Transfusion of Prematures Trial (TOP)

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?

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Infant, Newborn, Diseases; Anemia; Infant, Extremely Low Birth Weight; Bronchopulmonary Dysplasia (BPD); Infant, Small for Gestational Age
• Intervention / Treatment: Procedure: Restricted red cell transfusion; Procedure: Liberal Cell Transfusion

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.

• Study Type: Interventional
• Enrollment (Actual): 1824
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90025
      • University of California - Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univeristy of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 days (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Threshold Transfusion; Transfusions will be administered using a lower threshold hemoglobin value. The low threshold values reflect more common practice, so this is considered the 'usual treatment' group	Procedure: Restricted red cell transfusion
Active Comparator: High Threshold Transfusion; Transfusions will be administered using a higher threshold hemoglobin value.	Procedure: Liberal Cell Transfusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Neurodevelopmental Impairment	A composite outcome that measures the occurrence of death or neurodevelomental impairment between birth and 22-26 months corrected age.	Birth to 22-26 months corrected age
Death	This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.	Birth to 22-26 months corrected age
Neurodevelopmental Impairment	This is measured as Yes if any hearing impairment or visual impairment is noted, if severe or moderate cerebral palsy is noted, or if the cognitive score of the Bayley III score is more than 1 standard deviation below the average; Otherwise, No.	at 22-26 months corrected age
Cognitive Delay	This is measured as Yes if the Bayley Scale of Infant and Toddler Development (BSID)-III cognitive score is more than 1 standard deviation below the average; Otherwise, No.	at 22-26 months corrected age
Moderate or Severe Cerebral Palsy	This is measured as Yes if the Gross Motor Function Classification System (GMFCS) score is level II or higher; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of "I" denotes mild cerebral palsy (CP); level "II" or "III" moderate CP; level "IV" or "V" severe CP.	at 22-26 months corrected age
Severe Vision Impairment	This is measured as Yes if the corrected visual acuity in the better eye of less than 20/200; Otherwise, No.	at 22-26 months corrected age
Severe Hearing Impairment	This is measured as Yes if bilateral hearing loss occurred for which hearing aids or cochlear implants were warranted; Otherwise, No.	at 22-26 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival to Discharge Without Severe Complications	This is measured as Yes if survived to discharge without severe morbidity, defined as bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher or requiring treatment), or serious brain abnormality; Otherwise, No.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age	This is measured as Yes if experienced bronchopulmonary dysplasia, diagnosed on the basis of the need for supplemental oxygen after a standardized oxygen reduction test at 36 weeks of postmenstrual age; Otherwise, No.	at 36 weeks postmenstrual age
Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received	This is measured as Yes if experienced Retinopathy of Prematurity (ROP) Stage >=3 or received treatment for that condition; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for "mild" disease, to 5 for "severe" disease.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination	This is measured as Yes if experienced Grade 3 or 4 intraventricularhemorrhage, cystic periventricular leukomalacia, or ventriculomegaly diagnosed on ultrasonographic examination; Otherwise, No.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Necrotizing Enterocolitis, Bell's Stage >=2	This is measured as Yes if experienced necrotizing enterocolitis (NEC), Bell's stage >=2; Otherwise, No. Higher scores of Bell's staging criteria denote a worse outcome, where "1" denotes suspect, "2" definite and "3" advanced NEC.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days)
Number of Transfusions Per Infant	This is measured as the number of protocol compliant transfusions, clinically justified non-protocol transfusions and unjustified non-protocol transfusions (violations)	Birth, up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age (PMA)
Weight-for-age: Z-score	This is measured as the weight-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average weight-for-age, and negative scores denote less than average weight-for-age.	at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Length-for-age: Z-score	This is measured as the length-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average length-for-age, and negative scores denote less than average length-for-age.	at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Head Circumference-for-age: Z-score	This is measured as the head circumference-for-age Z-score at 36 weeks postmenstrual age or at initial hospital discharge, whichever occurs first. The Z-score is determined using Olsen percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age.	at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first
Postmenstrual Age at Final Trachael Extubation	This is measured as the average postmenstrual age (in weeks) at final tracheal extubation in infants who were intubated.	at final trachael extubation, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment	This is measured as the average postmenstrual age (in weeks) at final caffeine dose in infants who received caffeine treatment.	at final caffeine dose, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age
Length of Stay	This is measured as the length of stay (in days) up to initial hospital discharge or death, whichever occurred first.	at initial hospital discharge or at death if it occurs earlier (a median of 97 days)
Time to Full Enteral Feeding	This is measured as the amount of days it took for full enteral feeding to occur.	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)
Severe Cerebral Palsy	This is measured as Yes if Gross Motor Function Classification System (GMFCS) is levels IV or V; Otherwise, No. Higher values of the GMFCS are worse than lower values; a level of "I" denotes mild cerebral palsy (CP); level "II" or "III" moderate CP; level "IV" or "V" severe CP.	at 22-26 months corrected age
Hydrocephalus Shunt	This is measured as Yes if experienced Hydrocephalus shunt by follow-up; Otherwise, No.	Initial hospital discharge to 22-26 months corrected age
Microcephaly	This is measured as a head circumference-for-age Z-score of less than -2; Otherwise, No. The Z-score is determined using WHO percentile curves, and is derived from a normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age.	at 22-26 months corrected age
Seizure Disorder	This is measured as Yes if experienced one or more seizures since discharge or of regular use of anticonvulsants or seizure medications; Otherwise, No.	Initial hospital discharge to 22-26 months corrected age
Respiratory Disease Necessitating Readmission Before Follow-up	This is measured as Yes if obtained Respiratory disease necessitating readmission before follow-up; Otherwise, No.	Initial hospital discharge to 22-26 months corrected age
Composite Language Score Less Than 85	This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.	at 22-26 months corrected age
Composite Motor Score Less Than 85	This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.	at 22-26 months corrected age
Composite Cognitive Score Less Than 70	This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.	at 22-26 months corrected age
Composite Language Score Less Than 70	This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite language score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.	at 22-26 months corrected age
Composite Motor Score Less Than 70	This is measured as Yes if scored less than 85 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score; Otherwise, No. Higher scores indicate better performance. Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.	at 22-26 months corrected age

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ravi Patel, MD, Emory University; Principal Investigator: Brenda Poindexter, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Kathleen A Kennedy, MD, MPH, The University of Texas Health Science Center, Houston; Study Director: Haresh M Kirpalani, MD, University of Pennsylvania; Principal Investigator: Bradley Yoder, MD, University of Utah; Principal Investigator: Waldemar A Carlo, MD, University of Alabama at Birmingham; Principal Investigator: Abhik Das, PhD, RTI International; Principal Investigator: Uday Devaskar, MD, University of California, Los Angeles; Principal Investigator: Carl T D'Angio, MD, University of Rochester; Principal Investigator: Abbot R Laptook, MD, Brown University, Women & Infants Hospital of Rhode Island; Principal Investigator: Krisa P Van Meurs, MD, Stanford University; Principal Investigator: Kristi L Watterberg, MD, University of New Mexico; Principal Investigator: Myra Wyckoff, MD, University of Texas, Southwestern Medical Center at Dallas; Principal Investigator: Pablo Sanchez, MD, Research Institute at Nationwide Children's Hospital; Principal Investigator: Michele C Walsh, MD, Case Western Reserve University, Rainbow Babies and Children's Hospital; Principal Investigator: Greg Sokol, MD, Indiana University; Principal Investigator: William Truog, MD, Children's Mercy Hospital Kansas City; Principal Investigator: Beena Sood, MD, Wayne State University; Principal Investigator: Michael Cotten, MD, Duke University

Publications and helpful links

General Publications

• 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.

Helpful Links

• NICHD NRN Website
• NICHD Pregnancy & Perinatology Branch

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2012
• Primary Completion (Actual): January 1, 2020
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: August 30, 2012
• First Submitted That Met QC Criteria: October 5, 2012
• First Posted (Estimated): October 8, 2012

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); Transfusions
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Body Weight; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Birth Weight; Bronchopulmonary Dysplasia; Infant, Newborn, Diseases
• Other Study ID Numbers: NICHD-NRN-0050; U01HL112776 (U.S. NIH Grant/Contract); U01HL112748 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov)