Prospective Randomized Clinical Trial of Fetal Atrial Flutter & Supraventricular Tachycardia Therapy (FAST RCT)

Study Overview
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Brief Summary
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Few studies are specifically designed to address health concerns relevant during pregnancy. The consequence is a lack of evidence on best clinical practice. This includes mothers and their babies when pregnancy is complicated by an abnormally fast heart rate up to 300 beats per minute due to supraventricular tachyarrhythmia (SVA) in the unborn baby (fetus). Although fetal SVA, including atrial flutter (AF) and other forms of supraventricular tachycardia (SVT), is the most common cause of intended in-utero fetal therapy, none of the medication used to date has been evaluated for their effects on the mother and her baby in a randomized controlled trial (RCT). As a consequence, physicians need to make decisions about the management of such pregnancies without any evidence from controlled trials on drug efficacy and safety and no consensus among specialists for the optimal management. The Fetal Atrial Flutter and Supraventricular Tachycardia (FAST) Therapy Trial is a prospective multi-center trial that addresses this knowledge gap to guide future fetal SVA therapy to the best of care. Study components of FAST include three prospective sub-studies to determine the efficacy and safety of commonly used transplacental drug regimens in suppressing fetal AF without hydrops (RCT A), SVT without hydrops (RCT B), and SVT with hydrops (RCT C). All RCTs are open label phase III trials of standard 1st line therapy, which either is started as monotherapy (no hydrops) or as dual therapy (hydrops). The primary study aim is the probability of a normal pregnancy outcome after treatment start with Digoxin or Sotalol (AF without hydrops); Digoxin or Flecainide (SVT without hydrops); and Digoxin plus Sotalol or Digoxin plus Flecainide (SVT with hydrops).

Official Title
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FAST RCT: Prospective Randomized Clinical Trial of Fetal Atrial Flutter & Supraventricular Tachycardia Therapy

Conditions
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Fetal Atrial Flutter Without Hydrops, Fetal Supraventricular Tachycardia Without Hydrops, Fetal Supraventricular Tachycardia With Hydrops

Intervention / Treatment
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* Drug: Digoxin (monotherapy)
* Drug: Sotalol (monotherapy)
* Drug: Flecainide (monotherapy)
* Drug: Digoxin (dual therapy)
* Drug: Sotalol (dual therapy)
* Drug: Flecainide (dual therapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mother has provided written informed consent to participate Either fetal AF without hydrops, SVT without hydrops or SVT with hydrops Tachyarrhythmia that is significant enough to justify immediate transplacental pharmacological treatment: Tachycardia ≥ 180 bpm during at least 10% of observation time of 30 minutes or longer Tachycardia ≥ 170 bpm during +100% of time (≤ 30 0/7 weeks of gestation) Tachycardia ≥ 280 bpm (irrespective of SVA duration) SVT with fetal hydrops (irrespective of duration) Gestational age > 12 0/7 weeks and <36 0/7 weeks at time of enrollment Untreated tachycardia at time of enrollment Singleton Pregnancy Healthy mother with ± normal pre-treatment cardiovascular findings: ECG without significant abnormalities (sinus rhythm; QTc ≤ 0.47; PR ≤ 0.2 sec; QRS: ≤ 0.12 sec; isolated PACs or PVCs or isolated complete right bundle branch block allowed) Resting heart rate ≥ 50 bpm Systolic BP ≥ 85 bpm Exclusion Criteria: AF with hydrops (eligible for FAST Registry only) 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) Relevant preexisting 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 (at start of treatment) Maternal ionized serum calcium level of <1 mmol/L / <4 mg/dL) or total serum calcium level <2 mmol/L / <8mg/dL (at start of treatment) Maternal serum creatinine level > 97.2 µmol/L (>1.1 mg/dl)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RCT A (1st arm): AF without hydrops<br>Atrial Flutter (AF) without hydrops: Treatment with Digoxin as monotherapy. | Drug: Digoxin (monotherapy)<br>* Oral or IV loading dose: 0.5 mg q 12 h (total 4 doses over 48 hours) followed by Oral maintenance dose: 0.25 mg-1mg/day<br>|
| Active Comparator: RCT A (2nd arm): AF without hydrops<br>Atrial Flutter (AF) without hydrops: Treatment with Sotalol as monotherapy. | Drug: Sotalol (monotherapy)<br>* Oral dose: 80 mg TID or 120 mg BID (240 mg/day)<br>|
| Active Comparator: RCT B (1st arm): SVT without hydrops<br>Supraventricular Tachycardia (SVT) without hydrops: Treatment with Digoxin as monotherapy. | Drug: Digoxin (monotherapy)<br>* Oral or IV loading dose: 0.5 mg q 12 h (total 4 doses over 48 hours) followed by Oral maintenance dose: 0.25 mg-1mg/day<br>|
| Active Comparator: RCT B (2nd arm): SVT without hydrops<br>Supraventricular Tachycardia (SVT) without hydrops: Treatment with Flecainide as monotherapy. | Drug: Flecainide (monotherapy)<br>* Oral dose: 100 mg TID (300 mg/day)<br>|
| Active Comparator: RCT C (1st arm): SVT with hydrops<br>Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Sotalol. | Drug: Digoxin (dual therapy)<br>* Oral or IV loading dose: 0.5 mg q 8 h (total 4 doses over 32 hours) followed by oral maintenance dose: 0.25 mg-1mg/day<br>Drug: Sotalol (dual therapy)<br>* Oral dose: 160 mg BID (320 mg/day)<br>|
| Active Comparator: RCT C (2nd arm): SVT with hydrops<br>Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Flecainide. | Drug: Digoxin (dual therapy)<br>* Oral or IV loading dose: 0.5 mg q 8 h (total 4 doses over 32 hours) followed by oral maintenance dose: 0.25 mg-1mg/day<br>Drug: Flecainide (dual therapy)<br>* Oral dose:100 mg TID (300 mg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of live-born children with a delivery at term and a normal cardiac rhythm | Term delivery (≥37 0/7 weeks gestation) with a normal cardiac rhythm (ECG). | Term: 37 0/7 to 41 6/7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with cardioversion over time | Number of participants with persistent tachycardia compared to number of participants with cardioversion to a normal rhythm over time | From date of randomization until the date of first documented cardioversion or until the date of delivery/fetal death without cardioversion, whichever comes first, assessed up to 30 gestational weeks | 
| Proportion of participants with treatment failure | Number of participants with treatment failure compared to number of participants with successful treatment. Treatment 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. | From date of randomization until the date of first documented fetal cardioversion or until the date of treatment failure, whichever comes first, assessed up to 30 gestational weeks | 
| Proportion of participants with arrhythmia-related death | Number of participants with arrhythmia-related death compared to other outcomes | From date of randomization to 30 days of life | 
| Average gestational age at birth | Mean of the gestational age at birth | At birth | 
| Birth weight z-scores | A birth weight z-score compares a child's birth weight to the weight of a child of the same length/height and gender to classify nutritional status | At birth | 
| Total days of treatment related maternal and neonatal hospitalizations | Average days of maternal and neonatal hospitalization related to SVA therapy | From date of randomization to 30 days of life | 
| Maternal prevalence of adverse events and outcome | Maternal prevalence of pregnancy/treatment-related AEs and outcomes | From date of randomization to 30 days of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RCT A: Fetal Atrial Flutter without Hydrops, RCT B: Fetal Supraventricular Tachycardia without Hydrops, RCT C: Fetal Supraventricular Tachycardia with Hydrops