Transfusion of Prematures Trial
- Conditions
- AnemiaInfant, Newborn, DiseasesInfant, Small for Gestational AgeBronchopulmonary Dysplasia (BPD)Infant, Extremely Low Birth Weight
- Interventions
- Procedure: Liberal Cell TransfusionProcedure: Restricted red cell transfusion
- Registration Number
- NCT01702805
- Lead Sponsor
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 1824
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description High Threshold Transfusion Liberal Cell Transfusion Transfusions will be administered using a higher threshold hemoglobin value. Low Threshold Transfusion Restricted red cell 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
- Primary Outcome Measures
Name Time Method Severe Vision Impairment 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.
Death 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.
Neurodevelopmental Impairment 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.
Moderate or Severe Cerebral Palsy 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.
Severe Hearing Impairment 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.
Death or Neurodevelopmental Impairment 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.
Cognitive Delay 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.
- Secondary Outcome Measures
Name Time Method Survival to Discharge Without Severe Complications 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.
Weight-for-age: Z-score 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.
Head Circumference-for-age: Z-score 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.
Postmenstrual Age 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 This is measured as the average postmenstrual age (in weeks) at final caffeine dose in infants who received caffeine treatment.
Composite Motor Score Less Than 85 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.
Composite Language Score Less Than 70 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.
Composite Motor Score Less Than 70 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.
Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received 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.
Grade 3 or 4 Intraventricular Hemorrhage, Cystic Periventricular Leukomalacia, or Ventriculomegaly Diagnosed on Ultrasonographic Examination 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.
Length-for-age: Z-score 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.
Hydrocephalus Shunt Initial hospital discharge to 22-26 months corrected age This is measured as Yes if experienced Hydrocephalus shunt by follow-up; Otherwise, No.
Respiratory Disease Necessitating Readmission Before Follow-up 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.
Composite Language Score Less Than 85 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.
Bronchopulmonary Dysplasia, Diagnosed on the Basis of the Need for Supplemental Oxygen After a Standardized Oxygen Reduction Test at 36 Weeks of Postmenstrual Age 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.
Necrotizing Enterocolitis, Bell's Stage >=2 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.
Number of Transfusions Per Infant 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)
Postmenstrual Age at Final Trachael Extubation 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.
Length of Stay 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.
Time to Full Enteral Feeding 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.
Severe Cerebral Palsy 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.
Microcephaly 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.
Seizure Disorder 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.
Composite Cognitive Score Less Than 70 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.
Trial Locations
- Locations (20)
University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
University of California - Los Angeles
🇺🇸Los Angeles, California, United States
Stanford University
🇺🇸Palo Alto, California, United States
Duke University
🇺🇸Durham, North Carolina, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Cincinnati Children's Medical Center
🇺🇸Cincinnati, Ohio, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital
🇺🇸Cleveland, Ohio, United States
Research Institute at Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Univeristy of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Brown University, Women & Infants Hospital of Rhode Island
🇺🇸Providence, Rhode Island, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Rochester
🇺🇸Rochester, New York, United States
RTI International
🇺🇸Durham, North Carolina, United States