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

Phase 3

Completed

• Conditions: Fetal Atrial Flutter Without Hydrops; Fetal Supraventricular Tachycardia Without Hydrops; Fetal Supraventricular Tachycardia With Hydrops
• Interventions: Drug: Digoxin (monotherapy); Drug: Digoxin (dual therapy); Drug: Sotalol (monotherapy); Drug: Flecainide (monotherapy); Drug: Flecainide (dual therapy); Drug: Sotalol (dual therapy)

• Registration Number: NCT02624765
• Lead Sponsor: Edgar Jaeggi

Brief Summary

The Fetal Atrial Flutter and Supraventricular Tachycardia (FAST) Therapy Trial is a prospective multi-center trial that examines the efficacy and safety of standard prenatal antiarrhythmic treatment. 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 (Randomized Clinical Trial (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).

Detailed Description

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).

Study Timeline

• Study First Submitted: 2015-11-30
• Study First Submitted QC: 2015-12-03
• Study First Posted: 2015-12-08
• Study Start: 2016-02
• Primary Completion: 2024-03-31
• Study Completion: 2024-03-31
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-21
• Last Update Posted: 2024-05-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 105

Inclusion Criteria

1. Mother has provided written informed consent to participate

2. Either fetal AF without hydrops, SVT without hydrops or SVT with hydrops

3. 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)

4. Gestational age > 12 0/7 weeks and <36 0/7 weeks at time of enrollment

5. Untreated tachycardia at time of enrollment

6. Singleton Pregnancy

7. 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

1. AF with hydrops (eligible for FAST Registry only)

2. 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)

3. 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)

4. Relevant preexisting maternal obstructive airway disease including asthma

5. Current therapy with the following medications:

   • Antiarrhythmic drugs
   • Pentamidine

6. Maternal serum potassium level <3.3 mmol/L / <3.3 mEq/L (at start of treatment)

7. 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)

8. Maternal serum creatinine level > 97.2 µmol/L (>1.1 mg/dl)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RCT C (2nd arm): SVT with hydrops	Flecainide (dual therapy)	Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Flecainide.
RCT B (1st arm): SVT without hydrops	Digoxin (monotherapy)	Supraventricular Tachycardia (SVT) without hydrops: Treatment with Digoxin as monotherapy.
RCT C (1st arm): SVT with hydrops	Digoxin (dual therapy)	Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Sotalol.
RCT C (2nd arm): SVT with hydrops	Digoxin (dual therapy)	Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Flecainide.
RCT A (2nd arm): AF without hydrops	Sotalol (monotherapy)	Atrial Flutter (AF) without hydrops: Treatment with Sotalol as monotherapy.
RCT A (1st arm): AF without hydrops	Digoxin (monotherapy)	Atrial Flutter (AF) without hydrops: Treatment with Digoxin as monotherapy.
RCT B (2nd arm): SVT without hydrops	Flecainide (monotherapy)	Supraventricular Tachycardia (SVT) without hydrops: Treatment with Flecainide as monotherapy.
RCT C (1st arm): SVT with hydrops	Sotalol (dual therapy)	Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Sotalol.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Proportion of patients with cardioversion 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	Number of participants with persistent tachycardia compared to number of participants with cardioversion to a normal rhythm over time
Proportion of participants with treatment failure	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	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.
Proportion of participants with arrhythmia-related death	From date of randomization to 30 days of life	Number of participants with arrhythmia-related death compared to other outcomes
Average gestational age at birth	At birth	Mean of the gestational age at birth
Birth weight z-scores	At birth	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
Total days of treatment related maternal and neonatal hospitalizations	From date of randomization to 30 days of life	Average days of maternal and neonatal hospitalization related to SVA therapy
Maternal prevalence of adverse events and outcome	From date of randomization to 30 days of life	Maternal prevalence of pregnancy/treatment-related AEs and outcomes

Trial Locations

Locations (22)

Pediatrix Medical Services, Inc,; 🇺🇸 Austin, Texas, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

West Virginia University Research Corporation; 🇺🇸 Morgantown, West Virginia, United States

Academic Medical Center - AMC; 🇳🇱 Amsterdam, Netherlands

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

UCSF Benioff Children's Hospital; 🇺🇸 San Francisco, California, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

British Columbia Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

Children's National Health System; 🇺🇸 Washington, District of Columbia, United States

Morgan Stanley Children's Hospital of New York-Presbyterian; 🇺🇸 New York, New York, United States

Cohen Children's Medical Center; 🇺🇸 New York, New York, United States

CHU Sainte-Justine Hospital; 🇨🇦 Montreal, Quebec, Canada

The Royal Women's Hospital; 🇦🇺 Melbourne, Victoria, Australia

University of Alberta/WCCHN; 🇨🇦 Edmonton, Alberta, Canada

Mount Sinai Hospital; 🇨🇦 Toronto, Ontario, Canada

UKB Universitätsklinikum BONN; 🇩🇪 Bonn, Germany

St George's University Hospital Foundation Trust; 🇬🇧 London, United Kingdom

Leiden University Medical Center - LUMC; 🇳🇱 Leiden, Netherlands

Children's Hospital of Colorado; 🇺🇸 Aurora, Colorado, United States

Children's Hospital of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States