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

Study Overview
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Brief Summary
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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.

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

Conditions
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Ductus Arteriosus, Patent

Intervention / Treatment
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* Device: Percutaneous Patent Ductus Arteriosus Closure (PPC)
* Combination Product: Responsive Management Intervention
* Diagnostic Test: Echocardiogram, cardiac


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 32 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Primary Comparator<br>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)<br>* 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.<br>Combination Product: Responsive Management Intervention<br>* 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).<br>Diagnostic Test: Echocardiogram, cardiac<br>* 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.<br>|
| Other: Secondary Intervention<br>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)<br>* 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.<br>Diagnostic Test: Echocardiogram, cardiac<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days free of ventilatory support requirement (ventilator-free days; VFDs) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | A diagnosis of left-ventricular output by echocardiography (ECHO) at 36 weeks post-menstrual age. | 36 weeks post-menstrual age | 
| Abnormal cardiac remodeling | 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) | 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 | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDA