Investigation of Tetralogy of Fallot in Neonates (RIFAN)

A Multi-center, Randomized, Controlled Investigation of Tetralogy of Fallot in Neonates

Child health serves as the foundation for overall public health, with neonatal mortality recognized globally as a comprehensive indicator of national health standards and societal advancement. The Healthy Children Action Improvement Plan (2021-2025) sets a national target to reduce neonatal mortality in China to below 3.1‰. Congenital heart disease (CHD), the most prevalent congenital defect among neonates, constitutes a significant cause of disability and premature death in the Chinese population. Annually, approximately 70,000-80,000 neonates are born with CHD, among whom nearly 10,000 present with critical congenital heart disease (CCHD). Postnatal manifestations of CCHD often include cyanosis, hypoperfusion, and respiratory distress, with untreated cases resulting in approximately 50% mortality. CCHD is one of the leading causes of infant death.

Tetralogy of Fallot (TOF), the most common form of CCHD, accounts for a substantial proportion of cyanotic congenital heart diseases. It is characterized by four anatomical abnormalities: ventricular septal defect, pulmonary stenosis, overriding aorta, and right ventricular hypertrophy. These structural defects disrupt intracardiac blood flow, reduce arterial oxygen saturation, and result in cyanosis and other related symptoms. Untreated TOF leads to significant health issues early in life, including growth retardation, recurrent hypoxic episodes, heart failure, and increased susceptibility to infections. Long-term survival is markedly reduced, with only a small proportion surviving into adulthood. Thus, surgical intervention is pivotal for improving outcomes in TOF(Tetralogy of Fallot) patients.

Despite advances in medical technology yielding satisfactory early outcomes, long-term prognosis following TOF correction remains a challenge. Historically, surgical strategies emphasized complete relief of right ventricular outflow tract obstruction, often at the expense of pulmonary valve function. Recent studies, however, highlight the critical role of preserving pulmonary valve function in improving long-term outcomes, as pulmonary valve dysfunction is a leading cause of late right ventricular failure and reintervention. Additionally, surgical approaches, whether via atrial or ventricular access, have inherent advantages and limitations, but neither can fully eliminate the risk of postoperative arrhythmias associated with TOF's anatomical complexity and surgical impact. These issues underscore the necessity for further advancements in long-term management strategies.

Surgical correction of TOF in a single-stage procedure has become standard practice, with the timing of surgery progressively shifting to earlier ages-from school age in the 1990s to the current standard of 3-6 months of age. This timing ensures sufficient weight and organ maturity to withstand the complexities of cardiac surgery. However, in clinical practice, significant challenges persist, including: (1) Deterioration during the waiting period, during which patients may experience recurrent hypoxic episodes, inadequate weight gain, and exacerbated pulmonary vascular underdevelopment, thereby complicating definitive surgery and increasing perioperative risk. (2) Developmental delays due to chronic hypoxemia and heart failure, potentially leading to neurological deficits and pulmonary hypertension, adversely affecting cognitive and motor development. Neonatal repair, performed within 28 days of life, may mitigate these challenges by restoring normal circulatory physiology at the earliest possible stage.

International guidelines endorse neonatal TOF repair for capable centers, citing the potential for enhanced clinical benefits and superior prognoses. Clinical observations at our center indicate several advantages of neonatal TOF repair, including reduced intraoperative bleeding, cleaner surgical fields, and better pulmonary vascular development. These benefits may be attributed to the regenerative potential of neonatal myocardial cells and the absence of prolonged pathological circulatory states, which otherwise exacerbate anatomical abnormalities. Early intervention may reduce right ventricular fibrosis and pulmonary vascular pathology, thereby improving long-term outcomes.

With advancements in surgical techniques and perioperative care, neonatal TOF repair has become a routine practice at our center, with over 100 cases performed annually for two consecutive years. This success is supported by an integrated prenatal-to-postnatal care model, establishing a comprehensive treatment framework.

Given this context, the investigators propose a multicenter, randomized controlled trial (RCT) to compare the safety and efficacy of neonatal and infant TOF repair. This study aims to provide high-quality evidence for clinical practice, determine optimal surgical timing, and enhance overall survival rates and quality of life for TOF patients.

Study Overview

• Status: Recruiting
• Conditions: Double Outlet Right Ventricle; Pulmonary Stenosis; Tetralogy of Fallot (TOF); Ventricular Septal Defects (VSD)
• Intervention / Treatment: Procedure: corrective surgery within 28 days of birth; Procedure: corrective surgery between 3-6 months of age

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Qiang Wang Prof Beijing Anzhen Hospital,Capital Medical University; Phone Number: 8613811548581; Email: wq.cory@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100013
      • Recruiting
      • Beijing Anzhen Hospital
      • Contact: Qiang Wang MD Beijing Anzhen Hospital,Capital Medical University; Phone Number: 8613811548581; Email: wq.cory@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Clinical diagnosis of TOF's Disease. Full-term neonates aged ≤28 days. Birth weight of all eligible male or female patients >2.5 kg. All included study participants must be able to give an informed consent

Exclusion Criteria:

Preterm infants . Coexisting complex cardiac anomalies. Severe TOF with pulmonary artery hypoplasia , recurrent hypoxic episodes , or conditions warranting palliative or single-ventricle repair.

Extra-cardiac anomalies, including genetic or chromosomal abnormalities. Neonatal bronchopulmonary dysplasia. Deteriorating conditions in the control group precluding surgery by 3 months of age.

Parental refusal to participate in the clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: control group	Procedure: corrective surgery between 3-6 months of age; Participants will be randomized into two groups with a 1:1 allocation: Control Group: Infants undergoing surgical correction of TOF between 3-6 months of age
Active Comparator: intervention group	Procedure: corrective surgery within 28 days of birth; Participants will be randomized into two groups with a 1:1 allocation: Intervention Group: Neonates undergoing surgical correction of TOF within 28 days of birth.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events(mortality)	All-cause mortality within 30 days postoperatively, encompassing cardiovascular and non-cardiovascular causes.	up to 30 days
Rate of re-intervention 12 months after surgery	Reoperation rate within 12 months postoperatively based on defined criteria, excluding in-hospital reinterventions.	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perioperative situation	Perioperative indicators：surgery duration in minutes	during surgery
Perioperative situation	Perioperative indicators：bypass time in minutes	during surgery
Perioperative situation	Perioperative indicators：intensive care unit length of stay in hours	up to 720 hours
Perioperative situation	Perioperative indicators：duration of ventilation in hours	up to 720 hours
Perioperative situation	Perioperative indicators：hospital length of stay in days	up to 30 days
Surgical complications	Surgical complications:postoperative ECMO support in hours	up to 720 hours
Surgical complications	Surgical complications:peritoneal dialysis in hours	up to 720 hours
Cardiac related examination indicators	Echocardiographic parameter：right ventricular wall thickness in millimeters	through study completion, an average of 3 year
Cardiac related examination indicators	Echocardiographic parameter：right ventricular outflow tract gradients in mmHg	through study completion, an average of 3 year
Cardiac related examination indicators	Echocardiographic paramete：pulmonary regurgitation area in cm^2	through study completion, an average of 3 year
Cardiac related examination indicators	Echocardiographic parameter：tricuspid regurgitation area in cm^2	through study completion, an average of 3 year
Follow up indicators	weight in kilograms	through study completion, an average of 3 year
Follow up indicators	height in meters	through study completion, an average of 3 year
Follow up indicators	weight and height will be combined to report BMI in kg/m^2	through study completion, an average of 3 year
Economic indicators	hospitalization costs in yuan	up to 30 days
Economic indicators	operation costs in yuan	during surgery
Economic indicators	medical costs in yuan during perioperative and postoperative follow-up	through study completion, an average of 3 year

Collaborators and Investigators

• Sponsor: Beijing Anzhen Hospital
• Collaborators: Children's Hospital of Fudan University; West China Second University Hospital; Shenzhen Children's Hospital; Suzhou University Affiliated Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2025
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: January 2, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): February 12, 2025

Study Record Updates

• Last Update Posted (Estimated): September 10, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: surgery; RCT; Infant; Neonatal
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Heart Septal Defects; Transposition of Great Vessels; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Tetralogy of Fallot; Heart Septal Defects, Ventricular; Pulmonary Valve Stenosis; Double Outlet Right Ventricle; Physiological Phenomena; Growth and Development; Pregnancy; Reproduction; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena; Parturition; Aging
• Other Study ID Numbers: 20241226

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

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