TITRE: Trial of Indication-Based Transfusion of Red Blood Cells in ECMO

Sponsor

Boston Children's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05405426

Collaborator

(none)

228

Enrollment

Locations

Arms

Anticipated Duration (Months)

12.7

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

TITRE - Trial of Indication-based Transfusion of Red Blood Cells in ECMO, is a multicenter, prospective, randomized clinical trial. The overarching goal of TITRE is to determine whether restricting red blood cell (RBC) transfusion according to an indication-based strategy for those with bleeding and/or deficit of tissue oxygen delivery, compared with transfusion based on center-specific hemoglobin or hematocrit thresholds, can reduce organ dysfunction and improve later neurodevelopment in critically ill children receiving Extracorporeal Membrane Oxygenation (ECMO) support.

Condition or Disease	Intervention/Treatment	Phase
Extracorporeal Membrane Oxygenation Red Blood Cell Transfusion Organ Failure, Multiple	Other: Red blood cell transfusion	N/A

Detailed Description

Observational studies of children on ECMO have shown an association between large-volume RBC transfusion and mortality. However, the hematocrit (or hemoglobin) level at which optimal tissue oxygen delivery occurs is unknown. TITRE - Trial of Indication-based Transfusion of Red Blood Cells in ECMO, is a prospective, randomized clinical trial to be conducted at 18-20 study sites. The overarching goal of TITRE is to determine whether restricting RBC transfusion according to an indication-based strategy for those with bleeding and/or deficit of tissue oxygen delivery, compared with transfusion based on center-specific hemoglobin or hematocrit thresholds, can reduce organ dysfunction and improve later neurodevelopment in critically ill children receiving ECMO support.

Aim 1: To test whether children < 6 years of age on ECMO support who are randomized to a strategy of indication-based versus center-specific threshold-based RBC transfusion will have greater improvement in organ function.

Aim 2: To test whether survivors among children age < 6 years on ECMO support who are randomized to indication-based compared to center-specific threshold-based RBC transfusion will have better neurodevelopmental outcomes and health-related QOL at one year post-randomization.

Key design features include: Randomization stratified by patient age (neonate, <28d vs. non-neonate) and by diagnosis (CHD vs. other diagnosis); and a target sample size of 228 patients. Endpoints will be evaluated during ECMO, at hospital discharge, and at 3, 6, 9, and 12 months. To ensure trial integrity, the primary outcome (pSOFA: Pediatric Sequential Organ Failure Assessment score) will be adjudicated by an independent committee and neurodevelopmental assessments will be blinded.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

228 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two independent study arms will be used: indication-based red blood cell transfusion strategy vs. a center-specific standard of care hemoglobin/hematocrit threshold-based red blood cell transfusion strategyTwo independent study arms will be used: indication-based red blood cell transfusion strategy vs. a center-specific standard of care hemoglobin/hematocrit threshold-based red blood cell transfusion strategy

Masking:

Double (Participant, Outcomes Assessor)

Masking Description:

Adjudicators for the primary endpoint (organ failure assessment score) will be blinded to treatment assignment. Specialists for neurodevelopmental assessment of participants will be blinded to treatment assignment. Parents/guardians completing assessment of child behavior, functioning, and health-related quality of life will be blinded to treatment assignment.

Primary Purpose:

Other

Official Title:

TITRE: Trial of Indication-Based Transfusion of Red Blood Cells in ECMO

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2024

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Indication-based red blood cell transfusion strategy Red blood cell transfusion will occur if the center-specific hemoglobin/hematocrit threshold for transfusion is met AND at least one of the following conditions is present: a) moderate or severe bleeding; b) reduced tissue oxygen delivery, defined as serum lactate >3 mmol/L; or c) hemoglobin < 8 g/dL or hematocrit < 25% or, for children with single ventricle heart disease, 5% lower than institutional standard hematocrit threshold for transfusion during ECMO.	Other: Red blood cell transfusion The intervention is a strategy for when red blood cell transfusion will be administered (see description of Arms). However, volume of RBC transfused in the two arms is not specified by this study. Red blood cell transfusion strategy for ECMO weaning and decannulation is not specified by this study. Red blood cell transfusion after ECMO decannulation is not specified by this study.
Other: Center-specific hemoglobin/hematocrit threshold-based red blood cell transfusion strategy Red blood cell transfusion will occur according to each study center's standard of care strategy, typically based on a particular hemoglobin threshold or hematocrit threshold. When hemoglobin or hematocrit decrease to the threshold, red blood cell transfusion is administered.	Other: Red blood cell transfusion The intervention is a strategy for when red blood cell transfusion will be administered (see description of Arms). However, volume of RBC transfused in the two arms is not specified by this study. Red blood cell transfusion strategy for ECMO weaning and decannulation is not specified by this study. Red blood cell transfusion after ECMO decannulation is not specified by this study.

Arm

Intervention/Treatment

Active Comparator: Indication-based red blood cell transfusion strategy

Red blood cell transfusion will occur if the center-specific hemoglobin/hematocrit threshold for transfusion is met AND at least one of the following conditions is present: a) moderate or severe bleeding; b) reduced tissue oxygen delivery, defined as serum lactate >3 mmol/L; or c) hemoglobin < 8 g/dL or hematocrit < 25% or, for children with single ventricle heart disease, 5% lower than institutional standard hematocrit threshold for transfusion during ECMO.

Other: Red blood cell transfusion

The intervention is a strategy for when red blood cell transfusion will be administered (see description of Arms). However, volume of RBC transfused in the two arms is not specified by this study. Red blood cell transfusion strategy for ECMO weaning and decannulation is not specified by this study. Red blood cell transfusion after ECMO decannulation is not specified by this study.

Other: Center-specific hemoglobin/hematocrit threshold-based red blood cell transfusion strategy

Red blood cell transfusion will occur according to each study center's standard of care strategy, typically based on a particular hemoglobin threshold or hematocrit threshold. When hemoglobin or hematocrit decrease to the threshold, red blood cell transfusion is administered.

Other: Red blood cell transfusion

Outcome Measures

Primary Outcome Measures

Baseline-adjusted change in pSOFA (pediatric Sequential Organ Failure Assessment) score [At randomization and at 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
The pSOFA score ranges from 0 (no organ dysfunction) through 24 (severe dysfunction in all 6 organs assessed). If death occurs during ECMO within 30 days, a score of 24 is assigned.
Bayley Infant Scales of Development, 4th edition (Bayley-4) [One year post-randomization (+/- 2 mo)]
Scales for Cognitive, Language (Expressive and Receptive), Motor (Gross and Fine), and Social-Emotional. For ages 16 days to 42 months. Composite score range is 40 to 160. Higher scores indicate better performance.
Wechsler Preschool and Primary Scale of Intelligence (WPPSI - IV) [One year post-randomization (+/-2 mo)]
Index scores include Verbal Comprehension, Visual Spatial, Working Memory, and Full Scale Intelligence Quotient (IQ). Score range is 40 to 160. Higher scores indicate better performance.

Secondary Outcome Measures

Mixed venous oxygen saturation [Daily AM (6 AM - 12 AM), during ECMO (up to 30 days post-randomization, whichever is earlier)]
Oxygen content of blood that returns to the heart after meeting tissue needs
Total volume of blood products administered [30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
Packed RBC and whole blood, cryoprecipitate, plasma, platelets
Presence vs. absence of hospital-acquired Infection [30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient)]
Nosocomially-acquired infection that is not present or incubating at the time of admission to hospital
Daily renal function [Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
Serum creatinine, blood urea nitrogen (BUN)
Acute kidney injury > stage 2 [30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient)]
Kidney Disease Improving Global Outcomes (KDIGO) definition
Presence vs. absence of transfusion-related allergic reactions [30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
Using accepted definition
Presence vs. absence of transfusion-related acute lung injury (TRALI) [30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
Using accepted definition
Number of ECMO circuit component replacements [At 30 days post-randomization]
Replacement of oxygenator and/or pump
Presence vs. absence of hemolysis [Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)]
According to plasma hemoglobin values
All-cause mortality [30 days, in-hospital, and 1 year post-randomization]
Death from any cause
Number of ICU-free days [At 60 days post-randomization]
Minimum value is zero, maximum value is 60 minus ICU length of stay
Number of hospital-free days [At 90 days post-randomization]
Minimum value is zero, maximum value is 60 minus hospital length of stay
Discharge location [At time of hospital discharge (assessed up to 1 year)]
Home vs. rehabilitation facility
Adaptive Behavior Assessment System-3 (ABAS-3) [1 year post-randomization (+/- 2 mo)]
Composite scores for overall adaptive functioning (General Adaptive Composite, GAC), Conceptual, Social and Practical domains as well as nine subscales. Higher score indicates better behavior.
Child Behavior Checklist (CBCL) [1 year post-randomization (+/- 2 mo)]
Parent-report; child minimum age 1.5 years. Higher score indicates worse behavior.
Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) [9 months post-randomization (+/- 1 mo)]
Parent-report; child minimum age 2.0 years. Higher score indicates better quality of life.
Pediatric Quality of Life Inventory Cardiac Module [9 months post-randomization (+/- 1 mo)]
Parent-report; child minimum age 2.0 years. To be completed for participants with a congenital heart disease diagnosis. Higher score indicates better quality of life.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 6 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age < 6 year at ECMO cannulation
Veno-arterial (VA) mode of ECMO
First ECMO run during the index hospitalization

Exclusion Criteria:

Gestationally-corrected age < 37 weeks
Veno-venous (VV) mode of ECMO
Patients initially started on VV-ECMO and then transitioned to VA ECMO
ECMO used for procedural support (ECMO deployed and decannulated in procedural area with no ICU ECMO care)
ECMO duration expected to be < 48 h
Limitation of care or withdrawal of support expected < 48 h after ECMO deployment
Congenital bleeding disorders
Hemoglobinopathies
Primary Residence outside United States or Canada

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	Lucile Packard Children's Hospital	Palo Alto	California	United States	94304
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
6	Lurie Children's Hospital	Chicago	Illinois	United States	60611
7	Boston Children's Hospital	Boston	Massachusetts	United States	02115
8	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
9	Washington University in St. Louis School of Medicine	Saint Louis	Missouri	United States	63110
10	Duke University Hospital	Durham	North Carolina	United States	27710
11	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
12	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
13	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
14	Children's Health Dallas University of Texas Southwestern	Dallas	Texas	United States	75235
15	Texas Children's Hospital - Baylor College of Medicine	Houston	Texas	United States	77030
16	Primary Children's Hospital	Salt Lake City	Utah	United States	84132
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8