Transfusion of Prematures Trial (TOP)

Study Description

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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 < 29 weeks GA 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.

Study Design

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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
Estimated Primary Completion Date :	October 2019
Estimated Study Completion Date :	December 2019

Arms and Interventions

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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

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Primary Outcome Measures :

1. Death or significant neurodevelopmental impairment [ Time Frame: Birth to 22-26 months corrected gestational age ]
   Number of children surviving without significant neurodevelopmental impairment at 22-26 months of corrected age.

Secondary Outcome Measures :

1. Grade 3 or 4 IVH, cystic PVL, or ventriculomegaly [ Time Frame: Birth to 36 weeks PMA ]
2. Moderate or severe cerebral palsy [ Time Frame: Birth to 26 months corrected age ]
3. Episodes of necrotizing enterocolitis [ Time Frame: Birth to 36 weeks PMA ]
   Episodes of NEC Bell stage II or higher.
4. Time to full feeds [ Time Frame: Birth to 36 weeks PMA ]
   The amount of time it takes for infant to achieve full feeds.
5. Length of hospital stay [ Time Frame: Birth to 36 weeks PMA ]
6. Number of transfusions [ Time Frame: Birth to 36 weeks PMA ]
   Number of transfusions, numbers of donor exposures by RBC donors or other blood product
7. Age at final tracheal extubation [ Time Frame: Birth to 36 weeks PMA ]
8. Age at final caffeine dose [ Time Frame: Birth to 36 weeks PMA ]
9. Growth [ Time Frame: Birth to 36 weeks PMA ]
   Weight, length, and head circumference at 36 weeks postmenstrual age
10. Survival to discharge without severe morbidity [ Time Frame: Birth to 36 weeks PMA ]
    Survival to discharge without severe morbidity, defined as any of the following: bronchopulmonary dysplasia, retinopathy of prematurity (stage >3 or requiring treatment), or serious brain abnormality (grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, or ventriculomegaly).
11. Respiratory disease [ Time Frame: Birth to 26 months corrected age ]
    The presence of respiratory disease necessitating readmission before 22-26 months follow-up.
12. Hydrocephalus shunt, microcephaly, or seizure disorder [ Time Frame: Birth to 26 months corrected age ]
13. Economic cost-benefit analysis [ Time Frame: Birth to 26 months corrected age ]

Eligibility Criteria

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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 1000 grams.
• Gestational age at least 22 weeks but less than 29 completed 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
• 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

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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

More Information

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Additional Information:

NICHD NRN Website 

NICHD Pregnancy &amp; Perinatology Branch 

Responsible Party:	NICHD Neonatal Research Network
ClinicalTrials.gov Identifier:	NCT01702805 History of Changes
Other Study ID Numbers:	NICHD-NRN-0050; U01HL112776 ( U.S. NIH Grant/Contract ); U01HL112748 ( U.S. NIH Grant/Contract )
First Posted:	October 8, 2012
Last Update Posted:	January 26, 2018
Last Verified:	January 2018
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:

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