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Patent Ductus ArteriosusPhase 2PDA:TOLERATENCT01958320

Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

A Phase 2 study testing pharmacologic treatment of the PDA, no pharmacologic treatment of the PDA and NSAID in people with Patent Ductus Arteriosus and Surgery, run by University of California, San Francisco at 18 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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… Read more about this study

Who is it for?
Ages 5 to 14 days
What is being tested?
pharmacologic treatment of the PDA, no pharmacologic treatment of the PDA and NSAID
Could I receive a placebo?
No, everyone receives an active treatment
How many people
202 participants
Where
18 sitesin 4 countries
Study dates
Dec 2013to Jun 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 5 to 14 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 \& 0/7 - 27 \& 6/7 weeks gestation:
  • infants must be between 5-14 days old (if delivered between 23 and 0/7 - 25 and 6/7 weeks) or 7-14 days old (if delivered between 26 \& 0/7 - 27 \& 6/7 weeks) and
  • have a "moderate size PDA" (defined as a PDA on echocardiogram that has at least one of the following criteria: internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or >0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta)(13, 68, 69) and
  • are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min.
  • -

Who cannot join

  • prior treatment with indomethacin, ibuprofen, or acetaminophen, contraindications 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, platelet count <50, 000/mm3, abnormal coagulation studies, or total bilirubin concentration (in mg/dL) > 8 x weight (in kg)), chromosomal anomalies, congenital or acquired gastrointestinal anomalies, prior episode of necrotizing enterocolitis or intestinal perforation.
  • -

Trial locations and contacts

18 sites in 4 countries.

18 sites in 4 countries

United States13 sites
  • Johns Hopkins University

    Baltimore, Maryland, 21218

  • University of Chicago Medicine

    Chicago, Illinois, 60637

  • Northshore University Health System

    Evanston, Illinois, 60201

  • South Miami Hospital

    Miami, Florida, 33143

  • Morristown Medical Center

    Morristown, New Jersey, 07960

  • Columbia University

    New York, New York, 10032

  • Providence St Vincent Medical Center

    Portland, Oregon, 97225

  • Mayo Clinic

    Rochester, Minnesota, 55902

  • University of California San Diego

    San Diego, California, 92093-0934

  • Sharp Mary Birch Hospital for Women and Newborns

    San Diego, California, 92123

  • University of California San Francisco

    San Francisco, California, 94143

  • Mednax Neonatology of San Jose/Pediatrix Medical Group

    San Jose, California, 92868

  • Kaiser Permanente Santa Clara

    Santa Clara, California, 95051

Other trials in United States

Turkey (Türkiye)3 sites
  • Ankara University School of Medicine Children's Hospital

    Ankara

  • Sisli Hamidiye Etfal Training and Research Hospital

    Istanbul

  • Inonu University School of Medicine Turgut Ozal Medical Center

    Malatya

Other trials in Turkey (Türkiye)

Sweden1 site
  • University Hospital, Umea, Sweden

    Umeå

Other trials in Sweden

United Kingdom1 site
  • University of Glasgow, Royal Hospital for Sick Children

    Glasgow, Scotland, G38SJ

Other trials in United Kingdom

About this study

Official title: Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial

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".

Read the detailed description

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.

Being tested
pharmacologic treatment of the PDA, no pharmacologic treatment of the PDA, NSAID
Keywords
patent ductus arteriosus, patent ductus arteriosus ligation, necrotizing enterocolitis, spontaneous intestinal perforation
Medical subject headings
Ductus Arteriosus, Patent, Enterocolitis, Necrotizing, Intestinal Perforation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • pharmacologic treatment of the PDAOther

    Following randomization, infants will be treated with medications used to produce PDA closure.

  • no pharmacologic treatment of the PDAOther

    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).

  • NSAIDDrug

    Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Study groups in NCT01958320
Study groupRoleWhat they receive
Early treatmentExperimentalInfants 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.
Receives: Other: pharmacologic treatment of the PDA; Drug: NSAID
Conservative TreatmentActive comparatorInfants 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.
Receives: Other: no pharmacologic treatment of the PDA; Drug: NSAID

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: through hospital discharge (approximately 6 months unless death occurs first)

Secondary outcomes (8)
  1. Duration of Gavage Feeding Assistance

    duration of gavage feeding assistance

    Measured: up to 20 weeks of age

  2. Incidence of Necrotizing Enterocolitis or Spontaneous Perforation

    incidence of necrotizing enterocolitis or spontaneous perforation

    Measured: through hospital discharge (approximately 6 months unless death occurs first)

  3. the Average Daily Weight Gain

    the average daily weight gain

    Measured: up to 20 weeks of age

  4. Incidence of Bronchopulmonary Dysplasia or Death

    incidence of bronchopulmonary dysplasia or death

    Measured: determined between 36-37 weeks corrected age

  5. Incidence of Death

    incidence of death

    Measured: through hospital discharge (approximately 6 months unless death occurs first)

  6. 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.

    Measured: 10 days after enrollment

  7. 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).

    Measured: through hospital discharge (approximately 6 months unless death occurs first)

  8. Number of Infants Receiving ≥ 14 Days of Diuretic Treatment

    number of infants receiving ≥ 14 days of diuretic treatment

    Measured: through hospital discharge (approximately 6 months unless death occurs first)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Oct 2013 (estimated)
  2. Study startDec 2013
  3. Primary completionJun 2017
  4. Study completionJun 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
202 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01958320
Sponsor's protocol ID
RC4
Acronym
PDA:TOLERATE
Status last verified
Nov 2018
First submitted
4 Oct 2013
Last updated
30 Nov 2018
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
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.

Publications

  • Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A; PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019 Feb;205:41-48.e6. doi: 10.1016/j.jpeds.2018.09.012. Epub 2018 Oct 16.

    PubMed 30340932
  • 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 Enrolled in the Trial and Those Treated Outside the Trial. J Pediatr. 2019 Oct;213:222-226.e2. doi: 10.1016/j.jpeds.2019.05.049. Epub 2019 Jun 27.

    PubMed 31255386
  • Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Wolf IS, Kimball A, Sankar M, Leone T, Perez J, Serize A, Clyman RI. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol. 2019 May;39(5):599-607. doi: 10.1038/s41372-019-0347-4. Epub 2019 Mar 8.

    PubMed 30850756

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing pharmacologic treatment of the PDA, no pharmacologic treatment of the PDA and NSAID in people with Patent Ductus Arteriosus and Surgery, run by University of California, San Francisco at 18 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in United States, Turkey (Türkiye), Sweden, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01958320, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2018.

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