Prehospital Tranexamic Acid Use for Traumatic Brain Injury
Palavras-chave
Resumo
Descrição
1. Overview This multi-center, Phase II trial is designed to determine if Tranexamic Acid (TXA) initiated in the prehospital setting improves long-term neurologic outcome compared to placebo in patients with moderate to severe TBI who are not in shock. This study protocol will be conducted as part of the Resuscitation Outcomes Consortium (ROC) at trauma centers in the United States and Canada. ROC is funded by the National Heart Lung and Blood Institute (NHLBI) in partnership with the US Army Medical Research and Materiel Command (USAMRMC), Canadian Institutes of Health Research, the Heart & Stroke Foundation of Canada, the American Heart Association (AHA), and the Defense Research and Development Canada. ROC is a clinical trials network focusing on research primarily in the area of prehospital cardiopulmonary arrest and severe traumatic injury. The mission of ROC is to provide infrastructure and project support for clinical trials and other outcome-oriented research in the areas of cardiopulmonary arrest and severe traumatic injury that lead to evidence-based change in clinical practice.
2. Specific Aims/Hypothesis Statement
2.1 Clinical Hypotheses and Aims
Specific aim 1: To compare 6-month neurologic outcome between subjects who are randomly assigned to TXA to subjects who are randomly assigned to placebo by evaluating the Glasgow Outcome Scale Extended score (GOS-E) at 6 months post-injury.
Primary Hypotheses: We will perform a one-sided test of the following null hypothesis: The proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) at six months post injury who are randomly assigned to TXA is not different from the proportion of subjects who have a favorable neurologic outcome (GOS-E > 4) who are randomly assigned to placebo. This hypothesis will be tested versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is higher than in subjects who are randomly assigned to placebo at the .1 level and versus the alternative that the proportion of subjects with a favorable neurologic outcome who are randomly assigned to TXA is lower than it is in the placebo group at the .025 level
Specific aim 2: To assess differences in morbidity and mortality measured from randomization through 28 days or initial hospital discharge and differences in neurologic outcomes at 6 months between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.
Secondary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: both absolute and relative volume of intracranial hemorrhage (ICH) progression, proportion of subjects with ICH progression, frequency of neurosurgical interventions, GOS-E measured at discharge and 6 months, Disability Rating Scale score (DRS) measured at discharge and 6 months, 28-day survival, and ventilator-free, intensive care unit (ICU)-free, and hospital-free days.
Specific aim 3: To assess differences in adverse events measured from randomization to initial hospital discharge between subjects in the bolus/maintenance arm, bolus only arm, and placebo arm.
Tertiary Hypotheses: The null hypotheses are that there will be no difference between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo in the following: proportion of subjects experiencing seizures, cerebral ischemic events, myocardial infarction (MI), deep venous thrombosis (DVT), or pulmonary thromboembolism (PE) post randomization through 28 days or discharge, whichever occurs first.
2.2 Laboratory Hypotheses and Aims
Specific aim 1: To compare coagulation profiles over time using kaolin activated thrombelastography (TEG) results between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Primary hypothesis: The null hypothesis is that there will be no difference in the degree of fibrinolysis as assessed by percentage of clot lysis determined 30 minutes after the maximum amplitude is reached (LY30) between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Specific aim 2: To explore the underlying mechanism of TXA by comparing fibrinolytic pathway mediator activity between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Secondary hypothesis: The null hypothesis is that there will be no change in fibrinolytic pathway mediators between subjects who are randomly assigned to TXA and subjects who are randomly assigned to placebo.
Specific aim 3: To estimate the association between the degree of fibrinolysis based on kaolin activated TEG results and fibrinolytic pathway mediators on primary and secondary clinical outcomes.
Tertiary hypothesis: The null hypothesis is that no association will exist between the degree of fibrinolysis and fibrinolytic pathway mediators and primary and secondary clinical outcomes.
3. Study Enrollment
EMS agencies will carry blinded sealed study drug kits. Once the seal is broken in the presence of the patient, the patient is randomized. The EMS study drug kit will contain a vial of either 1 gram TXA, 2 grams TXA, or placebo. EMS will mix the study drug in a 250 mL bag of 0.9% sodium chloride and administer the bolus infusion as soon as life-saving interventions are performed. After randomization, EMS will provide the study drug kit ID# to the receiving pharmacy. The hospital pharmacist will obtain the randomization assignment from the coordinating center and prepare the appropriate drug to be administered in the hospital.
4. Sample Size and Statistical Analysis
The total sample size is 963 (321 per group) starting treatment, which will allow for 80% power to detect a 7.1% absolute difference in favorable long-term neurological outcome as determined by the GOS-E 6 months after injury comparing the combined TXA treatment groups to placebo, using a one-sided, level 0.1 test.
Statistical analysis of primary hypothesis: Modified intention-to-treat analysis using logistic regression to test for association and estimate the strength of the association of treatment group with a favorable 6-month outcome (defined as a GOS-E > 4), after adjustment for study site.
5. Human subjects protection
This study qualifies for the exception from informed consent (EFIC) required for emergency research outlined in FDA regulation 21CFR50.24. EFIC applies because of life-threatening situation, intervention must be administered before consent is feasible, no reasonable way to identify prospectively individuals at risk, patients have the prospect of benefit from the treatment, and the research could not practically be carried out without the waiver of consent.
datas
| Última verificação: | 11/30/2018 |
| Enviado pela primeira vez: | 10/29/2013 |
| Inscrição estimada enviada: | 11/14/2013 |
| Postado pela primeira vez: | 11/20/2013 |
| Última atualização enviada: | 12/30/2018 |
| Última atualização postada: | 01/13/2019 |
| Data dos primeiros resultados enviados: | 11/06/2018 |
| Data dos primeiros resultados de QC enviados: | 12/30/2018 |
| Data dos primeiros resultados postados: | 01/13/2019 |
| Data real de início do estudo: | 04/30/2015 |
| Data Estimada de Conclusão Primária: | 11/06/2017 |
| Data Estimada de Conclusão do Estudo: | 11/06/2017 |
Condição ou doença
Intervenção / tratamento
Drug: 1 gram Tranexamic Acid (TXA)
Drug: 2 grams TXA
Drug: 0.9% Sodium Chloride injectable
Fase
Grupos de Armas
| Braço | Intervenção / tratamento |
|---|---|
| Experimental: 1 gram Tranexamic Acid (TXA) Loading dose of 1 gram TXA given prior to hospital arrival followed by a 1 gram TXA infusion over 8 hours after hospital arrival | Drug: 1 gram Tranexamic Acid (TXA) TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. |
| Experimental: 2 grams TXA Loading dose of 2 gram TXA given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival | Drug: 2 grams TXA TXA produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. |
| Placebo Comparator: 0.9% Sodium Chloride injectable Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival | Drug: 0.9% Sodium Chloride injectable Loading dose of 0.9% Sodium Chloride solution given prior to hospital arrival followed by a placebo of 0.9% Sodium Chloride solution infusion over 8 hours after hospital arrival. No active drug is added to the solution. |
Critério de eleição
| Idades qualificadas para estudar | 15 Years Para 15 Years |
| Sexos elegíveis para estudo | All |
| Aceita Voluntários Saudáveis | sim |
| Critério | Inclusion Criteria: 1. Blunt or penetrating traumatic mechanism consistent with traumatic brain injury 2. Prehospital Glasgow Coma Score (GCS) score ≤ 12 at any time prior to randomization and administration of sedative and/or paralytic agents 3. Prehospital systolic blood pressure (SBP) ≥ 90 mmHg prior to randomization 4. Prehospital intravenous (IV) or intraosseous (IO) access 5. Estimated Age ≥ 15 (or estimated weight > 50 kg if age is unknown) 6. Emergency Medicine System (EMS) transport to a participating trauma center Exclusion Criteria: 1. Prehospital GCS=3 with no reactive pupil 2. Estimated time from injury to hospital arrival > 2 hours 3. Unknown time of injury - no known reference times to support estimation 4. Clinical suspicion by EMS of seizure activity or known history of seizures, acute myocardial infarction (MI) or stroke 5. Cardio-pulmonary resuscitation (CPR) by EMS prior to randomization 6. Burns > 20% total body surface area (TBSA) 7. Suspected or known prisoners 8. Suspected or known pregnancy 9. Prehospital TXA given prior to randomization 10. Subjects who have activated the "opt-out" process when required by the local regulatory board |
Resultado
Medidas de Resultado Primário
1. Dichotomized Glasgow Outcome Scale Extended (GOS-E) at 6 Months [6 months post-injury]
Medidas de Resultado Secundário
1. Number of Participants Who Died Within 28 Days [28 days after hospital arrival]
2. Disability Rating Scale (DRS) at 6 Months [6 months post-injury]
3. Number of Participants With Unfavorable Outcome on Dichotomized Glasgow Outcome Scale Extended (GOS-E) at Discharge [At the end of the hospital stay (average of 9 days post injury)]
4. Disability Rating Scale (DRS) at Discharge [At the end of the hospital stay (average of 9 days post injury)]
5. Number of Participants With Intracranial Hemorrhage (ICH) Progression [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 13 days among patients with multiple scans)]
6. Marshall Computed Tomography (CT) Score on Initial Head CT [Initial head CT (average of 1.9 hours post-injury)]
7. Rotterdam Computed Tomography (CT) Score Among Subjects With Intracranial Hemorrhage (ICH) on Initial Head CT [Initial head CT (average of 1.9 hours post-injury)]
8. Number of Participants With One or More Neurosurgical Interventions [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
9. Hospital-free Days [From hospital admission through day 28]
10. Intensive Care Unit (ICU)-Free Days [From hospital admission through day 28]
11. Ventilator-free Days [From hospital admission through day 28]
12. Number of Participants With Seizure [From start of study drug infusion through 28 days or the end of the hospital stay if sooner (average of 9 days)]
13. Number of Participants With Cerebral Ischemic Event [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
14. Number of Participants With Myocardial Infarction (MI) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
15. Number of Participants With Deep Vein Thrombosis (DVT) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
16. Number of Participants With Pulmonary Embolus (PE) [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
17. Number of Participants With Any Thromboembolic Event [From hospital admission through 28 days or the end of the hospital stay if sooner (average of 9 days)]
Outras medidas de resultado
1. Fibrinolysis at Hospital Admission [First blood draw (average of 1.6 hours post-injury)]
