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Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma (TORCH)

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ClinicalTrials.gov Identifier: NCT03582293
Recruitment Status : Recruiting
First Posted : July 11, 2018
Last Update Posted : August 11, 2020
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Prof. dr. W.P. Vandertop, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE June 19, 2018
First Posted Date  ICMJE July 11, 2018
Last Update Posted Date August 11, 2020
Actual Study Start Date  ICMJE June 19, 2018
Estimated Primary Completion Date September 20, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
surgery for cSDH [ Time Frame: within 12 weeks after start of treatment ]
number of patients who need to undergo surgery for cSDH
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
  • cSDH volume [ Time Frame: at four, eight and 12 weeks ]
    change in cSDH volume (in ml) on follow-up CT scan of the head
  • neurological impairment [ Time Frame: at four, eight and 12 weeks ]
    neurological impairment measured with the modified National Institutes of Health Stroke Scale (mNIHSS) score, range 0 (normal) to 31 (severe neurological deficit)
  • falling incidents [ Time Frame: during the 12 week study period ]
    number of falling incidents during study period
  • cognitive functioning [ Time Frame: at four, eight and 12 weeks ]
    cognitive functioning measured with the Montreal Cognitive Assessment (MOCA) test, range 0 - 30, with a score of 26 and higher generally considered normal.
  • performance in activities of daily living [ Time Frame: at 12 weeks ]
    performance in activities of daily measured with the Barthel Index scale (range 0-20, with lower scores indicating increased disability)
  • functional outcome [ Time Frame: at 12 weeks ]
    functional outcome measured with the modified Rankin Scale (mRS) score, range 0 (no symptoms) to 6 (death)
  • patient health status [ Time Frame: at 12 weeks ]
    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).
  • mortality rate [ Time Frame: at 12 weeks ]
    number and percentage of deaths during study period
  • use of care [ Time Frame: during the 12 week study period ]
    use of care measured with the Medical Consumption Questionnaire (iMCQ), which includes questions related to frequently occurring contacts with health care providers
  • performance in activities of daily living [ Time Frame: at 12 weeks ]
    performance in activities of daily measured with the Lawton-Brody scale, range 0 (low function, dependent) to 8 (high function, independent).
  • health-related costs [ Time Frame: during the 12 week study period ]
    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.
  • patient health status [ Time Frame: at 12 weeks ]
    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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma
Official Title  ICMJE Tranexamic Acid to Prevent OpeRation in Chronic Subdural Hematoma. A Double-blind, Placebo-controlled, Multicentre, Randomized Controlled Clinical Trial
Brief 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Double-blind, placebo-controlled, multicentre, randomized clinical trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
double-blind
Primary Purpose: Treatment
Condition  ICMJE Hematoma, Subdural, Chronic
Intervention  ICMJE
  • Drug: Tranexamic Acid 500Mg Tablet
    orally twice daily for 28 days
    Other Name: cyclokapron
  • Drug: Placebo oral capsule
    Oral placebo capsule two times a day for a total of 28 days
Study Arms  ICMJE
  • Active Comparator: Tranexamic Acid
    Tranexamic acid 500mg two times a day orally for a total of 28 days
    Intervention: Drug: Tranexamic Acid 500Mg Tablet
  • Placebo Comparator: PLACEBO
    Placebo capsules two times a day orally for a total of 28 days
    Intervention: Drug: Placebo oral capsule
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 9, 2018)
130
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date September 20, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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;
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: William P Vandertop, MD PhD +31205669111 ext 63316 w.p.vandertop@amc.nl
Contact: Dagmar Verbaan, PhD +31205663316 d.verbaan@amc.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03582293
Other Study ID Numbers  ICMJE NL63794.018.18
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Prof. dr. W.P. Vandertop, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators  ICMJE ZonMw: The Netherlands Organisation for Health Research and Development
Investigators  ICMJE Not Provided
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP