Massive Transfusion in Children-2: A Trial Examining Life Threatening Hemorrhage in Children

Study Overview
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Brief Summary
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The MATIC-2 is a multicenter clinical trial enrolling children who are less than 18 years of age with hemorrhagic shock potentially needing significant blood transfusion. The primary objective of the clinical trial is to determine the effectiveness of Low Titer Group O Whole Blood (LTOWB) compared to component therapy (CT), and Tranexamic Acid (TXA) compared to placebo in decreasing 24-hour all-cause mortality in children with traumatic life threatening hemorrhage.

Detailed Description
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The MATIC-2 trial is a Bayesian, randomized, multicenter, adaptive platform phase III trial. The trial will include injured children with hemorrhagic shock anticipated to require massive blood transfusion, who will be randomized to receive either LTOWB or CT and Tranexamic Acid or placebo. The study investigators hypothesize that the use of LTOWB is non-inferior and/or superior for 24-hour mortality and that LTOWB does not increase the risk of adverse events or outcomes, such as thrombotic events, compared to CT. The investigators also hypothesize that the use of TXA is superior for 24-hour mortality and does not increase the risk of adverse events or outcomes, such as thrombotic events, compared to placebo. Objectives: The primary objectives are to: Determine the effectiveness of LTOWB to reduce all-cause 24-hour mortality compared to CT in children with traumatic life-threatening hemorrhage. Determine the effectiveness of TXA to reduce all-cause 24-hour mortality compared to placebo in children with traumatic life-threatening hemorrhage. Secondary objectives are to determine the effectiveness and safety of LTOWB and TXA to improve secondary and exploratory outcomes (or endpoints) in children with traumatic life-threatening hemorrhage. Safety objectives are to determine the effect of LTOWB and TXA on safety related outcomes/endpoints. The safety outcomes include: Acute kidney injury Acute respiratory distress syndrome Sepsis Thromboembolism: arterial and venous Markers of hemolysis Alloimmunization in Rh negative female recipients of Rh+ LTOWB Transfusion-related adverse events 8 Serious Adverse Events (SAEs) Mechanistic Objectives are to: Define trauma induced coagulopathy (TIC) according to measures of shock, hemostasis, and endothelial and immune function. To determine if measures of shock, endothelial, immune, and hemostasis function upon admission (TIC endotype) predicts which hemostatic resuscitation therapies or combinations of therapies (LTOWB, CT, LTOWB + TXA, CT+TXA) for each study group improves outcomes without increasing the risk of adverse events. To determine the mechanisms of how hemostatic resuscitation therapies or combinations of therapies (LTOWB, CT, LTOWB + TXA, CT+TXA) improve TIC endotypes and outcomes. Pharmacokinetic objectives are to evaluate the PK and PD properties of TXA in a population of children with life-threatening traumatic bleeding.

Official Title
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Massive Transfusion in Children: a Platform RCT of Whole Blood Compared to Component Therapy and Tranexamic Acid to Placebo in Life-threatening Traumatic Bleeding

Conditions
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Hemorrhagic Shock, Trauma Injury

Intervention / Treatment
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* Biological: Low Titer Group O Whole Blood (LTOWB)
* Drug: Placebo
* Drug: Tranexamic Acid (TXA)
* Biological: Component Therapy (CT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children, defined as less than 18 years of age with traumatic injury MTP activation for confirmed or suspected active life-threatening traumatic bleeding AND Confirmed or suspected active life-threatening traumatic bleeding with at least 2 of 3 of the following criteria: Hypotension for age (< 5% tile) Tachycardia for age (>95th % tile) Traumatic injury with exam findings consistent with severe bleeding (e.g., penetrating injury, hemothorax, distended abdomen with bruising, amputation of limb). Exclusion Criteria: Unknown time of injury Greater than 3 hours since time of injury History of seizure after the injury event Known allergy or hypersensitivity reaction to TXA Comatose (Glasgow Coma Score of 3) with fixed and dilated pupils suggesting nonsurvivable brain injury MTP activated but no blood products given Patients who required an ED thoracotomy or received more than 5 consecutive minutes of cardiopulmonary resuscitation (prior to receiving randomized blood products) Patients who are obviously pregnant on clinical examination Known prisoners as defined in protocol Known ward of the state Isolated hanging, drowning or burns Previous enrollment in MATIC-2 Prior study opt-out with bracelet

Ages Eligible for Study
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Maximum Age: 17 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: Crossover Assignment
Interventional Model Description: MATIC-2 is a Bayesian, randomized, multicenter, adaptive platform phase III trial to examine the effectiveness and safety of LTOWB versus CT and TXA vs placebo in 1000 children at 20 US high volume academic pediatric trauma centers. Mechanisms of Trauma induced Coagulopathy (TIC) and resuscitation effects will also be investigated. The trial will stratify pediatric trauma centers based on their reported Massive Transfusion Protocol (MTP) volume and then randomize them into four treatment combinations. After an initial enrollment phase, treatment sites will cross over to ensure that all treatments are tested across every site, eliminating biases by the time of the first interim analysis.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1 (LTOWB+TXA)<br>Concurrent administration of LTOWB and TXA. | Biological: Low Titer Group O Whole Blood (LTOWB)<br>* LTOWB is whole blood from group O donors with low titer (<200) anti-A and anti-B antibodies. Up to 8 units of LTOWB will be allowed unless local clinical practice allows for a higher maximum dose.<br>Drug: Tranexamic Acid (TXA)<br>* TXA is a synthetic lysine analog that competitively inhibit activation of plasminogen, thereby decreasing the conversion of plasminogen to plasmin, preventing degradation of fibrin's matrix structure.<br>|
| Other: Group 2 (LTOWB+Placebo)<br>Concurrent administration of LTOWB and Placebo | Biological: Low Titer Group O Whole Blood (LTOWB)<br>* LTOWB is whole blood from group O donors with low titer (<200) anti-A and anti-B antibodies. Up to 8 units of LTOWB will be allowed unless local clinical practice allows for a higher maximum dose.<br>Drug: Placebo<br>* Placebo will be made by the research pharmacy at each of the clinical sites<br>|
| Other: Group 3 (TXA+CT)<br>Concurrent administration of TXA and CT | Drug: Tranexamic Acid (TXA)<br>* TXA is a synthetic lysine analog that competitively inhibit activation of plasminogen, thereby decreasing the conversion of plasminogen to plasmin, preventing degradation of fibrin's matrix structure.<br>Biological: Component Therapy (CT)<br>* Component Therapy (CT) will be RBCs, plasma and platelet units in a 1:1:1 unit ratio. This will be given with Placebo<br>|
| Other: Group 4 (CT+Placebo)<br>Concurrent administration of CT and Placebo | Drug: Placebo<br>* Placebo will be made by the research pharmacy at each of the clinical sites<br>Biological: Component Therapy (CT)<br>* Component Therapy (CT) will be RBCs, plasma and platelet units in a 1:1:1 unit ratio. This will be given with Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hours all cause mortality |  | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-hour, 72-hour and 28-day survival | Cumulative survival over time through 28 days post-enrollment: includes 6-hour, 72-hour and 28-day survival. | 6, 72 hours and 28 days | 
| 24 hours total blood product transfusion volumes | Total blood product transfusion in 24 hours after enrollment. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Pediatrics, Transfusion