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

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

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.

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:

1. Determine the effectiveness of LTOWB to reduce all-cause 24-hour mortality compared to CT in children with traumatic life-threatening hemorrhage.
2. 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:

1. Acute kidney injury
2. Acute respiratory distress syndrome
3. Arrhythmia
4. Abdominal compartment syndrome
5. Bleeding after hemostasis requiring intervention
6. Myocardial infarction
7. Pneumonia
8. Sepsis
9. Stroke
10. Seizure
11. Thrombotic events (arterial or venous)
12. Urinary Tract Infection
13. Alloimmunization in Rh negative female recipients of Rh+ LTOWB or RBC's
14. Organ failure (as determined by PELOD-2 score)

Mechanistic Objectives are to:

1. Define trauma induced coagulopathy (TIC) according to measures of shock, hemostasis, and endothelial and immune function.
2. 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.
3. 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.

General Inclusion Criteria:

1. Children, defined as less than estimated18 years of age with traumatic injury
2. 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:

1. Hypotension for age (< 5% tile)
2. Tachycardia for age (>95th % tile)
3. Traumatic injury with exam findings consistent with severe bleeding (e.g., penetrating injury, hemothorax, distended abdomen with bruising, amputation of limb).

General Exclusion Criteria:

1. Patient with devastating traumatic brain injury not expected to survive due to magnitude of injury (example: Transhemispheric gunshot wound with signs of herniation, GCS score of 3 with fixed and dilated pupils)
2. MTP activated but no blood products given
3. Patients who required an ED thoracotomy or received more than 5 consecutive minutes of cardiopulmonary resuscitation (prior to receiving randomized blood products)
4. Patients who are known or suspected to be pregnant on clinical examination
5. Known prisoners as defined in protocol
6. Known ward of the state
7. Isolated hanging, drowning or burns
8. Previous enrollment in MATIC-2
9. Prior study opt-out with bracelet

Exclusion Criteria for the TXA/Placebo Domain

1. Prehospital or pre-enrollment use of TXA
2. Greater than 3 hours since time of injury
3. History of seizure after the injury event
4. Known allergy or hypersensitivity reaction to TXA