The Use of Tranexamic Acid in the Treatment of Symptomatic Subdural Hematoma

Study Overview
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Brief Summary
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Subdural hematoma (SDH) is a common condition experienced after head injury. Blood collects on the surface of the brain, causing headaches which can progress to confusion, weakness, or even coma. While patients with SDH often receive surgery, not all patients require surgery right away to ease pressure on the brain. After surgery, there can be up to 30 percent chance of more bleeding and the need for more surgeries. Given this, a drug capable of lowering the chance of more bleeding and speeding the recovery of the patient is highly desirable. In this study, we will test a commonly used, cheap drug called Tranexamic Acid (TXA). While the body stops unwanted and sometimes dangerous bleeding naturally by forming blood clots, TXA stops these blood clots from breaking down, which helps to keep bleeding spots plugged. Our previous study showed that TXA helped speed up patients' recovery; but a larger number of patients is necessary to evaluate how well TXA works to reduce bleeding and improve patient-reported outcomes. In this study, regardless of the need for surgery, half of the patients will be randomly assigned to take TXA, while the other half will take a placebo, which is a look-alike substance that contains no active drug. We will measure multiple outcomes over time to determine if TXA is working and lowers healthcare and personal costs, while also taking blood and surgical samples, to better understand how this drug works in SDH patients.

Official Title
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TRACE STUDY: A Randomized Controlled Trial Using Tranexamic Acid in the Treatment of Subdural Hematoma

Conditions
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Subdural Hematoma

Intervention / Treatment
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* Drug: GD-Tranexamic Acid 500 MG Oral Tablet
* Drug: Sandoz-Tranexamic Acid 100 MG/ML
* Drug: Sandoz-Tranexamic Acid 100 Mg/mL Solution for Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 45 and older weighing between 45-150 kg diagnosed with symptomatic SDH will be included. SDH is defined as unilateral or bilateral crescentic collection of blood (hyper, iso, or hypodense, or mixed density) of greater than or equals to 8 mm in thickness along the cerebral convexity on CT of the head. Symptomatic SDH patients eligible for inclusion are those with SDH with one or more of the following symptoms attributable to the SDH: headache, gait disturbance, confusion or cognitive decline, limb weakness or numbness/paresthesia, speech or visual disturbance, drowsiness or impaired consciousness, seizures, impaired cognition, or memory loss at the time of assessment. Exclusion Criteria: - Patients will be excluded for any of the following conditions: Asymptomatic for longer than 72 hours SDH less than 8 mm in maximal thickness Have an acutely deteriorating neurological status (e.g., brain herniation with pupillary dilation, aneurysm rupture, etc.) that is likely to be fatal within 6 hours or less due to a predominantly acute SDH Presence of brain contusion larger than 5 cm or subarachnoid hemorrhage (SAH) thicker than 10 mm with Glasgow Coma Scale (GCS)< 13 Patients with primarily interhemispheric or tentorial SDH Hypersensitivity to TXA or any of the placebo ingredients Pregnancy Irregular menstrual bleeding with unidentified cause Known acquired colour vision disturbances Hematuria caused by renal parenchymal disease Acute and chronic renal insufficiency indicated by estimated Glomerular Filtration Rate (eGFR) ≤ 30 mL/min Concomitant (current) intake of birth control pill and/or hormonal replacement therapy, and anti-inhibitor coagulant concentrates (factor VIII inhibitor bypass activity (FEIBA), factor VII, activated factor IX) Consumption coagulopathy/disseminated intravascular coagulation (DIC) in the last 7 days Not competent to take study medication properly and regularly or not having access to caregiver that is able to comply with study medication administration Mechanical heart valve Contraindication to stopping full therapeutic doses of non-acetylsalicylic acid antiplatelets, warfarin, direct oral anticoagulant (e.g., apixaban) or other anticoagulant for 2 weeks after surgery or recent blood clot and/or recent thromboembolic complications in the last 2 weeks SDH caused by intracranial hypotension Known thrombophilia (e.g., antiphospholipid syndrome) Any active malignancy: metastatic cancer systemically or to the brain or a primary malignant brain tumour treated within the last 6 months Previous enrolment in this trial for a prior episode Time interval >3 days from the time of clinical assessment to eligibility assessment Patients weighing <45 kg or >150 kg

Ages Eligible for Study
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Minimum Age: 45 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: Vanguard trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard care + TXA<br>Non-surgical patients will be given a single oral or IV loading dose of 1g TXA within three hours of being randomized. For surgical patients, the same loading dose will be administered whenever possible prior to surgery. After 12 hours of the loading dose, patients will be given 500 mg TXA by mouth (or nasogastric tube for those unable to swallow or IV) three times a day, totalling 1500 mg/day, for 45 days. | Drug: GD-Tranexamic Acid 500 MG Oral Tablet<br>* Tranexamic acid film-coated oral tablet.<br>* Other names: Cyklokapron;Drug: Sandoz-Tranexamic Acid 100 MG/ML<br>* Sandoz-Tranexamic acid 100 milligram/millilitre (mg/mL) via nasogastric tube.<br>* Other names: Cyklokapron;Drug: Sandoz-Tranexamic Acid 100 Mg/mL Solution for Injection<br>* Sandoz-Tranexamic acid 100 mg/mL solution for injection via intravenous (IV).<br>* Other names: Cyklokapron;|
| Placebo Comparator: Standard care + placebo<br>Non-surgical patients will be given a single oral or IV loading dose of 1g placebo within three hours of being randomized. For surgical patients, the same loading dose will be administered whenever possible prior to surgery. After 12 hours of the loading dose, patients will be given 500 mg placebo by mouth (or nasogastric tube for those unable to swallow or IV) three times a day, totalling 1500 mg/day, for 45 days. | Drug: Placebo<br>* The placebo 500 mg will consist of an identical capsule to over-encapsulated tranexamic acid oral tablet entirely filled with microcrystalline cellulose, and sealed. Placebo 100 MG/ML via nasogastric tube and placebo 100 Mg/mL solution for injection via intravenous (IV). The solution form of the placebo will consist of 0.9% sodium chloride (saline).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) | A self-rated questionnaire that assesses a patient's health state in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. | Every 2 weeks after randomization up to 45±10 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 - Global Health. English and French versions | A 10-item measure that assesses an individual's general physical, mental, and social health as it is intended to globally reflect individuals' assessment of their physical and mental health in the last 7 days. | Baseline and every 2 weeks after randomization up to 45±10 days, and then at 60-90 days, and 180±10 days after randomization. | 
| PROMIS Item Bank v2.0 - Cognitive Function. English version | A measure that assesses cognitive function that will be administered as a computer adaptive test. | Baseline and every 2 weeks after randomization up to 45±10 days, and then at 60-90 days, and 180±10 days after randomization. | 
| PROMIS Item Bank v2.0 - Physical Function. English version | A measure that assesses self-reported capability rather than actual performance of physical activities that will be administered as a computer adaptive test. | Baseline and every 2 weeks after randomization up to 45±10 days, and then at 60-90 days, and 180±10 days after randomization. | 
| PROMIS Item Bank v2.0 - Ability to Participate in Social Roles and Activities. English version | A measure that assesses the perceived ability to perform one's usual social roles and activities that will be administered as a computer adaptive test. The item bank does not use a time frame (e.g. over the past 7 days) when assessing ability to participate in social roles and activities. | Baseline and every 2 weeks after randomization up to 45±10 days, and then at 60-90 days, and 180±10 days after randomization. | 
| Subdural hematoma volume change | Change in hematoma volume in millilitres on CT scan. | Baseline, 45±10 days after randomization, and 60-90 days if deemed necessary for the patient's routine care. | 
| Number of subdural hematoma-related surgical interventions |  | First admission, subsequent admissions up to 180 days after randomization | 
| Recurrence rate of SDH |  | 45±10 days, 60-90 days, and 180±10 days after randomization | 
| Mortality |  | During the course of study up to 180±10 days after randomization | 
| Modified Rankin Scale | A 6-point disability scale used to measure the degree of disability in patients who have had a stroke. | Baseline, 45±10 days, 60-90 days, and 180±10 days after randomization | 
| Disability Rating Scale | Eight questions regarding body function, activity, participation, communication, and movements each rated on a 3-5-point scale that is summed to give a total score. | Baseline, 45±10 days, 60-90 days, and 180±10 days after randomization | 
| Montreal Cognitive Assessment | This assessment evaluates the patient's cognition based on eight areas: visuospatial/executive function, naming, memory, attention, language, abstraction, delayed recall, and orientation. | Baseline, 45±10 days, and 60-90 days after randomization | 
| Medical Consumption Questionnaire | Health-related cost questionnaire on the use of healthcare in the past month. | Baseline, 45±10 days, and 180±10 days after randomization | 
| EQ-5D-5L | A self-rated questionnaire that assesses a patient's health state in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. | Baseline, 60-90 days, and 180±10 days after randomization | 
| Adverse events | Adverse events of grade 3 or higher as defined by Good Clinical Practice Guidelines. | Discharge, 45±10 days, 60-90 days, and 180±10 days after randomization | 
| Length of stay in hospital due to subdural hematoma |  | During the course of the study up to 180±10 days after randomization | 
| Disposition after discharged from hospital |  | During the course of the study up to 180±10 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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symptomatic subdural hematoma, tranexamic acid, TXA, clinical trial, neurosurgery