Selective Early Medical Treatment of Patent Ductus Arteriosus in Extremely Low Gestational Age Infants: A Pilot RCT

Study Overview
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Brief Summary
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Background: Among preterm infants, those born at a gestational age less than 26 weeks are considered the most vulnerable with a high risk of short- and long-term health problems that include chronic lung disease, brain bleeds, gut injury, kidney failure and death. Patent ductus arteriosus (PDA) is the most common heart condition with almost 70% preterm infants in this gestational age group being diagnosed with a PDA. Though many PDAs spontaneously resolve on their own, research suggests that if the PDA persists, it may contribute to a number of these short- and long-term health problems. Non-steroidal anti-inflammatory medications such as ibuprofen are commonly used to treat a PDA. Such drugs can also have harmful effects on the gut and kidneys of extremely preterm infants. Therefore, we are unsure if early treatment of a symptomatic PDA in this age group is at all beneficial. Given the wide variation in PDA treatment approaches in this age group, a randomized trial design, where extremely preterm infants with a symptomatic PDA are randomly assigned to early treatment or no early treatment, is essential to address this question. Purpose of the study: The overall purpose of this pilot study is to assess the feasibility of conducting a large study to explore the following research question: In preterm infants born <26 weeks' gestation, is a strategy of selective early medical treatment of a symptomatic PDA better than no treatment at all in the first week of life? The main feasibility objectives of this study are: To assess how many eligible infants can be enrolled in the study To assess how many enrolled infants properly complete the study protocol Importance: To our knowledge this will be the first study on PDA management in preterm infants that specifically aims to enroll preterm infants born at <26 weeks of gestational age who are at the highest risk for PDA-related problems but have been mostly under-represented in previous PDA studies.

Official Title
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Selective Early Medical Treatment of the Patent Ductus Arteriosus in Extremely Low Gestational Age Infants: A Pilot Randomized Controlled Trial

Conditions
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Patent Ductus Arteriosus After Premature Birth

Intervention / Treatment
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* Drug: Ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants less than 26 completed weeks (i.e., up to and including 25 weeks and 6 days) of gestation Exclusion Criteria: no PDA on initial screening echocardiography congenital heart disease (excluding patent foramen ovale, atrial septal defect or ventricular septal defect with a defect size less than 2mm) other major congenital anomaly decision to withhold/withdraw care

Ages Eligible for Study
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Maximum Age: 72 Hours

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 |
| --- | --- |
| Experimental: Selective early medical treatment (SMART) strategy<br>Infants who are randomized to experimental group will follow the SMART treatment protocol, which includes echocardiographic screening every 72 hours to categorize PDA disease severity by combining clinical and echocardiographic features. At any evaluation if patients are found to have a severe PDA on echocardiography, irrespective of clinical symptoms, or a moderate PDA on echocardiography with at least moderate clinical illness, they will receive pharmacotherapy aimed at PDA closure (The PDA severity has been divided into mild, moderate or severe based on pre-defined clinical and echocardiographic criteria). | Drug: Ibuprofen<br>* Pharmacotherapy, when indicated (ie, for severe PDA on echocardiography, irrespective of clinical symptoms, or a moderate PDA on echocardiography with at least moderate clinical illness), will be provided in the form of ibuprofen as first line agent at a standard dosing of 10 mg/kg followed by 2 doses of 5mg/kg every 24 h. The route of administration may be intravenous or enteral, as determined by the treating team. For treated infants, follow-up echocardiography will be conducted at the end of the 3-day course and second course of treatment will be initiated if they still fulfill study treatment criteria as mentioned above. If any treatment-eligible infant has a contraindication to ibuprofen, use of acetaminophen will be permitted as an alternative agent.<br>|
| No Intervention: Early conservative management strategy<br>Infants randomized to this arm will not undergo any further echocardiographic assessment or pharmacological treatment of the PDA regardless of the clinical signs. If the infant gets an echocardiographic assessment for a reason different than PDA assessment (such as hypotension or oxygenation failure) and a PDA is incidentally noted that fits the treatment criteria, the infant will not be initiated on pharmacotherapy. After 7 days of age, decision on PDA assessment and treatment will be at the discretion of the treating physician. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of eligible infants recruited during the study period |  | 7 days postnatal age | 
| Proportion of randomized infants with no reported protocol deviations |  | 7 days postnatal age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of infants in control group meeting pre-defined safety criteria |  | 7 days postnatal age | 
| Reasons for non-recruitment | qualitative description of reasons for non-recruitment of eligible infants | 7 days postnatal age | 
| Reasons for non-adherence to protocol | qualitative description of reasons for non-adherence to protocol in randomized infants | 7 days postnatal age | 
| Completeness of data collection for clinical outcomes | Proportion of recruited infants with complete clinical outcome data | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| All-cause mortality during hospital stay |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Surgical/interventional PDA closure |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Receipt of any PDA pharmacotherapy |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Receipt of open-label rescue medical treatment in the control group |  | 7 days postnatal age | 
| Chronic lung disease | Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge | birth through 36 weeks post menstrual age | 
| Postnatal corticosteroid use |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Pulmonary hemorrhage | blood-stained respiratory secretions with a significant increase in respiratory requirements (MAP>12 and/or FiO2>60%) | 7 days postnatal age | 
| Duration of invasive mechanical ventilation | Number of days on mechanical ventilation with an endotracheal tube | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Intraventricular hemorrhage | Grade I-IV according to Papile Criteria | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Severe intraventricular hemorrhage | Grade III-IV according to Papile Criteria | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Periventricular leukomalacia |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Necrotizing enterocolitis | Stage 2 or greater as per Bell's criteria | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Gastrointestinal bleeding |  | within seven days of the first dose of pharmacotherapy | 
| Gastrointestinal perforation |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Severe retinopathy of prematurity | stage 3 or greater | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Definite sepsis | Clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at postmortem | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Oliguria | urine output less than 1 mL/kg/hour | 7 days postnatal age | 
| Duration of hospitalization (days) |  | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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extremely preterm infant, early medical treatment, randomized controlled trial