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

Extracorporeal Membrane Oxygenation Clinical Trial

— TITRE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05405426
• Other study ID #: W81XWH-22-1-0301
• Status: Recruiting
• Phase: N/A
• Start date: April 14, 2023
• Est. completion date: December 2025

Study information

• Verified date: May 2024
• Source: Boston Children's Hospital
• Contact: Ravi Thiagarajan, MBBS
• Phone: 617-355-4023
• Email: ravi.thiagarajan[@]cardio.chboston.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 228
• Est. completion date: December 2025
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 6 Years

Eligibility

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 at the time of ECMO cannulation

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. An exception: those cannulated for ECMO at another non-trial site location that is part of the same healthcare system and subsequently transferred to a trial site will be eligible

12. Randomization not possible within 36 h following ECMO cannulation (e.g., due to staffing or delays related to communication with participant family

13. ECMO deployed as a bridge to ventricular assist device

Related Conditions & MeSH terms

• Extracorporeal Membrane Oxygenation
• Multiple Organ Failure
• Organ Failure, Multiple
• Red Blood Cell Transfusion

Intervention

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.

Locations

Country	Name	City	State
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	MUSC Shawn Jenkins Children's Hospital	Charleston	South Carolina
United States	Lurie Children's Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Children's Health Dallas University of Texas Southwestern	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Inova Children's Hospital	Falls Church	Virginia
United States	Texas Children's Hospital - Baylor College of Medicine	Houston	Texas
United States	Riley Children's Hospital	Indianapolis	Indiana
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Lucile Packard Children's Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Boston Children's Hospital

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Number of ECMO circuit component replacements	Replacement of oxygenator and/or pump	At 30 days post-randomization
Secondary	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)
Secondary	All-cause mortality	Death from any cause	30 days, in-hospital, and 1 year post-randomization
Secondary	Number of ICU-free days	Minimum value is zero, maximum value is 60 minus ICU length of stay	At 60 days post-randomization
Secondary	Number of hospital-free days	Minimum value is zero, maximum value is 60 minus hospital length of stay	At 90 days post-randomization
Secondary	Discharge location	Home vs. rehabilitation facility	At time of hospital discharge (assessed up to 1 year)
Secondary	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)
Secondary	Child Behavior Checklist (CBCL)	Parent-report; child minimum age 1.5 years. Higher score indicates worse behavior.	1 year post-randomization (+/- 2 mo)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Pediatric Overall Performance Category (POPC)	Pediatric Overall Performance (POPC; score range 0 to 6; Unit: categories on a scale; value: lower is better) at Hospital Discharge, 3, 6, 9, 12 months post-randomization.	Randomization to study completion (completion of 12 month neurodevelopment assessment)
Secondary	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)
Secondary	ICU Length of Stay among survivors	Duration of hospitalization in the ICU among survivors in days. For ICU readmissions only the only days in the first 2 ICU readmissions will be included	ICU Admission to ICU discharge, death or 365 post-randomization, whichever occurs first
Secondary	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
Secondary	Pediatric Cerebral Performance Category (PCPC)	Pediatric Cerebral Performance Category (POPC; score range 0 to 6; Unit: categories 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)
Secondary	Number of ICU readmissions prior to discharge from index hospitalization among survivors	Number of ICU readmissions. ICU readmissions are defined as number of ICU admissions following discharge from the first ICU admission.	Index ICU discharge to Hospital discharge or 365 days post-randomization, whichever occurs first