Acetaminophen vs Indomethacin in Treating hsPDA

Sponsor

University of Tennessee (Other)

Overall Status

Terminated

CT.gov ID

NCT03537144

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

12.3

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

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 :

Jun 1, 2016

Actual Primary Completion Date :

Sep 1, 2018

Actual Study Completion Date :

Sep 1, 2018

Arms and Interventions

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

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 Names:

Indocin

Experimental: Acetaminophen

Acetaminophen as drug to treat PDA.

Drug: Acetaminophen

15mg/kg/dose every 6 hours for 12 doses

Other Names:

Ofirmev

Outcome Measures

Primary Outcome Measures

Successful treatment of PDA closure [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

PDA retreatment [1 year]
Did the patient require a second course of treatment with either indomethacin or acetaminophen. Did the PDA require surgical closure.
Supplement O2 requirement at 36 weeks PMA [Until 36 weeks PMA]
Was infant on >21% O2 at 36 weeks post-menstrual age
Nectrotizing enterocolitis [1 year]
As defined by Bell's Staging criteria, at any time during hospital stay
Gastrointestinal perforation [1 year]
As defined by xray demonstration of free peritoneal air or as diagnosed by surgery
Mortality [1 year]
Death before discharge from NICU stay
Days on invasive mechanical ventilation [1 year]
Days on invasive mechanical ventilation
Days on supplement oxygen [1 year]
Days on supplement oxygen
Days to full feeds [1 year]
Day till the infant reaches 120 kcal/kg/d
Length of stay [1 year]
Time from NICU admission to NICU discharge
Retinopathy of prematurity [1 year]
Stage of ROP and if any treatment was needed
Creatinine elevation greater than 1.5 mg/dL [1 year]
Creatinine elevation greater than 1.5 mg/dL

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Weeks to 32 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	LeBonheur Children's Hospital	Memphis	Tennessee	United States	38103
2	Methodist-Lebonheur Germantown Hospital	Memphis	Tennessee	United States	38138
3	Regional One Health	Memphis	Tennessee	United States	38163