Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma

Hematoma, Subdural, Chronic Clinical Trial

— TORCH  

Official title:

Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma. A Double-blind, Placebo-controlled, Multicentre, Randomized Controlled Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03582293
• Other study ID #: NL63794.018.18
• Status: Recruiting
• Phase: Phase 3
• Start date: June 19, 2018
• Est. completion date: October 30, 2029

Study information

• Verified date: June 2024
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: William P Vandertop, MD PhD
• Phone: +31205669111
• Email: w.p.vandertop[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rationale: Chronic subdural hematoma (cSDH) is a frequently occurring disease, occurring mainly in the elderly. Surgical evacuation is effective, but also associated with life-threatening risks. In these old, often frail, patients with multi-comorbidity, surgery also comes with significant risks for future cognitive functioning and therefore, loss of independency. In five small retrospective series, tranexamic acid (TXA), an antifibrinolytic drug, showed a beneficial effect on the spontaneous resolution of the hematoma and, with that, the necessity for surgery. This randomised, placebo-controlled clinical trial aims to prove the efficacy of TXA.

Objectives: Primarily to evaluate the efficacy of TXA to prevent surgery for cSDH. Secondarily to evaluate the efficacy of TXA to reduce cSDH volume, neurological impairment (mNIHSS), the incidence of falling incidents, the mortality rate, the use of care and health-related costs (iMCQ and iPCQ), to improve cognitive functioning (MOCA), performance in activities of daily living (Barthel and Lawton-Brody), functional outcome (mRS), the level of quality of life.

Study design: Double-blind placebo-controlled multicentre randomized clinical trial.

Study population: All patients, age 50 and above, diagnosed with cSDH for whom a conservative treatment is selected as primary treatment strategy.

Intervention: The intervention group will receive oral TXA 500mg twice daily for 4 weeks, the control group will receive a placebo twice daily. The TXA or placebo treatment is additional to standard care.

Main study endpoint: The number of patients requiring surgery within 12 weeks after start treatment.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will use the study medication twice daily for four weeks. Follow-up is at 4, 8and 12 weeks with a standard CT-scan of the head, outpatient clinic visits and 4 patient-reported questionnaires. These outpatient clinic visits are standard care; the third CT-scan, the questionnaires and extra clinical tests are extra. Each patient may benefit from the study if the study medication proves effective in preventing surgery for cSDH, whereas the risk of potential side effects of the medication is slight (e.g. the risk of thromboembolic events is only 0.01-0.1%). Surgery remains a possibility for those patients in whom study medication is not effective.

Description:

1. INTRODUCTION AND RATIONALE Chronic subdural hematoma (cSDH) is a frequently occurring neurological disease of the elderly and common in daily neurosurgical practice. It consists of an extracerebral encapsulated collection of mostly liquefied old hematoma, located between the dura and arachnoid. The original small, and often asymptomatic, haemorrhage is caused by rupture of a bridging vein after, often minor, head trauma. Due to generalized cerebral atrophy, increased venous fragility, and the more frequent use of anticoagulation therapy, older people are more at risk of developing a cSDH.

During several weeks, the original hematoma is encapsulated by a membrane consisting of weak neocapillaries from where recurrent small bleedings occur. The pathophysiological mechanism is thought to be a problem in the local haemostasis due to fibrin degradation products of the original small hematoma that inhibit further haemostasis in the subdural space. Together with an osmotic draw of water, owing to its high protein content, this results in growth of the hematoma. Therefore, it usually takes several weeks for the cSDH to grow and become symptomatic.

Signs and symptoms arise due to compression of brain tissue. These can be generalised, such as headaches, light-headedness, cognitive disturbances, apathy, somnolence, seizures, frequent falling and depression. Also focal deficits, such as dysphasia, motor weakness or sensory disturbances, can be symptoms of a cSDH.

The current incidence of cSDH is estimated to be 15/100,000 per year. The number of patients with cSDH is expected to increase considerably in the near future due to the continuing growth of the elderly population, and the increase in the use of anticoagulation and anti-aggregation therapy. By 2030, the incidence is expected to rise up to 20/100,000 per year, thus making cSDH the most common neurosurgical condition in adults. In The Netherlands, this comes down to 3,600 new patients each year.

Treatment Treatment options are conservative and surgical. Conservative treatment currently consists of a wait-and-scan policy in which the patient is regularly monitored for neurological deterioration and growth of the hematoma on follow-up imaging. Anticoagulation and antiplatelet therapy is discontinued in low-risk patients, based on individual risk-benefit assessment and the discretion of the treating physician. If the clinical condition of the patient worsens, the indication for surgical evacuation of the hematoma is re-evaluated.

Spontaneous resolution of cSDH with a conservative treatment occurs in approximately 2.5% of patients, and is therefore relatively rare. Of all patients diagnosed with cSDH in The Netherlands, about 50% is primarily treated conservatively. Of these, around 75% still need an operation (own data). If the symptoms are serious or worsen over time, surgical evacuation of the hematoma is currently the designated therapy. This therapy is an effective treatment, but is also associated with life-threatening risks. In these old, often frail, patients with multi-comorbidity, surgery comes with significant risks for future cognitive functioning and, therefore, loss of independency. In a large series of 1205 patients, symptomatic recurrence after surgery was 9%, mortality 2% and unfavourable functional outcome 22%.

Outcome measurement Studies evaluating quality of life and functional outcome with cSDH patients are scarce. The modified Rankin Scale (mRS) score is usually the only clinical outcome parameter. A literature search for quality of life in cSDH results in only two clinical studies. The first used the postoperative mRS, Barthel Index and Sickness Impact Profile as outcome measurements; the second used a pre- and postoperative Karnofsky Performance Score.

Tranexamic acid As hyperfibrinolysis is thought to play a role in the liquefaction and enlargement of cSDH, pharmaceutical options to block fibrinolysis have been explored in an effort to eliminate the necessity for surgery. The use of tranexamic acid (TXA), an antifibrinolytic drug, has so far been reported in five small series. In the first retrospective series, a total of 21 patients were treated with TXA, of whom three after primary burr hole surgery. In none of these 21 patients, additional surgery was necessary. The second, a prospective pilot study in 14 patients, showed a 41% reduction of cSDH after surgery, and an additional 91% residual volume reduction on CT after 90 days, during oral TXA treatment of 650 mg per day, for a mean (SD) duration of 90 (27) days, without recurrence, re-expansion, or any complicating venous thromboembolisms. The third study, a case report series of three patients treated with 650mg TXA per day for one month after surgery for cSDH, showed no recurrences and thromboembolic complications. The fourth, a case report of one patient successfully treated primarily with TXA, was recently published, and finally, in the abstract of a Asian article, the authors conclude that administration of Gorei-San, a Japanese herbal Kampo medicine, combined with TXA has the potential to prevent recurrences of cSDH.

With these limited, however promising, data no definitive conclusion can be made regarding the role of TXA in the treatment of cSDH. Therefore, a prospective study evaluating the efficacy and safety of TXA is needed. Currently, two prospective trials (the TRACS study and the TRACE study are running in an effort to answer this question. The first study, a phase 2b trial with the aim to provide preliminary data required to plan a larger phase III trial, excludes patients using anticoagulants. These patients comprise a significant portion of the cSDH patient population, and therefore, the results of the TRACS study will be difficult to extrapolate to the future care of all cSDH patients. The second study (TRACE) is a randomised, observer blinded trial, investigating the value of treating cSDH patients with TXA after surgery. This is a different patient population than proposed in the investigators' trial, in which they plan to include only patients in whom the primary treatment is conservative. Also, both trials are set up with a primary radiological outcome parameter and therefore potentially provide insufficient clinically relevant information.

This phase III trial aims to investigate the efficacy and safety of TXA as an addition to a primary conservative treatment of cSDH, in an effort to prevent surgery for cSDH. Since surgical treatment under general anaesthesia and a hospital admittance of a minimum of two days is associated with significant morbidity, as described earlier, the investigators assume that preventing surgery also prevents deterioration of patients' quality of life. This trial is also the first in describing functional outcome and quality of life of cSDH patients in a prospective manner. Since the target population partially comprises patients with a depressed level of consciousness, and patients using anticoagulants and antiplatelets, these patient groups will be included in this trial as well.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 554
• Est. completion date: October 30, 2029
• Est. primary completion date: April 30, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• On CT confirmed cSDH

• Primary conservative treatment, based on clinical symptoms: Glasgow Coma Scale score >=14, mNIHSS score <=4 and a stable neurological deficit (no new, or progression of, symptoms between the assessment by the neurologist and the assessment by the neurosurgeon).

Exclusion Criteria:

Primary surgical treatment based on one or more of the following symptoms or parameters:

medically intractable headache, midline shift >10mm, imminent death within 24 hours;

• Structural causes for subdural haemorrhage, e.g. arachnoid cysts, cortical vascular malformations and a history of cranial surgery <1year;

• Aneurysmal subarachnoid haemorrhage;

• Active treatment for deep vein thrombosis, pulmonary embolism or cerebral thrombosis (secondary prophylaxis is not considered to be active treatment);

• Active intravascular clotting or disseminated intravascular coagulation;

• Known hypersensitivity or allergy to TXA or to any of the ingredients;

• History of a blood coagulation disorder (hypercoagulability disorder);

• History of severe impairment of renal function (eGFR <30ml/min or serum creatinine >150µmol/L);

• History of anaemia (haemoglobin <6mmol/L);

• History of convulsions;

• History of inability to safely swallow oral medication.

• Inability to obtain informed consent from the patient or legal representative (when the patient has a depressed level of consciousness as described in paragraph 11.2), including language barrier;

Related Conditions & MeSH terms

• Hematoma
• Hematoma, Subdural, Chronic

Intervention

Drug:
• Tranexamic Acid 500Mg Tablet
orally twice daily for 28 days
• Placebo oral capsule
Oral placebo capsule two times a day for a total of 28 days

Locations

Country	Name	City	State
Netherlands	Academic Medical Center	Amsterdam

Sponsors (2)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

References & Publications (26)

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Berghauser Pont LM, Dippel DW, Verweij BH, Dirven CM, Dammers R. Ambivalence among neurologists and neurosurgeons on the treatment of chronic subdural hematoma: a national survey. Acta Neurol Belg. 2013 Mar;113(1):55-9. doi: 10.1007/s13760-012-0130-1. Epub 2012 Sep 14. — View Citation

Berghauser Pont LM, Dirven CM, Dippel DW, Verweij BH, Dammers R. The role of corticosteroids in the management of chronic subdural hematoma: a systematic review. Eur J Neurol. 2012 Nov;19(11):1397-403. doi: 10.1111/j.1468-1331.2012.03768.x. Epub 2012 May 29. Erratum In: Eur J Neurol. 2015 Dec;22(12):1575. — View Citation

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CRASH-2 trial collaborators; Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. doi: 10.1016/S0140-6736(10)60835-5. Epub 2010 Jun 14. — View Citation

Forster MT, Mathe AK, Senft C, Scharrer I, Seifert V, Gerlach R. The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma. J Clin Neurosci. 2010 Aug;17(8):975-9. doi: 10.1016/j.jocn.2009.11.023. Epub 2010 May 23. — View Citation

Gaillard S, Dupuis-Girod S, Boutitie F, Riviere S, Moriniere S, Hatron PY, Manfredi G, Kaminsky P, Capitaine AL, Roy P, Gueyffier F, Plauchu H; ATERO Study Group. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014 Sep;12(9):1494-502. doi: 10.1111/jth.12654. Epub 2014 Jul 29. — View Citation

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Sambasivan M. An overview of chronic subdural hematoma: experience with 2300 cases. Surg Neurol. 1997 May;47(5):418-22. doi: 10.1016/s0090-3019(97)00188-2. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	surgery for cSDH	number of patients who need to undergo surgery for cSDH	within 12 weeks after start of treatment
Secondary	cSDH volume	change in cSDH volume (in ml) on follow-up CT scan of the head	at four, eight and 12 weeks
Secondary	neurological impairment	neurological impairment measured with the modified National Institutes of Health Stroke Scale (mNIHSS) score, range 0 (normal) to 31 (severe neurological deficit)	at four, eight and 12 weeks
Secondary	falling incidents	number of falling incidents during study period	during the 12 week study period
Secondary	cognitive functioning	cognitive functioning measured with the Montreal Cognitive Assessment (MOCA) test, range 0 - 30, with a score of 26 and higher generally considered normal.	at four, eight and 12 weeks
Secondary	performance in activities of daily living 1	performance in activities of daily measured with the Barthel Index scale (range 0-20, with lower scores indicating increased disability)	at 12 weeks
Secondary	functional outcome	functional outcome measured with the modified Rankin Scale (mRS) score, range 0 (no symptoms) to 6 (death)	at 12 weeks
Secondary	patient health status 1	quality of life measured with the patient-reported Short Form Health Survey questionnaire (SF-36; eight scaled scores, range 0 (maximum disability) -100 (no disability).	at 12 weeks
Secondary	mortality rate	number and percentage of deaths during study period	at 12 weeks
Secondary	use of care	use of care measured with the Medical Consumption Questionnaire (iMCQ), which includes questions related to frequently occurring contacts with health care providers	during the 12 week study period
Secondary	performance in activities of daily living 2	performance in activities of daily measured with the Lawton-Brody scale, range 0 (low function, dependent) to 8 (high function, independent).	at 12 weeks
Secondary	health-related costs	health-related costs measured with the Productivity Cost Questionnaire (iPCQ), a standardized instrument including three modules for measuring and valuing productivity losses of paid work due to 1) absenteeism and 2) presenteeism and productivity losses related to 3) unpaid work.	during the 12 week study period
Secondary	patient health status 2	quality of life measured with the five dimensional EuroQol questionnaire (EQ-5D-3L, five dimensions with each 3 levels: 1-no problems, 2-some problems, and 3-extreme problems).	at 12 weeks

External Links

•   article on subdural haemorrhage
•   Central Committee on Research Involving Human Subjects (CCMO) legal frameworks, codes of conduct
•   cost of medicine
•   guidelines for economic evaluation
•   Institute for Medical Technology Assessment