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

Overview

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.

Interventions

• 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 (describ
• 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.

Primary outcome measures

• Number of days free of ventilatory support requirement (ventilator-free days; VFDs) [Time frame: 30 days post-randomization]

Secondary outcome measures (12)

• Positive-pressure dependency or death [Time frame: 36 weeks post-menstrual age]
• Diagnosis of pulmonary hypertension or death [Time frame: 36 weeks post-menstrual age]
• Total days on mechanical ventilation [Time frame: 4 months corrected age]
• Days requiring positive-pressure assisted breathing [Time frame: Randomization through 4 months corrected age]
• Days on supplemental oxygen [Time frame: Randomization through 4 months corrected age]
• Time to death [Time frame: Randomization through 4 months corrected age]
• Diagnosis of cardiac dysfunction [Time frame: 36 weeks post-menstrual age]
• Abnormal cardiac remodeling [Time frame: 36 weeks post-menstrual age]
• General Movements Assessment (GMA) [Time frame: 34 - 36 weeks post-menstrual age]
• Need for rescue intervention [Time frame: Randomization through 4 months corrected age]
• Hammersmith Neonatal Neurological Examination (HNNE) [Time frame: 34 - 36 weeks post-menstrual age]
• Hammersmith Infant Neurological Examination (HINE) [Time frame: 3 - 4 months of corrected age]

Eligibility criteria

Inclusion criteria

• EPIs born between 22-weeks+0 days (220/7 wks) and 27-weeks+6 days (276/7 wks) gestation, inclusive
• Admitted to a study NICU
• Birth weight ≥700-grams
• Mechanically ventilated at time of consent and randomization
• HSPDA ("PDA Score" ≥6) noted on echocardiogram (ECHO)
• 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

• 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;
• Congenital lung abnormalities, (e.g. restrictive lung disease);
• Pharyngeal or airway anomalies (tracheal stenosis, choanal atresia);
• Treatment for acute abdominal process (e.g., necrotizing enterocolitis);
• Infants with planned surgery;
• Active infection requiring treatment;
• Chromosomal defects (e.g., Trisomy 18);
• Neuromuscular disorders;
• 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)
• 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

• 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;
• Evidence of cardiac thrombus that might interfere with device placement;
• PDA diameter larger than 4 mm at the narrowest portion (consistent with FDA-approved instructions for Piccolo™ device use).
• PDA length smaller than 3 mm (consistent with FDA-approved instructions for Piccolo™ device use).
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 24 centers

• University of Alabama — Birmingham
• Arkansas Children's Hospital — Little Rock
• Children's Hospital Los Angeles — Los Angeles
• Cedars-Sinai Medical Center — Los Angeles
• Lucille Packard Children's Hospital at Stanford — Palo Alto
• UC Davis Children's Hospital — Sacramento
• Children's Hospital Colorado — Aurora
• Joe DiMaggio Children's Hospital — Hollywood
• … and 16 more centers

Publications

• Benitz WE; Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-3730. Epub 2015 Dec 15. PMID 26672023
• Benitz WE. Patent ductus arteriosus: to treat or not to treat? Arch Dis Child Fetal Neonatal Ed. 2012 Mar;97(2):F80-2. doi: 10.1136/archdischild-2011-300381. Epub 2011 Dec 15. PMID 22174019
• Liebowitz M, Katheria A, Sauberan J, Singh J, Nelson K, Hassinger DC, Aucott SW, Kaempf J, Kimball A, Fernandez E, Carey WA, Perez J, Serize A, Wickremasinghe A, Dong L, Derrick M, Wolf IS, Heuchan AM, Sankar M, Bulbul A, Clyman RI; PDA-TOLERATE (PDA: TOLEave it alone or Respond And Treat Early) Trial Investigators. Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enro PMID 31255386
• Donovan JL, Rooshenas L, Jepson M, Elliott D, Wade J, Avery K, Mills N, Wilson C, Paramasivan S, Blazeby JM. Optimising recruitment and informed consent in randomised controlled trials: the development and implementation of the Quintet Recruitment Intervention (QRI). Trials. 2016 Jun 8;17(1):283. doi: 10.1186/s13063-016-1391-4. PMID 27278130
• Wilson C, Rooshenas L, Paramasivan S, Elliott D, Jepson M, Strong S, Birtle A, Beard DJ, Halliday A, Hamdy FC, Lewis R, Metcalfe C, Rogers CA, Stein RC, Blazeby JM, Donovan JL. Development of a framework to improve the process of recruitment to randomised controlled trials (RCTs): the SEAR (Screened, Eligible, Approached, Randomised) framework. Trials. 2018 Jan 19;19(1):50. doi: 10.1186/s13063-017 PMID 29351790
• Donovan JL, Lane JA, Peters TJ, Brindle L, Salter E, Gillatt D, Powell P, Bollina P, Neal DE, Hamdy FC; ProtecT Study Group. Development of a complex intervention improved randomization and informed consent in a randomized controlled trial. J Clin Epidemiol. 2009 Jan;62(1):29-36. doi: 10.1016/j.jclinepi.2008.02.010. Epub 2008 Jul 10. PMID 18619811
• Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, Davis M, Peters TJ, Turner EL, Martin RM, Oxley J, Robinson M, Staffurth J, Walsh E, Bollina P, Catto J, Doble A, Doherty A, Gillatt D, Kockelbergh R, Kynaston H, Paul A, Powell P, Prescott S, Rosario DJ, Rowe E, Neal DE; ProtecT Study Group. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N E PMID 27626136
• Rooshenas L, Scott LJ, Blazeby JM, Rogers CA, Tilling KM, Husbands S, Conefrey C, Mills N, Stein RC, Metcalfe C, Carr AJ, Beard DJ, Davis T, Paramasivan S, Jepson M, Avery K, Elliott D, Wilson C, Donovan JL; By-Band-Sleeve study group; CSAW study group; HAND-1 study group; Optima prelim study group; Romio feasibility study group. The QuinteT Recruitment Intervention supported five randomized trial PMID 30339938

Identifiers

NCT: NCT05547165 · 00002501 · UG3HL161338

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗