Transfusion of Prematures Trial (TOP)

• ClinicalTrials.gov Identifier: NCT01702805
• Recruitment Status: Active, not recruiting
• First Posted: October 8, 2012
• Results First Posted: February 11, 2022
• Last Update Posted: March 23, 2023
• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): NICHD Neonatal Research Network

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Infant, Newborn, Diseases; Infant, Extremely Low Birth Weight; Infant, Small for Gestational Age; Bronchopulmonary Dysplasia (BPD); Anemia	Procedure: Liberal Cell Transfusion; Procedure: Restricted red cell transfusion	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1824 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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?
• Actual Study Start Date: December 2012
• Actual Primary Completion Date: January 2020
• Estimated Study Completion Date: August 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Death or Neurodevelopmental Impairment [ Time Frame: Birth to 22-26 months corrected age ]
   A composite outcome that measures the occurrence of death or neurodevelomental impairment between birth and 22-26 months corrected age.
2. Death [ Time Frame: Birth to 22-26 months corrected age ]
   This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.
3. Neurodevelopmental Impairment [ Time Frame: at 22-26 months corrected age ]
   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.
4. Cognitive Delay [ Time Frame: at 22-26 months corrected age ]
   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.
5. Moderate or Severe Cerebral Palsy [ Time Frame: at 22-26 months corrected age ]
   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.
6. Severe Vision Impairment [ Time Frame: at 22-26 months corrected age ]
   This is measured as Yes if the corrected visual acuity in the better eye of less than 20/200; Otherwise, No.
7. Severe Hearing Impairment [ Time Frame: at 22-26 months corrected age ]
   This is measured as Yes if bilateral hearing loss occurred for which hearing aids or cochlear implants were warranted; Otherwise, No.

Secondary Outcome Measures :

1. Survival to Discharge Without Severe Complications [ Time Frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) ]
   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.
2. Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age [ Time Frame: at 36 weeks 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.
3. Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received [ Time Frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) ]
   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.
4. Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination [ Time Frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) ]
   This is measured as Yes if experienced Grade 3 or 4 intraventricularhemorrhage, cystic periventricular leukomalacia, or ventriculomegaly diagnosed on ultrasonographic examination; Otherwise, No.
5. Necrotizing Enterocolitis, Bell's Stage >=2 [ Time Frame: Birth to initial hospital discharge or to death if it occurs earlier (a median of 97 days) ]
   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.
6. Number of Transfusions Per Infant [ Time Frame: Birth, up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age (PMA) ]
   This is measured as the number of protocol compliant transfusions, clinically justified non-protocol transfusions and unjustified non-protocol transfusions (violations)
7. Weight-for-age: Z-score [ Time Frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first ]
   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.
8. Length-for-age: Z-score [ Time Frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first ]
   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.
9. Head Circumference-for-age: Z-score [ Time Frame: at 36 weeks postmenstrual age or initial hospital discharge, whichever occurs first ]
   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.
10. Postmenstrual Age at Final Trachael Extubation [ Time Frame: at final trachael extubation, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age ]
    This is measured as the average postmenstrual age (in weeks) at final tracheal extubation in infants who were intubated.
11. Postmenstrual Age at Final Caffeine Dose in Infants Who Received Caffeine Treatment [ Time Frame: at final caffeine dose, assessed from birth up to the earliest of: death, hospital discharge, or 36 weeks postmenstrual age ]
    This is measured as the average postmenstrual age (in weeks) at final caffeine dose in infants who received caffeine treatment.
12. Length of Stay [ Time Frame: at initial hospital discharge or at death if it occurs earlier (a median of 97 days) ]
    This is measured as the length of stay (in days) up to initial hospital discharge or death, whichever occurred first.
13. Time to Full Enteral Feeding [ Time Frame: 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) ]
    This is measured as the amount of days it took for full enteral feeding to occur.
14. Severe Cerebral Palsy [ Time Frame: at 22-26 months corrected age ]
    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.
15. Hydrocephalus Shunt [ Time Frame: Initial hospital discharge to 22-26 months corrected age ]
    This is measured as Yes if experienced Hydrocephalus shunt by follow-up; Otherwise, No.
16. Microcephaly [ Time Frame: at 22-26 months corrected age ]
    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.
17. Seizure Disorder [ Time Frame: Initial hospital discharge to 22-26 months corrected age ]
    This is measured as Yes if experienced one or more seizures since discharge or of regular use of anticonvulsants or seizure medications; Otherwise, No.
18. Respiratory Disease Necessitating Readmission Before Follow-up [ Time Frame: Initial hospital discharge to 22-26 months corrected age ]
    This is measured as Yes if obtained Respiratory disease necessitating readmission before follow-up; Otherwise, No.
19. Composite Language Score Less Than 85 [ Time Frame: at 22-26 months corrected age ]
    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.
20. Composite Motor Score Less Than 85 [ Time Frame: at 22-26 months corrected age ]
    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.
21. Composite Cognitive Score Less Than 70 [ Time Frame: at 22-26 months corrected age ]
    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.
22. Composite Language Score Less Than 70 [ Time Frame: at 22-26 months corrected age ]
    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.
23. Composite Motor Score Less Than 70 [ Time Frame: at 22-26 months corrected age ]
    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.

Eligibility Criteria

• Ages Eligible for Study: up to 48 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

University of California - Los Angeles

Los Angeles, California, United States, 90025

Stanford University

Palo Alto, California, United States, 94304

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30303

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87131

United States, New York

University of Rochester

Rochester, New York, United States, 14642

United States, North Carolina

RTI International

Durham, North Carolina, United States, 27705

Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States, 45267

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75235

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84108

Sponsors and Collaborators

NICHD Neonatal Research Network

National Heart, Lung, and Blood Institute (NHLBI)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Michele C Walsh, MD; Case Western Reserve University, Rainbow Babies and Children's Hospital
• Principal Investigator: Abhik Das, PhD; RTI International
• Principal Investigator: Beena Sood, MD; Wayne State University
• Principal Investigator: Abbot R Laptook, MD; Brown University, Women & Infants Hospital of Rhode Island
• Principal Investigator: Michael Cotten, MD; Duke University
• Principal Investigator: Ravi Patel, MD; Emory University
• Principal Investigator: Greg Sokol, MD; Indiana University
• Principal Investigator: Krisa P Van Meurs, MD; Stanford University
• Principal Investigator: Brenda Poindexter, MD; Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Waldemar A Carlo, MD; University of Alabama at Birmingham
• 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: Kathleen A Kennedy, MD, MPH; The University of Texas Health Science Center, Houston
• Principal Investigator: Carl T D'Angio, MD; University of Rochester
• Principal Investigator: Pablo Sanchez, MD; Research Institute at Nationwide Children's Hospital
• Principal Investigator: William Truog, MD; Children's Mercy Hospital Kansas City
• Principal Investigator: Uday Devaskar, MD; University of California, Los Angeles
• Study Director: Haresh M Kirpalani, MD; University of Pennsylvania
• Principal Investigator: Bradley Yoder, MD; University of Utah

  Study Documents (Full-Text)

Documents provided by NICHD Neonatal Research Network:

Study Protocol and Statistical Analysis Plan  [PDF] April 7, 2016

More Information

Additional Information:

NICHD NRN Website 

NICHD Pregnancy & Perinatology Branch 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT01702805
• Other Study ID Numbers: NICHD-NRN-0050; U01HL112776 ( U.S. NIH Grant/Contract ); U01HL112748 ( U.S. NIH Grant/Contract )
• First Posted: October 8, 2012
• Results First Posted: February 11, 2022
• Last Update Posted: March 23, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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)

Keywords provided by NICHD Neonatal Research Network:

NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); Transfusions

Additional relevant MeSH terms:

Bronchopulmonary Dysplasia; Infant, Newborn, Diseases; Birth Weight; Body Weight; Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases