
Vaginal bleeding or discharge 
 
 
Infant Events:  
 
Birth injury 
 
Neonatal aspiration, hypoxia 
 
Respiratory distress of newborn 
 
Hyperbilrubinemia 
 
Neonatal hypoglycemia 
 
Neonatal Infection 
 
Hospitilization for observation after birth 
 
Hypoglycemia requiring treatment 
 
Genetic disorder 
 
Intrapartum and Postpartum Maternal Events  
 
Hospitalization for delivery 
 
Anesthesia-related complications  
 
Cesarean delivery  
 
Hysterectomy 
 
Postpartum depression 
 
Postpartum hemorrhage 
 
Infections 
 
Ventilation 
 
Birth related complications 
 
5.3 ADVERSE EVENT REPORTING. Completed AE worksheets of all documented events will be captured on 
REDCap. All SAEs irrespective of their relatedness to the therapy or study procedures must be reported to the 
Sponsor. The site investigator must pursue any AE and if possible obtain information adequate both to determine 
the outcome and assess the relatedness to treatment so it can be determined by the PI and Sponsor whether it 
meets the criteria of a SUADR. 
Serious Unexpected Adverse Drug Reaction (SUADR): All noxious and unintended responses to an 
investigational product related to any dose which is serious and unexpected.  
 
 

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REPORTING PROCEDURES 
Any SAE (irrespective of relatedness to study procedures) must be notified to the study Sponsor (SickKids) 
immediately upon the investigator becoming aware of the event (see guidelines below).  
Completed SAE reporting forms are to be sent to: 
 
Sponsor (SickKids)  via fax +1-416-813-2148 or E-mailed to Fast.trial@sickkids.ca  
SERIOUS ADVERSE EVENTS 
(Recorded by site investigator) 
REPORTING BY SITES TO 
SPONSOR  
REPORTING BY SITES TO LOCAL 
REB 
Unexpected, possibly, probably or 
definitely related to medication or study 
procedures 
 Notification within 24 hours 
 Full report to follow as requested by  
    the Sponsor  
 According to Institutional guidelines  
Expected, possibly, probably or 
definitely related to medication or study 
procedures 
 
 Notification within 24 hours 
  Full report to follow as requested by 
the Sponsor 
 
 According to Institutional guidelines 
SAEs assessed to be unrelated to 
medication or study procedures 
 Notification within 24 hours  
 Follow-up report only if requested by 
 the Sponsor 
 
 According to Institutional guidelines 
 
The Sponsor will work with the National Coordinating centers in each regulatory jurisdiction to report events as 
required to the appropriate regulatory authority. 
5.4 EARLY STOPPING RULE. All three RCT sub-studies, individually or as a group, can be temporarily stopped 
for safety reasons at any time, at the discretion of the Data & Safety Monitoring Board [DSMB Charter; also see 
6.4]. An RCT can be stopped for benefit at the time of an interim analysis if results unequivocally favor one 
treatment arm over the other at the p<0.001 level. If one is demonstrably superior to the other, it would be 
unethical to continue the sub-study as is. Stopping of the study for benefit will be decided based on discussions of 
the DSMB with the study PI and the Trial Steering Committee. 
6.  STUDY MANAGEMENT & RESPONSIBILITIES 
6.1 MEDICAL OVERSIGHTMedical oversight ) of participants at each study site will be the responsibility of the 
PI at each centre. Procedures for medical oversight must be implemented at each site and responsibilities in care 
and assessments delegated to appropriately trained staff. Documentation of this oversight must be maintained for 
the length of the trial (as required by your institution and regulatory authority).  
6.2 TRIAL OVERSIGHT will be maintained by the Sponsor-Investigator, Edgar Jaeggi.1, 2, 7, 9, 23, 36, 45-52. He and his 
team of physicians and trial support staff will oversee the conduct of the study. 

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6.3 DATA MANAGEMENT. The password-protected REDCap data management system (www.project-
redcap.org) will be used to enter de-identified patient data by the participating sites. Credentialing to access 
REDCap will be managed centrally by the FAST Trial study team in cooperation with the Cardiovascular Data 
Management Centre (CVDMC). Individual access will be limited to data from individual sites. The system is 
deployed through a secured/encrypted server hosted at SickKids and will be managed by an experienced Clinical 
Research Project Manager (statistician and database manager) from the CVDMC. REDCap is available anytime, 
anywhere in the world, is completely automated and will allow new patient input and randomization 
instantaneously once a center becomes eligible to participate in the FAST Therapy Trial; thereafter all required 
CRFs (incl. patient characteristics, treatment information, outcomes) will be available with basic data validation at 
the time of data entry (physiological range, validation of time interval, pre-determined coding, required fields, 
etc.). Regular updates of key findings will be requested from the site investigator up to 1 month of life. Once 
completed, participant data will be verified for completeness and validity by the FAST Trial team, and any 
queries will be sent to the site investigator. Once the record is deemed complete/valid, it will be locked so that 
further edits will not be possible to ensure highest data quality. 
6.4 DATA & SAFETY MONITORING BOARD (DSMB). An independent DSMB of 4 members will monitor the 
progress of the RCT sub-studies and review the safety data [DSMB Charter of the Randomized Clinical Sub-
trials]. The DSMB will review the result of interim analyses and other safety data and, if required, will provide 
recommendations to the study sponsor including to stop the trial if there are safety concerns.  
6.5 STEERING COMMITTEE MEMBERS. The clinical research aspect of this study has been developed and will be 
conducted under the supervision of a highly experienced multidisciplinary team of experts in the field who 
collectively have published >1,300 refereed papers, incl. 45 on fetal tachyarrhythmia and >50 RCTs. The 
committee includes the PI, Edgar Jaeggi, and 10 co-investigators who initiated/designed the FAST Therapy Trial, 
including this Protocol and the Care Maps. Members include: Brian McCrindle, Director of the Cardiovascular 
Clinical Research Unit at SickKids Heart Center; Martin Offringa, Head of the Child Health Evaluative Science 
Program at SickKids with a vast experience in the design, conductance and reporting of evidence-based clinical 
trials in children; Nico Blom, Phil J Saul, Julene Carvalho, Bettina Cuneo, Anita Moon-Grady, Ulrich Gembruch 
and Greg Ryan, who are leading experts in electrophysiology, cardiology and maternal-fetal medicine, 
respectively, and last but not least, Ed Kelly who directs a large Neonatal Follow-up Clinic. Members of the 
Steering Committee may be consulted if there is disagreement between a study site and the Echo Core Lab 
regarding a fetal diagnosis. The committee will assist in interpretation of study outcome data and with the 
development of practice guidelines and interdisciplinary knowledge transfer. The committee will communicate 
via e-mail and have intermittent conference calls to discuss study issues. Annual meetings are planned to discuss 
study progress and any relevant issues. These meetings may also include national and site investigators. 
6.6 NATIONAL COORDINATORS. In countries with larger numbers of participating centers investigators have 
been identified to function as National Coordinators. Their role will be to assist the FAST Trial Team by 
providing regional oversight and support for running of the RCTs. Responsibilities of National Coordinating 
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and providing logistic support to sites if required. The study sponsor will assist all sites including centers of 
countries without a national coordinator.  
7.  CONDUCT OF THE RCTs 
The Table of Events below summarizes the different study steps from the time of prenatal identification and 
randomization to study end as they relate to the RCT sub-studies.  

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Patient identification, data entry, eligibility screening, randomization (Pre-treatment) and treatment initiation (Day 
1) are to occur on the same day if there is an immediate need of fetal treatment. 
7.1  PATIENT IDENTIFICATION. The site investigator will be responsible for identifying and recruiting RCT 
participants and conducting the study at the participating center. The investigator will inform a patient who fulfills 
eligibility criteria about the study early on with the help of a Patient Brochure.  
Study Logs for screening and enrolment are to be kept securely at sites with access only to FAST study team 
members. These Logs will be de-identified prior to inspections and audits or if requested by the Sponsor for 
monitoring purposes. De-identification is also necessary before being sent to the Sponsor at end of study.  
A Screening Log of all patients screened should be kept with the following information: screening date, patient 
name, institutional number, confirmation of sub-study screened for, eligibility status, enrolment status and a 
reason if not enrolled.  
Once patients have consented to participate in the study, screened for eligibility and are enrolled into the study, 
their information should be entered into an Enrolment Log with the following information: participant’s name, 
study ID number, institutional number, date and time of enrolment, study enrolled in, as well as an indication if 
and why a participant has withdrawn. Once a baby is born to a mother in the study, sites will need to keep a Child 
Enrolment Log with the child’s name and institutional number, as well as the mother’s corresponding study ID 
number.  
7.2 ELIGIBILITY CRITERIA.  Subjects are eligible for participation in an RCT sub-study if they meet ALL of the 
following inclusion criteria and NONE of the exclusion criteria. All subjects will be screened by Investigators for 
study eligibility prior to randomization and enrolment.  
INCLUSION CRITERIA:  
 Mother has provided written informed consent to participate in the RCT 
 Fetal AF without hydrops (RCT A) or SVT without hydrops (RCT B) or SVT with hydrops (RCT C) 
 Tachyarrhythmia that is significant enough to justify immediate transplacental pharmacological treatment: 
- Tachycardia ≥ 170 bpm during +100% of time (≤ 30 0/7 weeks of gestation) 
- Tachycardia ≥ 180 bpm during at least 10% of observation time 
- Tachycardia ≥ 280 bpm  
- Tachycardia with fetal hydrops  
 Gestational age > 12 0/7 weeks and  <36 0/7 weeks at time of enrolment 
 Untreated tachycardia at time of enrolment 
 Singleton Pregnancy 
 Healthy mother with ± normal pre-treatment cardiovascular findings: 
- ECG within normal range (sinus rhythm; QTc ≤ 0.47s; PR ≤ 0.2 s; QRS: ≤ 0.12 s; insignificant anomalies; 
isolated premature beats; isolated complete right bundle branch block; non-specific ST-T segment changes 
allowed) 

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- Maternal resting heart rate of 50 bpm or above 
- Maternal systolic BP of 85 mm Hg or above 
EXCLUSION CRITERIA:  
 AF with hydrops (condition is too infrequent to be studied in a separate RCT sub-study; eligible for Registry) 
 Any maternal-fetal conditions associated with high odds of premature delivery or death other than tachycardia 
(e.g. severe IUGR; premature rupture of membrane; life-threatening maternal disease (incl. pre-eclampsia; 
HELLP syndrome); severe congenital fetal abnormalities (T 13 or 18; surgery or death expected < 1 month)) 
 History of significant maternal heart condition (open heart surgery; sick sinus syndrome; channelopathy (long 
QT, Brugada syndrome); ventricular tachycardia; WPW syndrome; high-degree heart block; cardiomyopathy) 
 History of significant maternal obstructive airway disease including asthma 
 Current therapy with the following medications: 
– 
antiarrhythmic drugs 
– 
Pentamidine 
 Maternal serum potassium level <3.3 mmol/L / <3.3 mEq/L  
 Maternal ionized serum calcium level of <1 mmol/L / <4 mg/dL) or total serum calcium level <2 mmol/L  / 
<8mg/dL  
 Maternal serum creatinine level > 97.2 µmol/L (>1.1 mg/dl)  
 
7.3 INFORMED CONSENT (IC) The consent process at each site will be performed as approved by local REB or as 
per institutional practices. The study is explained to the patient in detail, including the alternatives (registry, non-
participation) and any questions are answered prior to signing the consent form. The person obtaining consent 
must co-sign the form with date and time. A copy of the consent form must be given to the patient.  
7.4 PATIENT DATA ENTRY.  Completion of the enrolment and randomization process requires submission of the 
following baseline information into the patient’s electronic REDCap form prior to any treatment:  
 Name and center of the site investigator, incl. contact information  
 SVA: date/gestational age at diagnosis, mechanism, pattern, rate and AV relationship 
 Fetal state: presence/location of effusion(s), skin edema, and fetal movements 
 Confirmation of enrolment into prospective randomized trial and selection of the sub-study 
 Checklist of eligibility criteria for participation 
Following randomization and treatment intitation, sites must upload de-identified images to REDCap that 
document the pretreatment fetal arrhythmia mechanism and health state (M-mode and/or Doppler still images, 2-
dimensional images of the fetal abdomen/chest for proof of hydrops) and maternal 12-lead ECG for review by the 
Sponsor Echo Core Lab. Moving clips confirming the fetal SVA mechanism should also be sent via secure file 
transfer for review by the FAST Trial Echo Core Lab. If de-identification is not possible at the site, an 
arrangement can be made with the Sponsor to have images and clips sent via secure file transfer for de-
identification prior to storage. 

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7.5 DATA REVIEW.  Accurate differentiation between “AF vs. SVT” and “hydrops vs. non-hydrops” is critical for 
the randomization into the appropriate sub-study. SickKids will function as the Echo Core Lab Facility to review 
patient diagnosis and fetal state to determine if the initiated drug therapy is appropriate. The Core Lab provides 
support to ensure accurate diagnosis and classification and if requested will provide a review of findings within 48 
hours. Other Core Lab physicians or steering committee members will arbitrate if there is no agreement in 
diagnosis with the site investigator. This approach will avoid inaccuracies in diagnosis and study results. 
7.6 RANDOMIZATION TO FIRST LINE THERAPY. An individual ID code is assigned by REDCap at first data entry 
to protect patient privacy. Once participant screening, eligibility data, and confirmation of consent data has been 
entered into REDCap, they will be asked to confirm diagnosis and then be allowed to randomize to a drug 
assignment in the selected treatment arm.  
Participants will be randomized into one of two possible 1st line therapy arms, which either will be started as 
monotherapy (AF or SVT without hydrops) or as dual therapy (SVT with hydrops). First line drug therapy is pre-
defined including the initial dose and mode of administration:  
AF WITHOUT HYDROPS (RCT A): DIGOXIN vs. SOTALOL  
RCT A ARM 1: DIGOXIN  
Aim: therapeutic maternal trough level of 1.0-2.0 ng/ml or 1.3-2.6 nmol/L (please verify the units your 
laboratory reports). 
→ Oral or intravenous loading dose: Initiate treatment with 0.5 mg Digoxin q 12 h (total 4 doses over 48 
hours) followed by: 
→ Oral maintenance dose: it is recommended to obtain maternal digoxin trough level 12 hours after the 4th 
loading dose just prior to the administration of the 1st maintenance dose*→ await the result and adjust 
the 1st maintenance dose according to the trough digoxin level as followed: 
(*alternatively, a digoxin level may be obtained prior to the 4th dose to adjust the 1st maintenance dose if 
levels are not rapidly measured in your center) 
Trough level 
(nmol/L) 
 Trough level  
(ng/ml) 
Maintenance digoxin dose 
Route 
2.6 to <2.9 
2 to <2.3 
0.25 mg/day  
Oral 
1.9 to <2.6 
1.5 to <2 
0.375 mg/day 
Oral 
1.5 to <1.9 
1.2 to <1.5 
0.5 mg/day 
Oral 
1.0 to <1.5 
0.8 to <1.2 
0.75 mg/day 
Oral 
<1.0 
<0.8 
1 mg/day 
Oral 
>2.9 
>2.3 
0 mg/day until digoxin level is <2 ng/ml 
→ recommended to repeat maternal trough level until steady state therapeutic drug levels are obtained.      
If using IV Digoxin loading see additional recommendations for IV Digoxin administration below. 
RCT A ARM 2: SOTALOL 
Initiate treatment with oral Sotalol 80 mg TID or 120 mg BID (240 mg/day). 

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SVT WITHOUT HYDROPS (RCT B): DIGOXIN vs. FLECAINIDE 
RCT B ARM 1: DIGOXIN  
Aim: therapeutic maternal trough level of 1.0-2.0 ng/ml or 1.3-2.6 nmol/L (please verify the units your 
laboratory reports). 
  
→ Oral or intravenous loading dose: Initiate treatment with 0.5 mg Digoxin q 12 h (total 4 doses over 
48 hours) followed by: 
→ Oral maintenance dose: it is recommended to obtain maternal digoxin trough level 12 hours after the 4th 
loading dose just prior to the administration of the 1st maintenance dose*→ await the result and adjust 
the 1st maintenance dose according to the trough digoxin level as followed: 
(*alternatively, a digoxin level may be obtained prior to the 4th dose to adjust the 1st maintenance dose if 
levels are not rapidly measured in your center) 
Trough level 
(nmol/L) 
 Trough level  
(ng/ml) 
Maintenance digoxin dose 
Route 
2.6 to <2.9 
2 to <2.3 
0.25 mg/day  
Oral 
1.9 to <2.6 
1.5 to <2 
0.375 mg/day 
Oral 
1.5 to <1.9 
1.2 to <1.5 
0.5 mg/day 
Oral 
1.0 to <1.5 
0.8 to <1.2 
0.75 mg/day 
Oral 
<1.0 
<0.8 
1 mg/day 
Oral 
>2.9 
>2.3 
0 mg/day until digoxin level is <2 ng/ml 
→ recommended to repeat maternal trough level until steady state therapeutic drug levels are obtained.      
If using IV Digoxin loading see additional recommendations for IV Digoxin administration below. 
 
RCT B ARM 2: FLECAINIDE  
Aim (if available): therapeutic maternal drug level of 0.2-1 µg/ml  
Initiate treatment with oral Flecainide 100 mg TID (300 mg/day). 
 
SVT WITH HYDROPS (RCT C): DIGOXIN PLUS FLECAINIDE vs. DIGOXIN PLUS SOTALOL 
RCT C: ARM 1 DIGOXIN Plus FLECAINIDE  
DIGOXIN 
Aim: therapeutic maternal trough level of 1.5-2.0 ng/ml or 1.9 – 2.6 nmol/L (please verify units that your 
laboratory reports).  
  
→ Intravenous or oral loading dose: Initiate treatment with 0.5 mg Digoxin q 8 h (total 4 doses over 32 
hours) 
 

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→ Maintenance dose: It is recommended to obtain maternal digoxin trough level preferably 10-12 hours 
after the 4th loading dose, prior to administrating the 1st maintenance dose. Adjust the 1st maintenance dose 
according to the trough digoxin level as followed: 
Trough level 
(nmol/L) 
 Trough level  
(ng/ml) 
Maintenance digoxin dose 
Route 
2.6 to <2.9 
2 to <2.3 
0.25 mg/day  
Oral 
1.9 to <2.6 
1.5 to <2 
0.375 mg/day 
Oral 
1.5 to <1.9 
1.2 to <1.5 
0.5 mg/day 
Intravenous or Oral 
1.0 to <1.5 
0.8 to <1.2 
0.75 mg/day 
Intravenous or Oral 
<1.0 
<0.8 
1 mg/day 
Intravenous or Oral 
>2.9 
>2.3 
0 mg/day until digoxin level is <2 ng/ml 
→ recommended to repeat maternal trough level until steady state therapeutic drug levels are obtained in 
the upper therapeutic range. 
If using IV Digoxin see additional recommendations for IV Digoxin administration below.       
 
PLUS FLECAINIDE:  
 
Initiate above Digoxin treatment in combination with oral Flecainide 100 mg TID (300 mg/day). 
 
 
RCT C ARM 2: DIGOXIN PLUS SOTALOL:  
 
DIGOXIN 
Aim: therapeutic maternal trough level of 1.5-2.0 ng/ml or 1.9 – 2.6 nmol/L (please verify units that your 
laboratory reports).  
→ Intravenous or oral loading dose: Initiate treatment with 0.5 mg Digoxin q 8 h (total 4 doses over 32 
hours) 
→ Maintenance dose: It is recommended to obtain maternal digoxin trough level preferably 10-12 hours 
after the 4th loading dose, prior to administrating the 1st maintenance dose. Adjust the 1st maintenance dose 
according to the trough digoxin level as followed: 
Trough level 
(nmol/L) 
 Trough level  
(ng/ml) 
Maintenance digoxin dose 
Route 
2.6 to <2.9 
2 to <2.3 
0.25 mg/day  
Oral 
1.9 to <2.6 
1.5 to <2 
0.375 mg/day 
Oral 
1.5 to <1.9 
1.2 to <1.5 
0.5 mg/day 
Intravenous or Oral 
1.0 to <1.5 
0.8 to <1.2 
0.75 mg/day 
Intravenous or Oral 
<1.0 
<0.8 
1 mg/day 
Intravenous or Oral 
>2.9 
>2.3 
0 mg/day until digoxin level is <2 ng/ml 
→ recommended to repeat maternal trough level until steady state therapeutic drug levels are obtained in 
the upper therapeutic range. 
If using IV Digoxin see additional recommendations for IV Digoxin administration below. 
 

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PLUS SOTALOL 
Initiate above Digoxin treatment in combination with oral Sotalol 160 mg BID (320 mg/day). 
 
IV DIGOXIN: additional recommendations 
For RCT A, B or C Digoxin can be administered as oral tablets or IV. For IV the Digoxin Injection can be 
administered undiluted or diluted with a 4-fold or greater volume of 0.9% NaCl injection, or 5% Dextrose 
Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. 
Immediate use of the diluted product is recommended. Slow infusion of digoxin over a period of 5 
minutes or longer is preferable to bolus administration. Rapid infusion of digitalis glycosides has been 
shown to cause systemic and coronary arteriolar constriction, which may be clinically undesirable. 
Mixing of intravenous digoxin with other drugs in the same container or simultaneous administration in 
the same intravenous line is not recommended. 
7.6.1 
CONCOMITANT MEDICATIONS 
Medication to be avoided during trial participation or, if no alternative exists, used with caution and appropriate 
monitoring of the QTc, include medications that prolong QT and/or increase risk for Torsades de Pointes (TDP) 
(List available online at:  https://crediblemeds.org/healthcare-providers/). Concomitant medication use of 
pentamidine is to be avoided and additional anti-arrhythmics to be used with caution. See relevant drug 
monographs for detailed information on precautions and possible drug interactions.  
7.7   STUDY CONDUCT   
PATIENT CARE. The treating physician will be responsible for the medical care of enrolled participants and 
medical oversight will be the responsibility of the local PI. The type and frequency of standard clinical care 
patient assessments, should not differ from a non-study participant with the same clinical findings. The medical 
management of study participants should also not differ from a non-study patient with comparable clinical 
findings. This includes, in agreement with accepted management guidelines53,  the recommendation to commence 
1st line treatment as well as any significant changes in drug therapy in-hospital to allow close monitoring of the 
fetal-maternal treatment effects and well-being by ECG, echocardiograms, digoxin level, and biophysical profile, 
until fetal cardioversion or heart rate control is achieved. After discharge from hospital, serial fetal heart rate 
monitoring to birth by the physician (usually by weekly fetal echocardiograms) and the mother (by daily Doppler 
monitoring at home) is recommended to detect SVA recurrences and to allow treatment adjustments, as required.  
What will differ from standard procedures is the requirement to assess and document AEs, including whether the 
event is serious, the severity, causality and expectedness of the event, as well as to follow-up on and document the 
outcome. The sponsor PI (Dr. Edgar Jaeggi and his team) will assume the role of Medical Monitor/Advisor and 
should be contacted for questions regarding the study and patient safety (e-mail: FAST.Trial@sickkids.ca). 
 
TREATMENT. All management decisions after initiation of the first-line treatment will be at the discretion of the 
primary physician. This means that the responsible physician is at any time free to adjust the dosage of 1st line 
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however important to recognize that 1st line treatment effects are incremental and it will take several days to reach 
therapeutic fetal drug levels with transplacental medication. A premature change to 2nd line therapy prior to 3-7 
days of therapy is therefore not advised unless there is significant worsening of the fetal state (e.g. new hydrops), 
the SVA pattern (>20% increase in SVA rates and duration), or both. Members of the FAST Trial steering 
committee have developed consensus-based recommendations [Care Maps] to adjust the prenatal 
pharmacotherapy to the most common treatment outcomes and clinical scenarios, e.g. if 1st, 2nd or 3rd line 
treatment appears ineffective. Care Map recommendations may include: a) no change in therapy (sinus rhythm; ↓ 
SVA <10% of time); b) escalation of drug dose (some SVA response); or c) addition of or change to different 
medication (no SVA response). The responsible physician is free to follow the recommendations or to elect 
treatment that differs from the Care Map. Cross over to a different medication, fetal demise, preterm delivery, and 
SVA that persists to birth will be considered as 1st line treatment failure. Removal of an agent from treatment 
following sustained conversion to a normal rhythm (treatment success) does not constitute treatment failure.  
Following sustained conversion to a normal rhythm of at least 24 hours (acute 1st line treatment success), it is 
recommended to not change the successful treatment until birth if the treatment is tolerated and the SVA does not 
recur. Any new documentation of fetal SVA on maintenance therapy that is confirmed by fetal echocardiography 
or by heart rate monitoring during labor will be considered as maintenance treatment failure. Near-complete 
suppression of SVA does usually not require a change in maintenance therapy. Maternal drug therapy will be 
maintained until time of delivery and discontinued immediately thereafter. The choice of postnatal neonatal drug 
therapy will be at the discretion of the primary physician. Postnatal outcomes will be assessed to a minimum of 1 
month of age.  
7.8  PROCEDURES OUTSIDE OF STANDARD CARE. The conduct of the RCT sub-studies requires procedures that 
are not part of usual patient management and documentation of findings. This includes:  
 The process of randomization to 1st line therapy  
 The mode of supply and dispensation of 1st line medication  
 Home fetal heart rate monitoring (FHRM) offered to participants 
 The documentation of de-identified study results in CRFs and REDCap 
 Participant questionnaires (AEs and fetal heart rate monitor), medication diary, fetal heart rate monitoring log 
 AE assessment and reporting 
 Adherence rate to treatment assessment   
DATA DOCUMENTATION: The table of events summarizes the study conduct and procedures  
PRENATAL. Following randomization and treatment intitation, sites must upload de-identified images to 
REDCap  of pre-treatment M-mode and/or Doppler still images, 2-dimensional images of the fetal abdomen, and 
12-lead maternal ECG for review and confirmation of diagnosis by the FAST Trial Echo Core Lab. Moving clips 
confirming the fetal SVA mechanism should be sent via secure file transfer for Echo Core Lab review.   
Following treatment initiation, it will be possible to document the result of up to 25 prenatal participant 
encounters in REDCap (from day 1 of treatment to birth or death). Pre-natal participant encounters during 

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maintenance therapy will occur every 1-3 weeks as clinically indicated/opinion of the Investigator. Information 
that is captured includes: 
 Date of encounter → gestational age at encounter and total days of prenatal treatment 
 Patient care: inpatient versus outpatient;  methods of maternal-fetal surveillance 
 Participant adherence to therapy (first-line therapy only) 
 Maternal findings*: Diagnoses; adverse symptoms (questionnaire); ECG; digoxin level 
 Fetal findings*: diagnoses; rhythm; atrial and ventricular rate; SVA characteristics; date of cardioversion; fetal 
state; cardiac function, AV regurgitation; umbilical venous flow, FHRM data (log) 
 Current medication and treatment recommendations to next encounter 
 Rationale of treatment modifications and adherence to Care Maps 
 File uploads of new clinically relevant test results#:  if relevant new findings, upload maternal 12-lead ECG, 
M-mode and/or Doppler of current rhythm. 
* = All data will be entered into CRFs and into REDCap. # = images of new, relevant results to be uploaded into REDCap 
(de-identified) or sent via secure file transfer. 
PERINATAL.  
 Pregnancy and treatment outcomes including date and gestational age at birth or demise 
 Number and duration of treatment related maternal hospitalization to birth and adverse outcomes 
 Mode of delivery 
POSTNATAL. Outcome of live-born babies and their mothers to at least 30 days of corrected postnatal life.  
 Newborn: 
- Date and gestational age at birth 
- Weight, height, and head circumference at birth 
- Gender 
- APGAR scores 
- Neonatal complications 
- Neonatal SVA (none, induced or spontaneous) and if applicable SVA mechanism and treatment 
- Neonatal outcome to 30 days 
- Date of discharge from hospital → length of in-hospital care (birth to discharge) 
- Upload: neonatal ECG; SVA tracing if applicable 
 Maternal: 
- Delivery complications, management and outcome 
- Date of discharge from hospital → length of in-hospital care (delivery to discharge) 
- Upload: FHRM Questionnaire if completed 
 

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MEDICATION-RELATED PROCEDURES: 
DRUG SUPPLY.  In accordance with institutional and national regulations, 1st line medication to birth or 
treatment failure will be supplied as specified in site agreements and dispersed as agreed with the pharmacy and in 
adherence with national regulatory guidelines. There may be brief periods of time when 1st line medication will be 
dispensed from an alternative clinical supply such as during labour and delivery. If this occurs it will be 
documented but not recorded as a protocol deviation, however attempts should be made to obtain information 
regarding the lot number and manufacturer. All responsibility for study medication, packaging and labeling is 
delegated to the Site Investigator as outlined in the Study Agreement. As this is a study of 1st line treatment 
only,once the participant changes therapy to second line medication the medication will be supplied from clinical 
supply and documentation of accountability will no longer be applicable. 
ACCOUNTABLITY.  An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by an Investigational Product Accountability Log kept by the Site 
Investigator.  The amount of study drug dispensed and returned by the subject will be recorded in this log.  The 
responsibility of keeping records of drug accountability will be delegated to the study site. This Accountability 
Log is only required for 1st line study medication for the RCTs. 
COMPLIANCE AND ADHERENCE. Most mothers with fetal SVA understand the importance of regular drug 
intake to improve the chances of a normal pregnancy outcome and non-compliance is highly unusual. 
Nonetheless, participant compliance should be assessed at each visit (for 1st line study medication) by inspecting 
the medication remaining since last dispensing. Adherence rate to treatment since last visit will be calculated as 
percentage of the prescribed medication that has been taken by the participant since last encounter. In the event 
that the mother is admitted to hospital and is administered treatment drugs from the hospital pharmacy and not 
from her personal study medication, self-reporting of dosage will be taken into account when determining 
adherence. Non-compliance may be suspected if the adherence rate is <80%, is self-reported, digoxin level tests 
turn out too low or is negative, among others.  
 
7.9   RCT CENTERS & DURATION. Requirements of a study site to be considered eligible to participate in the FAST 
Therapy RCT include:  
 The centre provides the primary care of RCT participants from the time of SVA diagnosis to birth or death.  
 Neonatal and maternal outcomes to 30 days after birth is ascertained. 
 The site investigator/site have the experience, the commitment, and the infrastructure to successfully conduct 
this research.  
 REB approval has been obtained including, if applicable, for affiliated institutions. 
 Regulatory approval has been obtained by the study site or, if applicable, the national coordinating center.  
 Contracts (data share, legal and financial agreements) have been finalized.          
With an anticipated 50 average sized centers and 80% consent rates per RCT, actual study periods are expected to 
take 1.9 years (SVT without hydrops), 3.8 years (AF without hydrops), and 4.4 years (SVT with hydrops), 
respectively. This will allow follow-up to 30 days after birth of corrected age of all study participants. Study 

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completion <5 years will require a minimum of 20 average sized centers in RCT B (SVT without hydrops RCT: 
4.7 years), 40 centers in the RCT A (AF without hydrops: 4.7 years), and 45 centers in RCT C (SVT with 
hydrops: 4.9 years).  
FOLLOW UP STUDIES. Participant outcomes will be ascertained to 30 days after birth or death. To be able to 
provide participants with information regarding the outcome of the study and to request their participation in 
follow-up studies (for example to determine the neurodevelopmental outcome of survivors beyond 1 month of 
life) we will request the parental permission for electronic contact information (e-mail). The information will be 
sent to the sponsor via secure file transfer and stored securely at SickKids with only study ID number and e-mail 
on the form.  
7.10 OUTCOME MEASURES. Identical outcome measures will be used for RCT and Registry subjects. We expect 
significant differences in various outcomes among drug regimens based on our preliminary work.1  
PRIMARY OUTCOME  
 Term delivery (≥37 0/7 weeks gestation) with a normal cardiac rhythm (ECG). 
SECONDARY OUTCOME 
 Proportion of participants with cardioversion over time 
 Proportion of participants with treatment failure 
- Number of participants with treatment failure compared to number of participants with successful treatment. 
Treament failure is defined as one of the following: 
1. cross-over to another drug 
2. SVT/AF that persists to birth 
3. preterm birth 
4. death  
 Cause of death (prenatal, postnatal) 
 Proportion of participants with arrhythmia related death 
 Average gestational age at birth 
 Birth weight (z-scores) 
 Average days of maternal and neonatal hospitalization related to SVA therapy 
 Maternal prevalence of pregnancy/treatment-related AEs and outcomes  
 Proportion of AEs / adverse outcomes (prenatal, postnatal) 
The primary outcome measure is absolute (term delivery without tachyarrhythmia) with no room for 
interpretation. Secondary outcomes will be the time interval from treatment initiation to the beginning of 
permanent cardioversion, and once established, the freedom from SVA recurrence on maintenance therapy. Only 
the final outcome will be considered to classify cases. Cross-over to another agent, fetal demise, development of 
fetal hydrops, and delivery for SVA will be considered treatment failures. Any recurrence of fetal SVA after 

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documentation of a normal cardiac rhythm >24 hours by echocardiography will be classified as maintenance 
treatment failure.  
7.11  STATISTICAL ANALYSES. All statistical analyses using SAS (SAS Institute, Cary NC) with standard settings 
will be performed by very experienced statistician from the Cardiovascular Data Management Centre (CVDMC) 
at SickKids. As a general precept, all 3 RCTs will be analyzed separately. RCT analyses will be performed on an 
intention-to-treat basis, although a separate subgroup analysis will be performed. Descriptive statistics for all 
study variables, for each study groups separately, will be created using means with standard deviation, median 
with inter-quartile range, and frequencies as appropriate. Baseline characteristics that should be equally 
distributed between groups through randomization (age at diagnosis, baseline fetal heart rate, incessant vs. 
intermittent SVA, maternal age) will be assessed in a test of randomization. The test of randomization will be 
performed using Fisher’s exact test for categorical variables and Student’s t-test (with Satterthwaite method for 
variance estimation) for continuous variables.  
The PRIMARY OUTCOME (proportion of term deliveries without SVA) will be a binary outcome (yes/no). For 
this type of outcome, the proportion of participants in each therapy arm will be compared using logistic regression 
models (PROC LOGISTIC) with likelihood ratio test to determine regression model fit, Wald chi-square test from 
maximum likelihood estimates (Fisher’s scoring technique) to determine statistical significance of the therapy arm 
and c-statistic from the regression model’s area under the curve (AUC) to measure model accuracy. Effect size 
estimate and standard error will be converted into odds ratio with 95% confidence (95% CI) limits to facilitate 
comparisons between the different trials.  
SECONDARY OUTCOME will also be expressed as binary variables (incl. proportions of participants: 
requiring 2nd line therapy and 3rd line therapy; with SVA recurrence on maintenance therapy; delivery without 
SVA termination; death <1 month; etc.) will be assessed between the different therapy arms in the same way as 
the primary outcome. For outcomes with time dependent variables (proportion of participants with cardioversion 
over time; timing of mortality from initiation of therapy), Kaplan-Meier survival curves will be used to depict the 
event proportion over time for each group. Single phase parametric hazard regression model (PROC PHREG) will 
be used to compare the 2 therapy arms (with likelihood ratio test to determine regression model fit and maximum 
likelihood estimates chi-square to determine statistical significance of the therapy arm. Effect size estimate and 
standard error will be converted into hazard ratio with 95% CI to facilitate comparisons between the different 
trials. Finally, for outcomes with continuous variables (average gestational age at birth/birth weight z-score; 
average days of neonatal hospitalization related to SVA therapy), linear regression models using maximum 
likelihood estimates for parameter estimation will be used (PROC GENMOD: Akaike's information criterion 
(AIC) criterion to assess regression model fit; Wald chi-square test from maximum likelihood estimates). Effect 
size estimate and standard error will determine the difference between the therapy arms in the same original units 
of measurement as the outcome. 
SUB-ANALYSIS will attempt to determine the factors associated with successful RCT outcomes. To accomplish 
this, we will use our primary outcome as the dependent variable. Fetal factors (age at diagnosis), SVA 
characteristics (heart rate; arrhythmia pattern; SVT subtypes) and treatment metrics (agent(s); dose) will be 
considered as potential independent variables. In a first, all variables will be evaluated separately in univariable 

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logistic regression models. Those with p-values <0.20 in those models will then be selected for further evaluation 
in a bootstrap bagging algorithm (500 random resamples). Those variables with high reliability (selected in >50% 
of the random resamples) will be included in a multivariable logistic regression model (PROC LOGISTIC) with 
likelihood ratio test to determine regression model fit, Wald chi-square test from maximum likelihood estimates 
(Fisher’s scoring technique) to determine statistical significance of the therapy arm and c-statistic from the 
regression model’s area under the curve (AUC) to measure model accuracy with backward selection of variable 
(p<0.05 to enter) to obtain a final model. Effect size estimate and standard error will be converted into odds ratio 
with 95% CI to facilitate comparisons of effect size between the different covariates. This final model would 
indicate factors associated with greater odds of positive outcome and, providing that analog results are found 
between the effects of 1st line therapy between the 2 models (primary RCT analysis as above and sub-analysis). 
FREQUENCY OF ANALYSIS. Pre-specified interim analyses of the 3 strata will be performed separately at 
50% of enrolment. Each analysis will focus on the primary outcome and safety report including review of 
between-groups differences and individual review of AEs, other maternal, fetal and infant outcomes, and other 
safety concerns, if any. All interim analyses will be blinded (with potential un-blinding at the request of the 
DSMB) as to not influence the final analysis.  
SUBGROUP ANALYSIS. Additional subgroup analyses will include comparisons with registry participants and 
impact of tachycardia rates: 1) cardioversion rates over time of RCT participants with SVT and AF + hydrops; 
and 2) tachycardia rates of cases with persistent SVA at ±1 week of acute therapy (all arms).1 
7.12  
QUALITY AND ETHICAL STANDARDS 
QUALITY. The FAST Therapy Trial will be conducted in accordance with the current approved protocol, GCP 
guidelines, relevant regulations and standard operating procedures. Regular monitoring will be performed by the 
FAST Therapy Trial Team as outlined in our Integrated Quality and Risk Management Plan (IQRMP). The Trial 
Monitor will verify that RCTs are conducted and data is generated, documented and reported in compliance with 
the protocols, GCP and the applicable regulatory requirements. REDCap files will be monitored regularly by the 
FAST team for any accidental upload of documents or images containing personal health information. Safety and 
accuracy of all equipment used in this study, such as ultrasound, ECG, and BP systems, is the responsibility of the 
study site/department where the equipment is clinically used. All equipment must be properly calibrated and 
maintained throughout the trial in accordance with the institution’s regulations.  
ETHICS.  RCT investigators will ensure that this trial is conducted in accordance with the principles of the 
Declaration of Helsinki, and that the trial is conducted in full conformity with relevant regulations and with 
Guidelines for GCP. The protocol, informed consent forms, participant brochures, and questionnaires will be 
submitted to the appropriate Research Ethics Committees, and as required to the relevant regulatory authorities, 
the host and affiliated institutions for written approval. The site investigator will submit and, where necessary, 
obtain approval from the above parties for amendments to the original approved documents. 
The trial staff will ensure that the participants’ anonymity is maintained.  Each participant will be assigned a 
unique study ID number to be used in the REDCap database and for communications between the study site and 

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the trial sponsor. All identifiable documents will be stored securely by the site investigator and will only be 
accessible by trial staff and authorized personnel.  
REIMBURSEMENTS OF SITES AND SUBJECTS.  Reimbursements of the study site and study participant 
are to cover expenses related to the preparation and submission of study documents to REB and regulatory 
authorities, the 1st line medication, the collection/reporting of participant data into CRFs and REDCap and fetal 
heart rate monitors as agreed to by the sponsor. No other participant expenditure will be covered as the care 
outlined in this protocol is standard of care for these participants and will not require extra-time or extra-visits 
from the participants.   
7.13  
AGREEMENTS AND POLICIES 
LEGAL AND FINANCIAL Financial and legal agreements will be made directly between the Trial Sponsor 
(Edgar Jaeggi and The Hospital for Sick Children) and the Primary Responsible Site Investigator(s) and his/her 
Institution(s). In some countries, site agreements and some responsibilities may be delegated to a National 
Coordinating Site. These Centres will manage and coordinate the national regulatory, and where applicable, the 
research ethics requirements. This may include delegation of certain on-site monitoring responsibilities as 
required, from the sponsor to a National Coordinating Site to the extent required by Health Canada. Whether there 
are requirements for additional monitoring by national regulatory authorities outside Canada will have to be 
further assessed. Reimbursements will be based on the role of a study site/investigator in the conduct of the trial 
(National Coordinating Center vs. Participating Center) and the total number of enrolled participants. 
Reimbursements will reflect a compromise between average costs per RCT participant and the available funds to 
allow us to successfully conduct and complete the FAST Therapy Trial. The FAST Therapy Trial receives no 
funds from pharmaceutical companies. 
HEART RATE MONITORS. We will be able to reimburse costs of up to 100 heart rate Doppler devices to 
allow fetal heart rate home monitoring of RCT participants at home (1-2 devices per site, depending on expected 
RCT enrolment rates of the site).  
ACCESS TO SOURCE DOCUMENTS.  The sponsor is obliged to monitor the accuracy and completeness of 
source documents of a portion of the participants in the trial. To comply with this Health Canada regulation, each 
trial site agrees upon request to provide direct access to a qualified team member of the study sponsor to monitor 
source documents and other trial related essential documents. Source document review and verification will be 
randomly chosen but may also be risk-based triggered. Documents may either be faxed to the study Monitor, or 
be sent via secure file transfer. These documents will be viewed and then securely deleted or destroyed according 
to SickKids policy on destruction of confidential documents. 
 
 
 

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8.  DISSEMINATION OF RESULTS AND PUBLICATION GUIDELINES  
Dissemination of results will be decided by the PI and Steering Committee. Publication policy for the FAST 
Therapy Trial will be included in the study agreement. It is expected that results of the FAST Therapy Trial will 
be published in several papers by Writing Committees to be determined by the Committee. Individual authorship 
will be based on the investigator’s contribution to a study component (RCTs, Registry; other outcome studies) and 
journal guidelines of authorship. As per the International Committee of Medical Journal Editors 
(http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-
contributors.html) authorship will be based on these 4 criteria: a) Substantial contributions to the conception or 
design of the work; or the acquisition, analysis, or interpretation of data for the work; AND b) Drafting the work 
or revising it critically for important intellectual content; AND c) Final approval of the version to be published; 
AND d) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy 
or integrity of any part of the work are appropriately investigated and resolved. Submission of case materials 
alone does not satisfy the ICMJE authorship requirement. Study Investigators and Collaborators who have 
significantly contributed but are not included as authors on a manuscript will be listed under "The FAST Therapy 
Trial Participants" which is a searchable designation in PubMed. 
 

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9. 
References 
1. 
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