Pilot Optimizing Transfusion Thresholds in Critically-ill Children With Anaemia

Study Overview
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Brief Summary
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The Pilot Optimizing Transfusion Thresholds in Critically-ill Children with Anaemia (P-OpTTICCA) study is a pilot trial for a large pragmatic international parallel open-label non-inferiority randomised controlled trial. The primary outcome of the pilot study is feasibility.

Detailed Description
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Patients in paediatric intensive care units (PICU) are among the main groups of transfusion recipients. Blood transfusions expose recipients to infectious and non-infectious serious hazards. Despite an increasing number of red blood cell (RBC) transfusion threshold randomised controlled trials (RCT) to date, only one large RCT, the Transfusion Requirement In PICU (TRIPICU) study (Lacroix. N Engl J Med 2007;356:1609-19) informs practice in PICU. This dearth of paediatric data was reiterated by a recent National Heart, Lung and Blood Institutes state of the art symposium. Despite being internally robust, the generalizability of TRIPICU has been questioned given that nearly 90% of critically ill children with haemoglobin (Hb) level ≤ 95 g/L were not enrolled for a range of pre-specified reasons including severity of illness, clinical instability and uncertain physician buy-in, thus threatening broader application of this critical knowledge into practice. Recent data and evidence summarised in systematic reviews support the need to explore the benefits and safety of Hb threshold ≤ 70 g/L for almost all critically ill children, not only those who would have been enrolled in TRIPICU. We propose an international pilot study that will inform the design of a large pragmatic non-inferiority RCT (termed OpTTICCA) conceived to derive generalizable transfusion guidance for physicians. Objectives of the pilot-RCT. Specific aims are to: Establish the feasibility of enrolling ≥80% of eligible patients. Document adherence to study intervention ≥80% (restrictive transfusion policy). Assess the incidence rate of the primary outcome measure of the full RCT (new and progressive multiple organ dysfunction syndrome, which includes mortality). Establish the feasibility of using routinely collected clinical information from electronic medical data monitoring system (eMDMS) to enhance cost-efficiency. In the pilot-RCT, we will enrol 120 patients (20 to 40/site) in PICUs equipped with electronic medical data monitoring system (eMDMS). This trial builds on successful prior RCTs that involved international collaboration and funding (Canada, United Kingdom, France): TRIPICU, Age of Blood Evaluation (ABLE) (Lacroix. N Engl J Med 2015) and Age of Blood in Children in PICU (ABC-PICU study: Tucci et al. Trials 2018). The pilot-RCT will be considered as the vanguard phase of the full OpTTICCA RCT if no important design changes are required. Expected results. This pilot-RCT will focus on feasibility parameters. It will explore whether we can 1) recruit a much broader eligible patient group, 2) assess protocol adherence, 3) assess the primary outcome measure, and 4) abstract most data electronically. A definitive trial will provide transfusion guidance for many important subgroups in whom evidence is presently lacking including children admitted with bone marrow failure, head injury, some cardiac disorders, and sepsis.

Official Title
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Pilot Optimizing Transfusion Thresholds in Critically-ill Children With Anaemia (P-OpTTICCA): a Pilot Trial for a Large Pragmatic International Parallel Open-label Non-inferiority Randomised Controlled Trial.

Conditions
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Anemia

Intervention / Treatment
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* Procedure: Less red blood cell transfusions
* Procedure: More red blood cell transfusion (standard transfusion strategy in PICU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Hemoglobin concentration ≤ 95 g/L, while in PICU 2. Not already participating to a randomized controlled trial on hemoglobin threshold to guide red blood cell transfusion practice Exclusion Criteria: Post conception age ≤ 36 weeks or > 18 years at PICU entry Refusal of consent by patient and/or parent Uncorrected cyanotic cardiac disease, univentricular physiology Sickle cell disease Brain Death Extracorporeal membrane oxygenation (ECMO)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: parallel open-label pragmatic non-inferiority randomised controlled trial (RCT)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Restrictive arm (intervention)<br>Less red blood cell transfusions. The protocol will require that no red blood cell transfusion be given unless the hemoglobin level is below or equal at 70 g per L. | Procedure: Less red blood cell transfusions<br>* The instructions given to caregivers will be to consider prescribing a red blood cell transfusion only if the hemoglobin level is ≤ 70 g per L.<br>* Other names: Restrictive red blood cell transfusion strategy;|
| Active Comparator: Standard care arm (comparator)<br>Clinical teams will follow their usual transfusion practices. | Procedure: More red blood cell transfusion (standard transfusion strategy in PICU)<br>* The instructions given to caregivers will be to prescribe a red blood cell transfusion according to their usual standard practice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment: screening | Proportion of patients eligible for consent approached > 90%; | One year | 
| Recruitment: consent | Proportion of approached patients who decline consent < 20%, | One year | 
| Recruitment: enrolment | Recruitment: ≥ 2 patients randomized/site/week. | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Representativeness: exclusion | We recruit > 80% of patients who would have been excluded from TRIPICU (Lacroix et al. N Engl Med 2007). | One year | 
| Representativeness: opt-out | Proportion of dropout and lost to follow-up is expected to be < 2%. | One year | 
| Compliance | Proportion of RBC transfusions given with hemoglobin > 70 g/L in the restrictive arm (definition of non-compliance) is < 20%. | One year | 
| Separation | Post randomisation separation of hemoglobin concentration between both arms in the pilot-RCT is ≥ 10 g/L. | One year | 
| Suspension | Proportion of children wha are suspended is < 20%. | One year | 
| Data collection | Most data (> 80%) are abstracted directly from electronic medical data monitoring system. | One year | 
| Data entry | Proportion of erroneous data entry is < 5%. | One year. | 
| Outcomes | Incidence rate of the primary outcome measure - new and progressive multiple organ dysfunction syndrome (NPMODS) - in the standard care arm of the pilot-trial is ≥ 20%. | One year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemoglobin threshold, critically ill children, randomized controlled trial, red blood cell tranfusions