Percutaneous Intervention Versus Observational Trial of Arterial Ductus in Low Weight Infants (PIVOTAL)

March 25, 2025 updated by: Carl Backes, MD, Nationwide Children's Hospital

Patent Ductus Arteriosus is a developmental condition commonly observed among preterm infants. It is a condition where the opening between the two major blood vessels leading from the heart fail to close after birth. In the womb, the opening (ductus arteriosus) is the normal part of the circulatory system of the baby, but is expected to close at full term birth. If the opening is tiny, the condition can be self-limiting. If not, medications/surgery are options for treatment.

There are two ways to treat patent ductus arteriosus - one is through closure of the opening with an FDA approved device called PICCOLO, the other is through supportive management (medications). No randomized controlled trials have been done previously to see if one of better than the other. Through our PIVOTAL study, the investigators aim to determine is one is indeed better than the other - if it is found that the percutaneous closure with PICCOLO is better, then it would immediately lead to a new standard of care. If not, then the investigators avoid an invasive costly procedure going forward.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

240

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • Recruiting
        • University of Alabama
        • Contact:
        • Contact:
        • Principal Investigator:
          • Andrea Kane, MD
    • Arkansas
      • Little Rock, Arkansas, United States, 72202
    • California
      • Los Angeles, California, United States, 90048
        • Recruiting
        • Cedars-Sinai Medical Center
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Michelle Allen-Sharpley, MD
        • Sub-Investigator:
          • Myriam Almeida-Jones, MD
      • Los Angeles, California, United States, 90027
        • Withdrawn
        • Children's Hospital Los Angeles
      • Palo Alto, California, United States, 94304
        • Withdrawn
        • Lucille Packard Children's Hospital at Stanford
      • Sacramento, California, United States, 95817
        • Recruiting
        • UC Davis Children's Hospital
        • Contact:
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Withdrawn
        • Children's Hospital Colorado
    • Florida
    • Illinois
    • Massachusetts
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Withdrawn
        • C.S. Mott Children's Hospital
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Withdrawn
        • University of Minnesota, Masonic Children's Hospital
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Recruiting
        • St. Louis Children's Hospital
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Manish Aggarwal, MD
    • New York
      • New York, New York, United States, 10032
        • Withdrawn
        • Morgan Stanley Children's Hospital of New York-Presbyterian
    • Ohio
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Withdrawn
        • Children's Hospital of Philadelphia
    • Tennessee
      • Memphis, Tennessee, United States, 38103
        • Recruiting
        • Le Bonheur Children's Medical Center
        • Contact:
      • Nashville, Tennessee, United States, 37232
        • Withdrawn
        • Monroe Carell Jr. Children's Hospital at Vanderbilt
    • Texas
    • Washington
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 week to 1 month (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. EPIs born between 22-weeks+0 days (220/7 wks) and 27-weeks+6 days (276/7 wks) gestation, inclusive
  2. Admitted to a study NICU
  3. Birth weight ≥700-grams
  4. Mechanically ventilated at time of consent and randomization
  5. HSPDA ("PDA Score" ≥6) noted on echocardiogram (ECHO)
  6. Randomization is able to be performed within 5 days of the qualifying ECHO and when infant is 7-32 days postnatal

Exclusion Criteria:

Clinical Exclusion Criteria

  1. Life-threatening congenital defects (including congenital heart disease such as aortic coarctation or pulmonary artery stenosis). PDA and small atrial/ventricular septal defects are permitted;
  2. Congenital lung abnormalities, (e.g. restrictive lung disease);
  3. Pharyngeal or airway anomalies (tracheal stenosis, choanal atresia);
  4. Treatment for acute abdominal process (e.g., necrotizing enterocolitis);
  5. Infants with planned surgery;
  6. Active infection requiring treatment;
  7. Chromosomal defects (e.g., Trisomy 18);
  8. Neuromuscular disorders;
  9. Infants whose parents have chosen to allow natural death (do not resuscitate order) or for whom limitation of intensive care treatment is being considered (e.g. severe intraventricular hemorrhage)
  10. Physician deems that the infant would not be a Percutaneous PDA Closure candidate due to clinical instability; however, if the infant's clinical status improves before 30-days postnatal and all inclusion criteria are still met, then the infant may be enrolled.

ECHO-based Exclusion Criteria

  1. Pulmonary hypertension (defined by ductal right to left shunting for >33% of the cardiac cycle) in which early PDA closure may increase right ventricular afterload and compromise pulmonary and systemic blood flow;
  2. Evidence of cardiac thrombus that might interfere with device placement;
  3. PDA diameter larger than 4 mm at the narrowest portion (consistent with FDA-approved instructions for Piccolo™ device use).
  4. PDA length smaller than 3 mm (consistent with FDA-approved instructions for Piccolo™ device use).
  5. PDA that does not meet inclusion requirements ("PDA Score" <6).* * If a potential participant is found to have a PDA meeting eligibility requirements on a subsequent ECHO during the required period of 7 - 30 postnatal days of age, they may then be declared eligible to participate and enrolled, provided all other inclusion criteria are met and exclusion criteria are not met.

Other Exclusion Criteria

1. Parents or legal guardian do not speak English or Spanish

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Primary Comparator
Interventional groups that subject will be randomly assigned to include Percutaneous Patent Ductus Arteriosus Closure (PPC) or Responsive Management. Those assigned to PPC will undergo active intervention to close a hemodynamically significant patent ductus arteriosus (HSPDA) whereas those assigned to Responsive Management will be treated to manage the symptoms of the HSPDA and permit natural closure over time.
Device: Percutaneous Patent Ductus Arteriosus Closure (PPC)
Infants in this group will undergo catheter-based PPC closure ≤48 hours following randomization and within 7-days of qualifying ECHO. All participants assigned to PPC will receive the Amplatzer Piccolo™ Occluder which will be implanted within the duct (intraductal placement). The Piccolo™ occluder is approved by the US FDA for this purpose.
Combination product: Responsive Management Intervention

Interventional PDA-closure, including PPC or surgical ligation and post-randomization pharmacologic (NSAID or acetaminophen) (enteral or intravenous) PDA treatment, are not allowed unless secondary treatment thresholds (see below) are met. Healthcare decisions for Responsive Management will be made at the discretion of the treatment team, while the infant is carefully monitored for any decline in status that may be attributed to the presence of PDA, in which case, Secondary Intervention (described below) may be considered.

Despite widespread acceptance of responsive PDA management, no consensus definition exists. The following Responsive Management interventions are permitted but not required per clinician discretion: 1) fluid restriction between 120-140 mL/kg/day; 2) diuretics (per local practice); 3) increases in positive end-expiratory pressure (PEEP).

Diagnostic test: Echocardiogram, cardiac
An echocardiogram, also known as "ECHO", is an ultrasound image of the heart. Echocardiography is a common test used for the diagnosis and management of cardiac diseases or conditions.
Other: Secondary Intervention
Sub-group of patients initially randomized to Responsive Management who may suffer a decline in health status that can be attributed to the presence of a hemodynamically significant patent ductus arteriosus (HSPDA). These patients, upon meeting pre-specified clinical criteria, will undergo active treatment via Percutaneous Patent Ductus Arteriosus Closure (PPC) as in the active comparator arm.
Device: Percutaneous Patent Ductus Arteriosus Closure (PPC)
Infants in this group will undergo catheter-based PPC closure ≤48 hours following randomization and within 7-days of qualifying ECHO. All participants assigned to PPC will receive the Amplatzer Piccolo™ Occluder which will be implanted within the duct (intraductal placement). The Piccolo™ occluder is approved by the US FDA for this purpose.
Diagnostic test: Echocardiogram, cardiac
An echocardiogram, also known as "ECHO", is an ultrasound image of the heart. Echocardiography is a common test used for the diagnosis and management of cardiac diseases or conditions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of days free of ventilatory support requirement (ventilator-free days; VFDs)
Time Frame: 30 days post-randomization
Ventilator free days (VFDs) are defined as the number of days that a subject is alive and free from mechanical ventilatory support. VFDs are an established respiratory outcome measure in pediatric clinical trials, and are a strong predictor of short-term and longer-term oucomes, including length of neonatal intensive care unit (NICU) stay, morbidities, and mortality.
30 days post-randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Positive-pressure dependency or death
Time Frame: 36 weeks post-menstrual age
A composite outcome measure (yes/no), positive pressure dependency at 36 weeks post-menstrual age (PMA) is an indicator of chronic lung disease (CLD), the most common and serious respiratory complication of prematurity. Both invasive and non-invasive positive pressure ventilation at 36 weeks PMA is associated with long-term respiratory and neurodevelopmental impairment.
36 weeks post-menstrual age
Diagnosis of pulmonary hypertension or death
Time Frame: 36 weeks post-menstrual age
A compositve binary outcome measure (yes/no), diagnosis of pulmonary hypertension will be determined by cardiac echocardiogram at 36 weeks post-menstrual age. Diagnosis of pulmonary hypertension is an indicator of increased pulmonary vasculature resistance, a marker for increased morbidity and mortality among infants with chronic lung disease.
36 weeks post-menstrual age
Total days on mechanical ventilation
Time Frame: 4 months corrected age
The total number of days (continuous variable) a study subject requires any use of invasive mechanical ventilatory support within a 24-hour calendar day.
4 months corrected age
Days requiring positive-pressure assisted breathing
Time Frame: Randomization through 4 months corrected age
The sum of days the study subject requires either invasive or non-invasive positive pressure assisted ventilation within a 24 hour calendar day.
Randomization through 4 months corrected age
Days on supplemental oxygen
Time Frame: Randomization through 4 months corrected age
Total number of days the study subject requires supplemental oxygen. The subject may be on either invasive or non-invasive ventilatory support during this time. The subject must be free from supplemental oxygen use for a period of at least 24 hours to interrupt or cease counting.
Randomization through 4 months corrected age
Time to death
Time Frame: Randomization through 4 months corrected age
A continuous measure, in days, of the time from a study subject's randomization to expiration, if this occurs.
Randomization through 4 months corrected age
Diagnosis of cardiac dysfunction
Time Frame: 36 weeks post-menstrual age
A diagnosis of left-ventricular output by echocardiography (ECHO) at 36 weeks post-menstrual age.
36 weeks post-menstrual age
Abnormal cardiac remodeling
Time Frame: 36 weeks post-menstrual age
Finding of left-ventricular end-diastolic volume (LV EDV) >97% on echocardiography (ECHO) at 36 weeks post-menstrual age.
36 weeks post-menstrual age
General Movements Assessment (GMA)
Time Frame: 34 - 36 weeks post-menstrual age
The General Movements Assessment (GMA) is a standardized video-based neurological exam to evaluate the presence of "fidgety" versus "absent fidgety" and "cramped-synchronized" versus "non cramped-synchronized" movement patterns at 34 - 36 weeks post-menstrual age. It is used to assist in the diagnosis of impaired motor neurodevelopment and cerebral palsy.
34 - 36 weeks post-menstrual age
Need for rescue intervention
Time Frame: Randomization through 4 months corrected age
Recording of incidence of need for study subjects randomized to Responsive Management to undergo Percutaneous Patent Ductus Arteriosus Closure (PPC) due to decline in health status.
Randomization through 4 months corrected age
Hammersmith Neonatal Neurological Examination (HNNE)
Time Frame: 34 - 36 weeks post-menstrual age
The HNNE is a standardized neurological examination of 34 items to evaluate tone, motor patterns, spontaneous movements, reflexes, visual and auditory attention, and behavior.
34 - 36 weeks post-menstrual age
Hammersmith Infant Neurological Examination (HINE)
Time Frame: 3 - 4 months of corrected age
The HINE is similar to the HNNE, used to assess neurological function at 3 - 24 months of age, including cranial nerve function, movements, reflexes, protective reactions and behavior, and age-dependent evaluation of gross and fine-motor function.
3 - 4 months of corrected age
Infant/Toddler Sensory Profile (Low Registration Domain)
Time Frame: 3 - 4 months of corrected age
Caregiver questionnaire responses to determine if their infant appropriately processes and responds to environmental stimuli, versus missing or taking longer to respond ("Low Registration"). There are 13 items with scores of 13 - 65 possible; scores of 42 - 51 are considered "Typical performance".
3 - 4 months of corrected age
Infant/Toddler Sensory Profile (Sensation Seeking Domain)
Time Frame: 3 - 4 months of corrected age
Caregiver questionnaire responses to determine if their infant is hyposensitive, seeking additional sensory stimulation. There are 6 items with scores of 6 - 30 possible; scores of 7 - 15 are considered "Typical performance".
3 - 4 months of corrected age
Infant/Toddler Sensory Profile (Sensory Sensitivity Domain)
Time Frame: 3 - 4 months of corrected age
Caregiver questionnaire responses to determine if their infant responds readily to sensory stimulation, without actively avoiding it. There are 12 items with scores of 12 - 60 possible; scores of 45 - 57 are considered "Typical performance)
3 - 4 months of corrected age
Infant/Toddler Sensory Profile (Sensation Avoiding Domain)
Time Frame: 3 - 4 months of corrected age
Caregiver questionnaire responses to determine if their infant avoids sensory stimulation. There are 5 items with scores of 5 - 25 possible; scores of 19 - 25 are considered "Typical performance".
3 - 4 months of corrected age
Infant/Toddler Sensory Profile (Low Threshold Domain)
Time Frame: 3 - 4 months of corrected age
Caregiver questionnaire responses which are the sum of the Sensory Sensitivity and Sensation Avoiding domains). Summed scores of 15 - 85 are possible; summed scores of 64 - 81 are considered "Typical performance".
3 - 4 months of corrected age
Baby Care Questionnaire (BCQ)
Time Frame: 3 - 4 months of corrected age
The BCQ is another caregiver-based questionnaire for parental perspectives of an infant's feeding and sleeping habits. It is used as an evaluation of a parent's reliance upon structure / routines and attunement (dependence upon infant's cues).
3 - 4 months of corrected age
Mother-Infant Bonding Scale (MIBS)
Time Frame: 3 - 4 months of corrected age
The MIBS is an 8-item questionnaire to evaluate a mother's bondedness towards her infant. Responses are scored from 0 to 3 for each item, with a total possible range of 0 - 24. Lower scores indicate more favorable outcomes for mother-infant bondedness, whereas higher scores indicate the potential for difficulties.
3 - 4 months of corrected age
Type and incidence of any adverse event
Time Frame: 3 - 4 months of corrected age
Reporting of type and frequency of any adverse event that occurs during percutaneous closure procedures, and post-procedurally that may be related to the intervention.
3 - 4 months of corrected age
Type and incidence of serious adverse event
Time Frame: 3 - 4 months of corrected age
Reporting of type and frequency of any serious adverse event (e.g., potentially life-threatening change in status) that occurs during percutaneous closure procedures, and post-procedurally that may be related to the intervention.
3 - 4 months of corrected age

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine whether neurodevelopment at 3-4 months CA is mediated by improved neurodevelopmental profiles at 34-36 weeks PMA.
Time Frame: 34-36 weeks post-menstrual age and 3 - 4 months corrected age
Analysis of HNNE / HINE scores to determine if neurodevelopmental evaluation scores conducted at 34 - 36 weeks post-menstrual age mediate outcomes at 3 - 4 months corrected age
34-36 weeks post-menstrual age and 3 - 4 months corrected age
Evaluation of effect modifiers on primary and secondary outcomes
Time Frame: Birth to 4 months of corrected age
Examination of the homogeneity of the effect of HSPDA on the primary and secondary outcomes will be carried out in statistical analyses using stratification variables (e.g., gender, gestational age, etc.) and characteristics not balanced through random assignment, if any such imbalances are found.
Birth to 4 months of corrected age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nationwide Children's Hospital

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)
University of Pittsburgh
University of Iowa
Emory University
National Institutes of Health (NIH)
Cedars-Sinai Medical Center
University of Bristol
Dartmouth College
Abbott
Children's Hospital Los Angeles

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 21, 2023

Primary Completion (Estimated)

February 28, 2026

Study Completion (Estimated)

February 28, 2026

Study Registration Dates

First Submitted

August 30, 2022

First Submitted That Met QC Criteria

September 15, 2022

First Posted (Actual)

September 21, 2022

Study Record Updates

Last Update Posted (Actual)

March 30, 2025

Last Update Submitted That Met QC Criteria

March 25, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 00002501
  • UG3HL161338 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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