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NCT Number: NCT01958320

Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

The primary goal of the trial is to compare two different Patent Ductus Arteriosus (PDA) treatment approaches: 1) an "early treatment" approach or 2) a "conservative" approach. For the purposes of the study infants will be enrolled if they are delivered before 28 weeks gestation and have a moderate/large PDA present at 5-7 days after birth.

The hypothesis is: treatment of a moderate size patent ductus arteriosus (PDA) will decrease the time needed for assisted respiratory support, diuretic therapy, and gavage feeding assistance, in addition to decreasing the incidence of ductus ligations or need for future outpatient cardiology follow-up appointments. The investigators hypothesize that one or more of these benefits will occur without an increase in the time taken to achieve full enteral feedings or in the incidence of necrotizing enterocolitis (NEC) or spontaneous intestinal perforations (SIP).The investigators will be comparing the effectiveness of early pharmacologic treatment with a control group of conservatively managed infants who will only receive treatment if they meet specific criteria for "rescue treatment".

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Key information

Conditions

Patent Ductus Arteriosus Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Ductus Arteriosus, Patent Enterocolitis Enterocolitis, Necrotizing Gastroenteritis Gastrointestinal Diseases Heart Defects, Congenital Heart Diseases Intestinal Diseases Intestinal Perforation Necrotizing Enterocolitis Surgery

Age range

5 day–14 day

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

University Hospital, Umea, Sweden, Umeå, Sweden

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About this study

Prior studies showed that, if a moderate/large Patent Ductus Arteriosus (PDA) is still present at 5 days after birth (among infants delivered at 23 and 0/7 to 25 and 6/7 weeks gestation) or at 7 days after birth (among infants delivered at 26 and 0/7 to 27 and 6/7 weeks gestation), it will persist for at least another 4-12 weeks if it is left untreated.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 & 0/7 - 27 & 6/7 weeks gestation:

  • infants must be between 5-14 days old (if delivered between 23 and 0/7 - 25 and 6/7 weeks) or 7-14 days old (if delivered between 26 & 0/7 - 27 & 6/7 weeks) and
  • have a "moderate size PDA" (defined as a PDA on echocardiogram that has at least one of the following criteria: internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or >0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta)(13, 68, 69) and
  • are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min.

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Exclusion criteria

prior treatment with indomethacin, ibuprofen, or acetaminophen, contraindications for the use of indomethacin, ibuprofen, or acetaminophen (these include: hydrocortisone administration within 24 hrs, urine output < 1 ml/kg/h during the preceding 8 h, serum creatinine level >1.6 mg/dl, platelet count <50, 000/mm3, abnormal coagulation studies, or total bilirubin concentration (in mg/dL) > 8 x weight (in kg)), chromosomal anomalies, congenital or acquired gastrointestinal anomalies, prior episode of necrotizing enterocolitis or intestinal perforation.

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Treatment and study plan

pharmacologic treatment of the PDA

Other

Following randomization, infants will be treated with medications used to produce PDA closure.

no pharmacologic treatment of the PDA

Other

Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).

NSAID

Drug

Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Primary outcomes

  1. Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits)

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits)

Secondary outcomes

  1. Duration of Gavage Feeding Assistance

    Time frame: up to 20 weeks of age

    duration of gavage feeding assistance

  2. Incidence of Necrotizing Enterocolitis or Spontaneous Perforation

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    incidence of necrotizing enterocolitis or spontaneous perforation

  3. the Average Daily Weight Gain

    Time frame: up to 20 weeks of age

    the average daily weight gain

  4. Incidence of Bronchopulmonary Dysplasia or Death

    Time frame: determined between 36-37 weeks corrected age

    incidence of bronchopulmonary dysplasia or death

  5. Incidence of Death

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    incidence of death

  6. the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment

    Time frame: 10 days after enrollment

    the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity > 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be "constricted" (small or closed) and not eligible for enrollment or treatment.

  7. the Incidence of Rescue Treatment Eligibility Criteria Met

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified "Rescue" criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: >15 days (if still required intubation and FiO2 >0.30), >20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 >0.30), >30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and >45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 <0.25).

  8. Number of Infants Receiving ≥ 14 Days of Diuretic Treatment

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    number of infants receiving ≥ 14 days of diuretic treatment

Other outcomes

  1. Number of Infants Who Received Dopamine for ≥3 Days

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    number of infants who received dopamine for ≥3 days

  2. Incidence of Bacteremia

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    incidence of bacteremia

  3. Incidence of Pulmonary Hemorrhage

    Time frame: through hospital discharge (approximately 6 months unless death occurs first)

    incidence of pulmonary hemorrhage

Sponsors and collaborators

Lead sponsor

University of California, San Francisco

Other

Registry information

Official study title

Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial

Acronym: PDA:TOLERATE

Important dates

Study start
2013
Primary completion
2017
Study completion
2017
First posted
Oct 9, 2013
Registry last updated
Nov 30, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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