Clinical trial NCT00114543: Trial of Aggressive Versus Conservative Phototherapy in Infants <1,000 Grams Birth Weight
Official title: A Randomized Trial of Aggressive or Conservative Phototherapy for Extremely Low Birth Weight Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperbilirubinemia, Neonatal
Jaundice, Neonatal
Infant, Newborn
Infant, Low Birth Weight
Infant, Small for Gestational Age
Infant, Premature
Keywords: NICHD Neonatal Research Network
Bilirubin
Phototherapy
Very Low Birth Weight (VLBW)
Extremely Low Birth Weight (ELBW)
Prematurity
Neurodevelopmental outcome
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
First posted: 2005-06-16
Enrollment: 1974
Sex: ALL
Minimum age (years): 12
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multi-center, randomized clinical trial compared different bilirubin levels as thresholds for timing of phototherapy in extremely low birth weight infants. The primary hypothesis was that there would be no difference in death or neurodevelopmental impairment at 18-22 months corrected age in infants treated by either aggressive or conservative threshold limits. 1,978 infants were enrolled.

Detailed description: In NICHD Neonatal Research Network (NRN) centers in 2002, phototherapy was administered to 94 percent of the extremely low birth weight (ELBW) infants who survive more than 12 hours. Yet, it is unclear what level of bilirubin in the blood is harmful for these very tiny infants -- no data existed from large or recent clinical trials to define the risks, benefits, and appropriate indications for phototherapy in these infants. The largest and most recent trial was the NICHD Collaborative Phototherapy Trial which involved infants treated in 1974-1976 and included only 77 ELBW infants. Data from this study and others suggested that phototherapy could have important hazards as well as benefits for ELBW infants.

This NRN study used two different bilirubin levels as thresholds for timing of phototherapy in 1,978 extremely low birth weight infants, examining the primary hypothesis that there would be no difference in death or neurodevelopmental impairment at 18-22 months corrected age between the aggressively and conservatively treated groups.

Enrolled infants were stratified by birth weight (501-750g and 751-1,000g) and randomized to receive phototherapy regimens based on either an aggressive threshold or a conservative threshold of total serum bilirubin.

In the Aggressive group:

* 501-750 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 5 mg/dl for day of life 1-14.
* 751-1,000 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 5 mg/dl for day of life 1-7 and 7 mg/dl for day of life 8-14.

In the Conservative group:

* 501-750 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 8 mg/dl for day of life 1-14.
* 751-1,000 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 10 mg/dl for day of life 1-14.

The phototherapy regimens are designed to fall within the range of clinical practice and to assure a sizable difference between groups in total serum bilirubin levels and duration of phototherapy.

The primary outcome was death or neurodevelopmental impairment at 18-22 months corrected age determined at an outpatient clinic visit. Secondary outcomes included death, abnormal neurodevelopmental outcome, severe hearing loss, cerebral palsy, blindness, and important medical outcomes.

Eligibility criteria: Inclusion criteria:

* 501-1000 grams birth weight
* 12-36 hours postnatal age

Exclusion criteria:

* Terminal condition (pH \<6.8 for \>2 hours OR persistent bradycardia, heart rate \<100 bpm, associated with hypoxia for \>2 hours\]
* Prior use of phototherapy
* Major congenital anomaly
* Hydrops fetalis or severe hemolytic disease diagnosed in-utero
* Overt congenital nonbacterial infection
* Parental refusal or inability to provide consent
* Attending physician refusal
* Parents who are considered unlikely to return for follow-up evaluation

Primary outcomes:
measure: Death or neurodevelopmental impairment (MDI <70; PDI <70; cerebral palsy; blindness; or severe hearing loss)
timeFrame: 0-22 months corrected age
Secondary outcomes:
measure: Patent ductus arteriosus requiring drug or surgical treatment
timeFrame: 36 weeks post conceptual age
measure: Retinopathy of prematurity
timeFrame: 36 weeks post conceptual age
measure: Bronchopulmonary dysplasia (BPD)
timeFrame: 36 weeks post conceptual age
measure: Ventilator settings and FiO2 at 36 weeks
timeFrame: 36 weeks post conceptual age
measure: Necrotizing enterocolitis (NEC)
timeFrame: 120 days old or at discharge
measure: Intraventricular hemorrhage (IVH) by grade
timeFrame: 120 days old or at discharge
measure: Periventricular leukomalacia
timeFrame: 120 days old or at discharge
measure: Sepsis
timeFrame: 120 days old or at discharge
measure: Hearing assessments
timeFrame: 120 days old or at discharge
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Wake Forest University
state: North Carolina
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
Study officials:
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R. Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C. Walsh, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Ronald N. Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Brenda B. Poindexter, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Ronnie Guillet, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Pablo J. Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Barbara J. Stoll, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P. Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Neil N. Finer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Kurt Schibler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A. Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Brenda H. Morris, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Richard A. Ehrenkranz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Shahnaz Duara, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University
name: T. Michael O'Shea, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008 Oct 30;359(18):1885-96. doi: 10.1056/NEJMoa0803024.
citation: Ahlfors CE, Vreman HJ, Wong RJ, Bender GJ, Oh W, Morris BH, Stevenson DK; Phototherapy Subcommittee; National Institute of Child Health and Development (NICHD) Neonatal Research Network. Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns. Clin Biochem. 2007 Feb;40(3-4):261-7. doi: 10.1016/j.clinbiochem.2006.09.006. Epub 2006 Sep 29.
citation: Bender GJ, Cashore WJ, Oh W. Ontogeny of bilirubin-binding capacity and the effect of clinical status in premature infants born at less than 1300 grams. Pediatrics. 2007 Nov;120(5):1067-73. doi: 10.1542/peds.2006-3024.
citation: Oh W, Stevenson DK, Tyson JE, Morris BH, Ahlfors CE, Bender GJ, Wong RJ, Perritt R, Vohr BR, Van Meurs KP, Vreman HJ, Das A, Phelps DL, O'Shea TM, Higgins RD; NICHD Neonatal Research Network Bethesda MD. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr. 2010 May;99(5):673-678. doi: 10.1111/j.1651-2227.2010.01688.x. Epub 2010 Jan 25.