Clinical trial NCT01702805: Transfusion of Prematures Trial
Official title: Transfusion of Prematures (TOP) Trial: Does a Liberal Red Blood Cell Transfusion Strategy Improve Neurologically-Intact Survival of Extremely-Low-Birth-Weight Infants as Compared to a Restrictive Strategy?
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Infant, Newborn, Diseases
Infant, Extremely Low Birth Weight
Infant, Small for Gestational Age
Bronchopulmonary Dysplasia (BPD)
Anemia
Keywords: NICHD Neonatal Research Network
Very Low Birth Weight (VLBW)
Extremely Low Birth Weight (ELBW)
Transfusions
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-10-08
Enrollment: 1824
Sex: ALL
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the TOP trial is to determine whether higher hemoglobin thresholds for transfusing ELBW infants resulting in higher hemoglobin levels lead to improvement in the primary outcome of survival and rates of neurodevelopmental impairment (NDI) at 22-26 months of age, using standardized assessments by Bayley.

Detailed description: Long-term outcomes of extremely low birth weight (ELBW) preterm infants, those weighing less than or equal to 1000 g at birth, are poor and pose a major health care burden. Virtually all of these infants are transfused, but at inconsistent hemoglobin (Hgb) thresholds.

The investigators propose in TOP to randomize infants less than or equal to 1000 g BW and gestational age at least 22 weeks but less than 29 weeks to receive red blood cell (RBC) transfusions according to one of two strategies of Hgb thresholds, either a high Hgb (liberal transfusion) or a low Hgb (restrictive transfusion) algorithm. It is currently unknown which transfusion strategy is superior. TOP is powered to demonstrate which strategy reduces the primary outcome of death or neurodisability in survivors at 22-26 months.

A secondary study entitled "Effect of Blood Transfusion Practices on Cerebral and Somatic Oximetry", also known as the NIRS study, will determine differences in cerebral oxygenation and fractional tissue oxygen extraction with NIRS between high and low hemoglobin threshold groups during red blood cell transfusions. The investigators also propose to determine whether abnormal cerebral NIRS measures are a better predictor of NDI than hemoglobin alone and whether abnormal mesenteric NIRS measures are associated with the development of NEC within the 48 hours following a transfusion.

A secondary study entitled "Economic Evaluation Ancillary to the Transfusion of Prematures Randomized Controlled Trial" will determine whether higher transfusion threshold will result in lower total costs to society over the first 22 to 26 corrected months of life and estimate the incremental cost-effectiveness ratio for survival without neurodevelopmental impairment, from the perspective of society, the third-party payer, and the family.

Extended follow-up: Subjects will be seen for a follow-up visit at 5-6 years corrected age to assess neurological and functional outcomes at early school age based on neonatal transfusion threshold.

Eligibility criteria: Inclusion Criteria:

* Birth weight less than or equal to 1000 grams.
* Gestational age at least 22 weeks but less than 29 weeks
* Admitted to the NICU within 48 hours of life

Exclusion Criteria:

* Considered nonviable by the attending neonatologist
* Cyanotic congenital heart disease
* Parents opposed to the transfusion of blood
* Parents with hemoglobinopathy or congenital anemia
* In-utero fetal transfusion
* Twin-to-twin transfusion syndrome
* Isoimmune hemolytic disease
* Lack of parental consent
* Severe acute hemorrhage, acute shock, sepsis with coagulopathy, or need for perioperative transfusion.
* Prior blood transfusion on clinical grounds beyond the first 6 hours of life
* Infant has received erythropoietin prior to randomization, or is intended to receive erythropoietin through the neonatal course
* Congenital condition, other than premature birth, that adversely affects life expectancy or neurodevelopment.
* High probability that the family is socially disorganized to the point of being unable to attend follow-up at 22-26 months.

Primary outcomes:
measure: Death or Neurodevelopmental Impairment
timeFrame: Birth to 22-26 months corrected age
measure: Death
timeFrame: Birth to 22-26 months corrected age
measure: Neurodevelopmental Impairment
timeFrame: at 22-26 months corrected age
measure: Cognitive Delay
timeFrame: at 22-26 months corrected age
measure: Moderate or Severe Cerebral Palsy
timeFrame: at 22-26 months corrected age
measure: Severe Vision Impairment
timeFrame: at 22-26 months corrected age
measure: Severe Hearing Impairment
timeFrame: at 22-26 months corrected age
Secondary outcomes:
measure: Survival to Discharge Without Severe Complications
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
measure: Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age
timeFrame: at 36 weeks postmenstrual age
measure: Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
measure: Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
measure: Necrotizing Enterocolitis, Bell's Stage >=2
timeFrame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
measure: Number of Transfusions Per Infant
timeFrame: Birth, up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age (PMA)
measure: Weight-for-age: Z-score
timeFrame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
measure: Length-for-age: Z-score
timeFrame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
measure: Head Circumference-for-age: Z-score
timeFrame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
measure: Postmenstrual Age at Final Trachael Extubation
timeFrame: at final trachael extubation, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
measure: Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment
timeFrame: at final caffeine dose, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
measure: Length of Stay
timeFrame: at initial hospital discharge or at death if it occurs earlier (a median of 97 days)
measure: Time to Full Enteral Feeding
timeFrame: at first full enteral feeding, assessed from birth up to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
measure: Severe Cerebral Palsy
timeFrame: at 22-26 months corrected age
measure: Hydrocephalus Shunt
timeFrame: Initial hospital discharge to 22-26 months corrected age
measure: Microcephaly
timeFrame: at 22-26 months corrected age
measure: Seizure Disorder
timeFrame: Initial hospital discharge to 22-26 months corrected age
measure: Respiratory Disease Necessitating Readmission Before Follow-up
timeFrame: Initial hospital discharge to 22-26 months corrected age
measure: Composite Language Score Less Than 85
timeFrame: at 22-26 months corrected age
measure: Composite Motor Score Less Than 85
timeFrame: at 22-26 months corrected age
measure: Composite Cognitive Score Less Than 70
timeFrame: at 22-26 months corrected age
measure: Composite Language Score Less Than 70
timeFrame: at 22-26 months corrected age
measure: Composite Motor Score Less Than 70
timeFrame: at 22-26 months corrected age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
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: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Univeristy of Pennsylvania
state: Pennsylvania
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
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C Walsh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Beena Sood, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Michael Cotten, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Ravi Patel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Greg Sokol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Brenda Poindexter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Kristi L Watterberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Myra Wyckoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Kathleen A Kennedy, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Carl T D'Angio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute at Nationwide Children's Hospital
name: Pablo Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Mercy Hospital Kansas City
name: William Truog, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Uday Devaskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Haresh M Kirpalani, MD
role: STUDY_DIRECTOR
affiliation: University of Utah
name: Bradley Yoder, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kirpalani H, Bell EF, Hintz SR, Tan S, Schmidt B, Chaudhary AS, Johnson KJ, Crawford MM, Newman JE, Vohr BR, Carlo WA, D'Angio CT, Kennedy KA, Ohls RK, Poindexter BB, Schibler K, Whyte RK, Widness JA, Zupancic JAF, Wyckoff MH, Truog WE, Walsh MC, Chock VY, Laptook AR, Sokol GM, Yoder BA, Patel RM, Cotten CM, Carmen MF, Devaskar U, Chawla S, Seabrook R, Higgins RD, Das A; Eunice Kennedy Shriver NICHD Neonatal Research Network. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. N Engl J Med. 2020 Dec 31;383(27):2639-2651. doi: 10.1056/NEJMoa2020248.