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Transfusion of Prematures Trial (TOP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01702805
Recruitment Status : Active, not recruiting
First Posted : October 8, 2012
Results First Posted : February 11, 2022
Last Update Posted : February 11, 2022
Sponsor:
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

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.

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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
Actual Primary Completion Date : January 2020
Estimated Study Completion Date : August 2023


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



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.



Information from the National Library of Medicine

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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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01702805


Locations
Show Show 20 study locations
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
Layout table for investigator information
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:
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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    Key Record Dates
Results First Posted: February 11, 2022
Last Update Posted: February 11, 2022
Last Verified: January 2022
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:
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Bronchopulmonary Dysplasia
Infant, Newborn, Diseases
Birth Weight
Body Weight
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases