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Acetaminophen vs Indomethacin in Treating hsPDA

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03537144
Recruitment Status : Terminated (Difficulty enrolling patients)
First Posted : May 25, 2018
Last Update Posted : December 3, 2019
Information provided by (Responsible Party):
University of Tennessee

Brief Summary:
The purpose of this study is to see if acetaminophen (Tylenol) is as effective as indomethacin in closing patent ductus arteriosus in premature infants.

Condition or disease Intervention/treatment Phase
Patent Ductus Arteriosus Drug: Indomethacin Drug: Acetaminophen Phase 3

Detailed Description:

The study will be a randomized, controlled, non-inferiority trial, and the investigators plan to enroll premature infants <32 weeks, <1500g, and who are < 21 days of age at Regional One Health, LeBonheur Children's Hospital, and Methodist Germantown NICUs in Memphis, TN. A study group of 42 patients for each group will be needed to allow a maximum difference of 25% to consider non-inferiority in the closure rate between IV acetaminophen and IV indomethacin (with power of 80% and alpha of 0.05).2 The investigators' goal will be to enroll 50 infants for each treatment group, to help with an expected 20% drop out rate either due to complications or parents removal of consent. Dosages: IV acetaminophen 15mg/kg/dose every 6 hours for 12 doses,6 IV indomethacin dose will depend on age.IV indomethacin will be given every 12 hours for 3 doses. The infants will be eligible for the study after primary attending has made the decision to treat the hsPDA. The goal will be 50 infants in the IV acetaminophen group and 50 infants in the IV indomethacin group.

Informed consent will be obtained from the parent after ECHO has been obtained and the primary attending has decided to treat PDA in the infant who meets inclusion criteria without any of the exclusion criteria. The investigators will use block randomization and stratify by site to generate 140 random values of either 0 for acetaminophen or 1 for indomethacin. The goal will be 50 infants randomized to acetaminophen group and 50 infants randomized to indomethacin group. The numbers will be placed in opaque envelope and opened after consent is obtained. The primary team will not be blinded given the different frequencies of administration of acetaminophen and indomethacin. The first ECHO will be read by staff pediatric cardiologist. A pediatric cardiologist will retrospectively go back and read all ECHOs blinded for standardization.

Prior to induction of treatment, we will record complete blood count (CBC) and complete metabolic panel (CMP) with AST/ALT. After treatment, the investigators will record AST/ALT within 48 hours, and will record follow-up ECHO reports that occur within seven days of initiation of treatment. The decision to repeat treatment will be left to primary attending's discretion. The primary attending will determine any additional medical or surgical treatment if indicated. Data regarding ROP, IVH, and BPD will be collected from patient's chart prior to discharge.

Primary outcome will be the rate of successful PDA treatment by ECHO in each group. Successful PDA treatment will be defined as no longer meeting ECHO criteria for hsPDA. Secondary outcome data will be recorded and include the following: retreatment, surgical closure, days on invasive mechanical ventilation, duration of supplemental oxygen requirement, respiratory support at 36 weeks post-menstrual age (PMA), NEC, ROP, days to full feeds, gastrointestinal perforation, length of stay, renal dysfunction defined by UOP < 1cc/kg/hr in an 8 hour period, creatinine elevation greater than 1.5 mg/dL, and discharge disposition.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Comparison of the Efficacy of IV Acetaminophen Versus IV Indomethacin in Treatment of Hemodynamically Significant PDA in VLBW Infants
Actual Study Start Date : June 2016
Actual Primary Completion Date : September 2018
Actual Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Indomethacin
Indomethacin as drug to treat PDA.
Drug: Indomethacin
IV indomethacin will be given every 12 hours for 3 doses. If <48 hours old, 1st dose 0.2 mg/kg, 2nd dose 0.1 mg/kg, and 3rd dose 0.1mg/kg. If 2-7 days old, 1st dose 0.2 mg/kg, 2nd dose 0.2 mg/kg, and 3rd dose 0.2 mg/kg. If >7 days old, 1st dose 0.2 mg/kg, 2nd dose 0.25 mg/kg, and 3rd dose 0.25 mg/kg.
Other Name: Indocin

Experimental: Acetaminophen
Acetaminophen as drug to treat PDA.
Drug: Acetaminophen
15mg/kg/dose every 6 hours for 12 doses
Other Name: Ofirmev

Primary Outcome Measures :
  1. Successful treatment of PDA closure [ Time Frame: Follow-up ECHO to assess for closure within 7 days of treatment initiation ]
    Definition of successful treatment of PDA is the PDA no longer meets the echocardiogram inclusion criteria.

Secondary Outcome Measures :
  1. PDA retreatment [ Time Frame: 1 year ]
    Did the patient require a second course of treatment with either indomethacin or acetaminophen. Did the PDA require surgical closure.

  2. Supplement O2 requirement at 36 weeks PMA [ Time Frame: Until 36 weeks PMA ]
    Was infant on >21% O2 at 36 weeks post-menstrual age

  3. Nectrotizing enterocolitis [ Time Frame: 1 year ]
    As defined by Bell's Staging criteria, at any time during hospital stay

  4. Gastrointestinal perforation [ Time Frame: 1 year ]
    As defined by xray demonstration of free peritoneal air or as diagnosed by surgery

  5. Mortality [ Time Frame: 1 year ]
    Death before discharge from NICU stay

  6. Days on invasive mechanical ventilation [ Time Frame: 1 year ]
    Days on invasive mechanical ventilation

  7. Days on supplement oxygen [ Time Frame: 1 year ]
    Days on supplement oxygen

  8. Days to full feeds [ Time Frame: 1 year ]
    Day till the infant reaches 120 kcal/kg/d

  9. Length of stay [ Time Frame: 1 year ]
    Time from NICU admission to NICU discharge

  10. Retinopathy of prematurity [ Time Frame: 1 year ]
    Stage of ROP and if any treatment was needed

  11. Creatinine elevation greater than 1.5 mg/dL [ Time Frame: 1 year ]
    Creatinine elevation greater than 1.5 mg/dL

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   22 Weeks to 32 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Gestational age at birth 22 weeks to 31 6/7 weeks.
  • Birth weight ≤ 1500 grams
  • Day of life ≤ 21 days
  • ECHO findings:

Left-to-right ductal flow AND 2 of the following 3:

  • Ductal size > 1.5mm at smallest diameter
  • Reversal of flow in descending aorta
  • Left atrial size to aortic root ratio >1.5
  • Platelet count > 50,000

Exclusion Criteria:

  • Ductal dependent congenital heart disease
  • Major congenital anomaly
  • Life-threatening infection
  • Urine output < 1cc/kg/hr in prior 8 hours
  • Serum creatinine > 1.8 mg/dL
  • Hyperbilirubinemia requiring exchange transfusion
  • Active NEC Stage 2 or 3 using Bell's staging criteria
  • Active intestinal perforation
  • Liver dysfunction [2x upper limit of normal for aspartate aminotransferase(AST) and/or alanine aminotransferase (ALT)]
  • Active GI bleeding
  • Concurrent hydrocortisone use
  • Known IVH Grade 3 or 4

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03537144

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United States, Tennessee
LeBonheur Children's Hospital
Memphis, Tennessee, United States, 38103
Methodist-Lebonheur Germantown Hospital
Memphis, Tennessee, United States, 38138
Regional One Health
Memphis, Tennessee, United States, 38163
Sponsors and Collaborators
University of Tennessee
Publications of Results:
Evans N, Malcolm G, Osborn D, Kluckow M. Diagnosis of patent ductus arteriosus in preterm infants. Neonatal Rev 2004; 5: e86-e97.
Thomson Reuters. Neofax 2011. Montvale, NJ: Thomson Reuters; 2011.
Martin, R. J., Fanaroff, A. A., & Walsh, M. C. (2015). Fanaroff and Martin's neonatal-perinatal medicine: Diseases of the fetus and infant (10th ed.). St. Louis, Mo.: Mosby/Elsevier
Clyman, R. Patent Ductus Arteriosus in the Preterm Infant. in: C.A. Gleason, SU Devaskar (Eds.) Avery's disease of the newborn.9th ed.WB Saunders, Philadelphia;2012:751-761.

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Responsible Party: University of Tennessee Identifier: NCT03537144    
Other Study ID Numbers: 16-04411-FB
First Posted: May 25, 2018    Key Record Dates
Last Update Posted: December 3, 2019
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University of Tennessee:
Patent ductus arteriosus
Additional relevant MeSH terms:
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Ductus Arteriosus, Patent
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants
Tocolytic Agents
Reproductive Control Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action