Transfusion of Prematures Trial

Study Overview
=================
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.

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?

Conditions
-----------------
Infant, Newborn, Diseases, Infant, Extremely Low Birth Weight, Infant, Small for Gestational Age, Bronchopulmonary Dysplasia (BPD), Anemia

Intervention / Treatment
-----------------
* Procedure: Liberal Cell Transfusion
* Procedure: Restricted red cell transfusion


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Maximum Age: 48 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Threshold Transfusion<br>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<br> <br> |
| Active Comparator: High Threshold Transfusion<br>Transfusions will be administered using a higher threshold hemoglobin value. | Procedure: Liberal Cell Transfusion<br> <br> |

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NICHD Neonatal Research Network, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Transfusions