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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Fetal Atrial Flutter Without Hydrops; Fetal Supraventricular Tachycardia Without Hydrops; Fetal Supraventricular Tachycardia With Hydrops
• Intervention / Treatment: Drug: Digoxin (monotherapy); Drug: Sotalol (monotherapy); Drug: Flecainide (monotherapy); Drug: Digoxin (dual therapy); Drug: Sotalol (dual therapy); Drug: Flecainide (dual therapy)

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 Type: Interventional
• Enrollment (Estimated): 105
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • The Royal Women's Hospital
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • University of Alberta/WCCHN
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • British Columbia Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • The Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada
      • CHU Sainte-Justine Hospital
• Germany
  • Bonn, Germany
    • UKB Universitätsklinikum BONN
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center - AMC
  • Leiden, Netherlands
    • Leiden University Medical Center - LUMC
• United Kingdom
  • London, United Kingdom
    • St George's University Hospital Foundation Trust
• United States
  • California
    • San Francisco, California, United States, 94158
      • UCSF Benioff Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • New York
    • New York, New York, United States, 10032
      • Morgan Stanley Children's Hospital of New York-Presbyterian
    • New York, New York, United States, 269-01
      • Cohen Children's Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78722
      • Pediatrix Medical Services, Inc,
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Research Corporation
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 48 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RCT A (1st arm): AF without hydrops; Atrial Flutter (AF) without hydrops: Treatment with Digoxin as monotherapy.	Drug: Digoxin (monotherapy); 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
Active Comparator: RCT A (2nd arm): AF without hydrops; Atrial Flutter (AF) without hydrops: Treatment with Sotalol as monotherapy.	Drug: Sotalol (monotherapy); Oral dose: 80 mg TID or 120 mg BID (240 mg/day)
Active Comparator: RCT B (1st arm): SVT without hydrops; Supraventricular Tachycardia (SVT) without hydrops: Treatment with Digoxin as monotherapy.	Drug: Digoxin (monotherapy); 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
Active Comparator: RCT B (2nd arm): SVT without hydrops; Supraventricular Tachycardia (SVT) without hydrops: Treatment with Flecainide as monotherapy.	Drug: Flecainide (monotherapy); Oral dose: 100 mg TID (300 mg/day)
Active Comparator: RCT C (1st arm): SVT with hydrops; Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Sotalol.	Drug: Digoxin (dual therapy); 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; Drug: Sotalol (dual therapy); Oral dose: 160 mg BID (320 mg/day)
Active Comparator: RCT C (2nd arm): SVT with hydrops; Supraventricular Tachycardia (SVT) with hydrops: Treatment with Digoxin and Flecainide.	Drug: Digoxin (dual therapy); 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; Drug: Flecainide (dual therapy); Oral dose:100 mg TID (300 mg/day)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Edgar Jaeggi
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Edgar Jaeggi, MD, The Hospital for Sick Children, Toronto

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Estimated): March 31, 2024
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: November 30, 2015
• First Submitted That Met QC Criteria: December 3, 2015
• First Posted (Estimated): December 8, 2015

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: RCT A: Fetal Atrial Flutter without Hydrops; RCT B: Fetal Supraventricular Tachycardia without Hydrops; RCT C: Fetal Supraventricular Tachycardia with Hydrops
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Tachycardia; Edema; Atrial Flutter; Tachycardia, Supraventricular; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Sympatholytics; Digoxin; Flecainide; Sotalol
• Other Study ID Numbers: 1000039945

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not planned

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No