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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Extracorporeal Membrane Oxygenation; Red Blood Cell Transfusion; Organ Failure, Multiple
• Intervention / Treatment: Other: Red blood cell transfusion

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 Type: Interventional
• Enrollment (Estimated): 228
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ravi Thiagarajan, MBBS; Phone Number: 617-355-4023; Email: ravi.thiagarajan@cardio.chboston.org
• Study Contact Backup: Name: Peta Alexander, MBBS; Phone Number: 617-355-1822; Email: peta.alexander@cardio.chboston.org

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital for Sick Children
      • Contact: Anne-Marie Guergerian, MD; Phone Number: 309696 416-816-7654; Email: anne-marie.guerguerian@sickkids.ca
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Recruiting
      • Phoenix Children's Hospital
      • Contact: Renee Potera, MD; Email: rpotera@phoenixchildrens.com
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Recruiting
      • Arkansas Children's Hospital
      • Contact: Matthew Malone, MD; Email: MPMalone@uams.edu
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital Los Angeles
      • Contact: Asavari Kamerkar, DO; Phone Number: 508-523-5382; Email: akamerkar@chla.usc.edu
      • Contact: Mayra Lomeli; Phone Number: 323-308-5409; Email: mylomeli@chla.usc.edu
    • Palo Alto, California, United States, 94304
      • Not yet recruiting
      • Lucile Packard Children's Hospital
      • Contact: Kathleen Ryan, MD; Phone Number: 650-723-7914; Email: kateryan@stanford.edu
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Contact: John Kim, MD; Phone Number: 720-777-2885; Email: John.Kim@childrenscolorado.org
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Not yet recruiting
      • Children's Healthcare of Atlanta
      • Contact: Heather Viamonte, MD; Email: Heather.chandler@choa.org
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Lurie Children's Hospital
      • Contact: Erin Bressler, MD; Phone Number: 312-227-1551; Email: ebressler@luriechildrens.org
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Riley Children's Hospital
      • Contact: Matthew Friedman, MD; Email: friedmml@iu.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Sally Vitali, MD; Phone Number: 617-355-7327; Email: Sally.Vitali@childrens.harvard.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Medical Center
      • Contact: Ryan Barbaro, MD, MSc; Phone Number: 734-936-6566; Email: barbaror@med.umich.edu
    • Detroit, Michigan, United States, 48201
      • Not yet recruiting
      • Children's Hospital of Michigan
      • Contact: Mina Hafzalah, MD; Email: MHafzala@dmc.org
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Tanya Perry, DO; Email: Tanya.Perry@cchmc.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Benjamin Kozyak, MD; Phone Number: 267-331-1183; Email: kozyakbw@chop.edu
      • Contact: Devlin Eckardt; Email: eckardtn@chop.edu
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Not yet recruiting
      • MUSC Shawn Jenkins Children's Hospital
      • Contact: Elise Zivick, MD; Phone Number: 843-792-2618; Email: emrath@musc.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
      • Contact: Brian Bridges, MD; Email: brian.c.bridges@vumc.org
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Children's Health Dallas University of Texas Southwestern
      • Contact: Sirine Baltagi, MD; Email: Sirine.Baltagi@UTSouthwestern.edu
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital - Baylor College of Medicine
      • Contact: Marc Anders, MD; Phone Number: 832-946-3834; Email: marc.anders@bcm.edu
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • Primary Children's Hospital
      • Contact: David Bailly, DO; Email: David.Bailly@hsc.utah.edu
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: John McGuire, MD; Phone Number: 206-987-5391; Email: john.mcguire@seattlechildrens.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Gestationally-corrected age < 37 weeks
2. Veno-venous (VV) mode of ECMO
3. Patients initially started on VV-ECMO and then transitioned to VA ECMO
4. ECMO used for procedural support (ECMO deployed and decannulated in procedural area with no ICU ECMO care)
5. ECMO duration expected to be < 24 h
6. Limitation of care or withdrawal of support discussed or in place after ECMO deployment
7. Congenital bleeding disorders
8. Hemoglobinopathies
9. Primary Residence outside country of enrollment
10. Concurrent participation in a separate interventional trial that has potential to impact neurodevelopment status of patient
11. Patients cannulated for ECMO at a non-trial center and transferred to a trial site
12. Randomization not possible within 36 h following ECMO cannulation (e.g., due to staffing or delays related to communication with participant family

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.
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 >5 mmol/L or 2 serum lactate levels > 3 mmol/L measured 2 hours apart; or c) hemoglobin < 8 g/dL or hematocrit < 25%, except for neonates (age =< 28 d) and children with single ventricle congenital heart disease (age < 1 y) RBC transfusion for hemoglobin < 10g/dL or hematocrit <30% is allowed.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted change in pSOFA (pediatric Sequential Organ Failure Assessment) score	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.	At randomization and at 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
Bayley Infant Scales of Development, 4th edition (Bayley-4)	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.	One year post-randomization (+/- 2 mo)
Wechsler Preschool and Primary Scale of Intelligence (WPPSI - IV)	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.	One year post-randomization (+/-2 mo)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mixed venous oxygen saturation	Oxygen content of blood that returns to the heart after meeting tissue needs	Daily AM (6 AM - 12 AM), during ECMO (up to 30 days post-randomization, whichever is earlier)
Total volume of blood products administered	Packed RBC and whole blood, cryoprecipitate, plasma, platelets	30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
Presence vs. absence of hospital-acquired Infection	Nosocomially-acquired infection that is not present or incubating at the time of admission to hospital	30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient)
Daily renal function	Serum creatinine, blood urea nitrogen (BUN)	Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
Acute kidney injury > stage 2	Kidney Disease Improving Global Outcomes (KDIGO) definition	30 days post-randomization (up to time of ECMO decannulation if earlier; varies according to patient)
Presence vs. absence of transfusion-related allergic reactions	Using accepted definition	30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
Number of ECMO circuit component replacements	Replacement of oxygenator and/or pump	At 30 days post-randomization
Presence vs. absence of hemolysis	According to plasma hemoglobin values	Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
All-cause mortality	Death from any cause	30 days, in-hospital, and 1 year post-randomization
Number of ICU-free days	Minimum value is zero, maximum value is 60 minus ICU length of stay	At 60 days post-randomization
Number of hospital-free days	Minimum value is zero, maximum value is 60 minus hospital length of stay	At 90 days post-randomization
Discharge location	Home vs. rehabilitation facility	At time of hospital discharge (assessed up to 1 year)
Adaptive Behavior Assessment System-3 (ABAS-3)	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.	1 year post-randomization (+/- 2 mo)
Child Behavior Checklist (CBCL)	Parent-report; child minimum age 1.5 years. Higher score indicates worse behavior.	1 year post-randomization (+/- 2 mo)
Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0)	Parent-report; child minimum age 2.0 years. Higher score indicates better quality of life.	9 months post-randomization (+/- 1 mo)
Pediatric Quality of Life Inventory Cardiac Module	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.	9 months post-randomization (+/- 1 mo)
Number of Donor Exposures	Number of Donor Exposures for RBC transfusion	Daily up to 30 days post-randomization (or up to time of ECMO decannulation if earlier; varies according to patient)
Recannulation for ECMO < 48 hours and < 72 hours after decannulation	No: of patients recannulated for ECMO within 48 hours and 72 hours post-decannulation	From ECMO decannulation hour to 72 hours following ECMO decannulation
ECMO duration	ECMO duration in hours: Time period from ECMO cannulation to first successful ECMO decannulation in hours. Time accrued during ECMO for additional ECMO runs (i.e. those cannulated within 36 hours following first decannulation) will be included as total ECMO duration	During Hospitalization: From ECMO cannulation to ECMO decannulation, death, transition to Ventricular Assist Device (VAD) or 365 days post-randomization, whichever is earliest
Duration of mechanical ventilation post-randomization	Duration of mechanical ventilation post-randomization in hours: Randomization to first successful extubation from mechanical ventilation hours; for patients with tracheostomy that require mechanical ventilatory support at the time of ICU discharge: time of ICU discharge to compute mechanical ventilation duration.	During Hospitalization: From Randomization to Extubation from Mechanical Ventilation, death, hospital discharge, or 365 days post-randomization, whichever is earliest
Occurrence of Seizures	Occurrence of electroencephalographic evidence of seizure prior to hospital discharge or within 90 d post randomization, whichever is earliest	Randomization to Hospital Discharge or 90 days post-randomization, whichever is earliest
Stroke or Intracranial Hemorrhage during ECMO	Occurrence of brain infarction, intracranial hemorrhage, or ischemic injury during ECMO (composite) confirmed using head ultrasound and Computed Tomography (CT) during ECMO	Time of ECMO cannulation to ECMO decannulation, death or 30 days post-randomization, whichever occurs first
Stroke or Intracranial Hemorrhage prior to Hospital Discharge	Proportion of patients with brain infarction, intracranial hemorrhage, or ischemic injury (composite) confirmed using head ultrasound, CT, or Magnetic Resonance Imaging (MRI) prior to hospital discharge or within 90 d post randomization, whichever is earliest	ECMO cannulation to 90 days post-randomization or hospital discharge, whichever occurs first
Pediatric Overall Performance Category (POPC)	Pediatric Overall Performance (POPC; score range 0 to 6; Unit: categories on a scale; value: lower is better) at 3, 6, 9, 12 months post-randomization.	Randomization to study completion (completion of 12 month neurodevelopment assessment)
Functional Status Score (FSS)	Functional Status Score (FSS; score range 6 to 30; Unit: numerical value on a scale; lower is better) at hospital discharge, 3, 6, 9, 12 months post-randomization	Randomization to study completion (completion of 12 month neurodevelopment assessment)
ICU Length of Stay among survivors	Duration of hospitalization in the ICU among survivors in days	ICU Admission to ICU discharge, death or 365 post-randomization, whichever occurs first
Hospital length of stay among survivors	Duration of hospitalization among survivors in days	Hospital Admission to discharge death, or 365 days post-randomization, whichever occurs first
Pediatric Cerebral Performance Category (PCPC)	Pediatric Cerebral Performance Category (POPC; score range 0 to 6; Unit: categories on a scale, lower is better) at 3, 6, 9, 12 months post-randomization.	Randomization to study completion (completion of 12 month neurodevelopment assessment)

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Lynn A. Sleeper, ScD, Boston Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2023
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: June 1, 2022
• First Posted (Actual): June 6, 2022

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: pediatric; children; ECMO; transfusion; neurodevelopment; TITRE
• Additional Relevant MeSH Terms: Pathologic Processes; Shock; Multiple Organ Failure
• Other Study ID Numbers: W81XWH-22-1-0301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No