A Phase 2 interventional study of pharmacologic treatment of the PDA and no pharmacologic treatment of the PDA in Patent Ductus Arteriosus, Surgery and Necrotizing Enterocolitis, sponsored by University of California, San Francisco. Completed at 18 sites in 4 countries. Open to participants aged 5 Days to 14 Days. Per ClinicalTrials.gov, last updated 2018-11-30.
Sponsored by University of California, San Francisco · Phase 2, Interventional, and Treatment
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".
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.
146 studies on the registry are indexed under Ductus Arteriosus, Patent; 21 are open to participants now.
This study's enrollment of 202 is above the median of 80 across 80 interventional studies indexed under Ductus Arteriosus, Patent.
Browse Ductus Arteriosus, Patent studies →University of California, San Francisco is the lead sponsor of 2,169 studies on the registry; 372 are open to participants now.
Of its 267 completed or terminated interventional studies of FDA-regulated products, 202 (76%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 \& 0/7 - 27 \& 6/7 weeks gestation:
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Exclusion Criteria:
prior treatment with indomethacin, ibuprofen, or acetaminophen, 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, count \<50, 000/mm3, abnormal coagulation studies, or total 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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Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.
Other: pharmacologic treatment of the PDA · Drug: NSAID
Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.
Other: no pharmacologic treatment of the PDA · Drug: NSAID
Following randomization, infants will be treated with medications used to produce PDA closure.
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).
Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment
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)
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)
Duration of Gavage Feeding Assistance
duration of gavage feeding assistance
Time frame: up to 20 weeks of age
Incidence of Necrotizing Enterocolitis or Spontaneous Perforation
incidence of necrotizing enterocolitis or spontaneous perforation
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
the Average Daily Weight Gain
the average daily weight gain
Time frame: up to 20 weeks of age
Incidence of Bronchopulmonary Dysplasia or Death
incidence of bronchopulmonary dysplasia or death
Time frame: determined between 36-37 weeks corrected age
Incidence of Death
incidence of death
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
the Incidence of Persistent Moderate-to-large PDA Shunt 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.
Time frame: 10 days after enrollment
the Incidence of Rescue Treatment Eligibility Criteria Met
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).
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
Number of Infants Receiving ≥ 14 Days of Diuretic Treatment
number of infants receiving ≥ 14 days of diuretic treatment
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
Number of Infants Who Received Dopamine for ≥3 Days
number of infants who received dopamine for ≥3 days
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
Incidence of Bacteremia
incidence of bacteremia
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
Incidence of Pulmonary Hemorrhage
incidence of pulmonary hemorrhage
Time frame: through hospital discharge (approximately 6 months unless death occurs first)
| Milestone | Early Treatment | Conservative Treatment |
|---|---|---|
| Started | 104 | 98 |
| Completed | 104 | 98 |
| Not completed | 0 | 0 |
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)
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| 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) | 33 | 38 |
duration of gavage feeding assistance
| days | Early Treatment | Conservative Treatment |
|---|---|---|
| Duration of Gavage Feeding Assistance | 76 (66 to 104) | 80 (61 to 97) |
incidence of necrotizing enterocolitis or spontaneous perforation
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Incidence of Necrotizing Enterocolitis or Spontaneous Perforation | 17 | 19 |
the average daily weight gain
| gm/kg/day | Early Treatment | Conservative Treatment |
|---|---|---|
| the Average Daily Weight Gain | 22.5 ± 4.8 | 22.8 ± 4.6 |
incidence of bronchopulmonary dysplasia or death
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Incidence of Bronchopulmonary Dysplasia or Death | 60 | 56 |
incidence of death
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Incidence of Death | 20 | 10 |
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.
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment | 43 | 78 |
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).
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| the Incidence of Rescue Treatment Eligibility Criteria Met | 32 | 61 |
number of infants receiving ≥ 14 days of diuretic treatment
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Number of Infants Receiving ≥ 14 Days of Diuretic Treatment | 36 | 45 |
number of infants who received dopamine for ≥3 days
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Number of Infants Who Received Dopamine for ≥3 Days | 14 | 25 |
incidence of bacteremia
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Incidence of Bacteremia | 31 | 21 |
incidence of pulmonary hemorrhage
| Participants | Early Treatment | Conservative Treatment |
|---|---|---|
| Incidence of Pulmonary Hemorrhage | 2 | 2 |
Collected over until hospital discharge (approximately 6 months unless death occurs first). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Early Treatment | 20/104 (19.2%) | 17/104 (16.3%) | — |
| Conservative Treatment | 10/98 (10.2%) | 19/98 (19.4%) | — |
| Event | Early Treatment | Conservative Treatment |
|---|---|---|
| necrotizing enterocolitisGastrointestinal disorders | 17/104 | 19/98 |
| Age, Categorical(Participants) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| <=18 years | 104 | 98 | 202 |
| Between 18 and 65 years | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(days after birth) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| Mean | 8.1 ± 2.1 | 8.3 ± 2.3 | 8.2 ± 2.2 |
| Sex: Female, Male(Participants) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| Female | 56 | 55 | 111 |
| Male | 48 | 43 | 91 |
| Ethnicity (NIH/OMB)(Participants) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| Hispanic or Latino | 25 | 19 | 44 |
| Not Hispanic or Latino | 79 | 79 | 158 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| American Indian or Alaska Native | 2 | 0 | 2 |
| Asian | 12 | 14 | 26 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 14 | 11 | 25 |
| White | 76 | 73 | 149 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| Sweden | 7 | 7 | 14 |
| Turkey | 14 | 15 | 29 |
| United States | 80 | 72 | 152 |
| United Kingdom | 3 | 4 | 7 |
| Gestation(weeks of gestation) | Early Treatment | Conservative Treatment | Total |
|---|---|---|---|
| Mean | 25.7 ± 1.2 | 25.9 ± 1.1 | 25.8 ± 1.2 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — What data in particular will be shared? Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). What other documents will be available? Study Protocol When will data be available (start and end dates)? Beginning 9 months and ending 36 months following article publication. With whom? Researchers who provide a methodologically sound proposal. For what types of analyses? To achieve aims in the approved proposal. Proposals should be directed to clymanr@ucsf.edu. To gain access, data requestors will need to sign a data access agreement.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
Time frame: Beginning 9 months and ending 36 months following article publication.
Access criteria: Researchers who provide a methodologically sound proposal. o achieve aims in the approved proposal. Proposals should be directed to clymanr@ucsf.edu. To gain access, data requestors will need to sign a data access agreement.
The record gives a start of Dec 2013, a primary completion of Jun 2017 and a completion of Jun 2017. It does not say whether these dates are actual or estimated.
Results were first posted in Nov 2018, 1 year 5 months after primary completion.
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