- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02684812
Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage. (ULTRA)
Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage. A Prospective, Randomized, Multicenter Study.
Study Overview
Detailed Description
Approximately 50% of all patients with a subarachnoid hemorrhage (SAH) die due to the hemorrhage or subsequent complications. There are several major causes for this course, such as in-hospital rebleed in 21.5% which most frequently occurs within the first 6 hours after the primary hemorrhage ("ultra-early rebleed"). A major part of the patients with a rebleed die during hospital admission and when they survive, they develop more severe cognitive dysfunctions. Reducing the rebleeds by ultra-early administration of tranexamic acid (TXA) could be a major factor in improving the functional outcome after SAH.
To evaluate whether SAH patients treated by state-of-the-art SAH management with additional ultra-early and short term TXA administration have a significantly higher percentage of favourable outcome after six months (score 0-3 on the Modified Rankin Scale) compared to the group treated by up-to-date SAH management without additional TXA.
To evaluate whether: 1) TXA reduces in-hospital rebleeds and case fatalities; 2) TXA causes more ischemic stroke 3) TXA causes more complications (such as thromboembolic events, hydrocephalus, extracranial thrombosis or hemorrhagic complications) during treatment, admission and follow-up; 4) there is a difference in causes of poor outcome between groups; 5) there is a difference in discharge locations between groups; 6) there is an association between the time between hemorrhage and TXA administration and outcome; 7) TXA increases (micro)infarctions after endovascular treatment; 8) TXA reduces health-care costs between discharge and six months after hemorrhage; 9) TXA improves quality of life at six months after hemorrhage; 10) there are differences in rebleed rates and outcome between genders or groups with different WFNS scores at admission.
Multicenter, prospective, randomized, open label treatment with blind endpoint assessment.
Adult patients (18 years and older) included within 24 hours after SAH. Group one: standard treatment with additional administration of 1 g TXA intravenously in ten minutes, immediately after the diagnosis SAH, succeeded by continuous infusion of 1 g per 8 hours until a maximum of 24 hours. Group two: standard treatment with no TXA administration. Both groups undergo a standardized and validated interview at discharge and six months after hemorrhage to assess the modified Rankin Scale score, and both groups receive a questionnaire to evaluate health-care costs and quality of life.
Primary: modified Rankin Scale score after six months, dichotomized into favourable and unfavourable outcome. Secondary: rebleed and case fatality rate, complications during the first six months after hemorrhage, (micro)infarctions at MR imaging after endovascular treatment, health-care costs from discharge until six months, quality of life at six months and differences in rebleed rates and outcome between genders or WFNS score at admission.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Subjects are randomly allocated to ultra-early TXA therapy or standard treatment. Complications are minor and the expected benefit is large compared with separate studies done with antifibrinolytic medications. In these studies, the safety of the use of these medications in this study population is confirmed. In this patient group there are adequate, disoriented and comatose patients on admission, so a part of the studied patients are incapacitated when undergoing the study. To extrapolate the conclusions of this study to clinical protocols it is necessary to include patients with a SAH in all different severity grades. Weighing carefully the benefits versus the burden and risks, it is assumed that patients will benefit from ultra-early TXA administration with minimal burden during therapy.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Amsterdam, Netherlands
- Academic Medical Centre
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Admission to one of the study centers or their referring hospitals
- CT-confirmed SAH with most recent ictus less than 24 hours ago Definition: subarachnoid hemorrhage is a bleeding pattern on computed tomography with hyperdensity in the basal cisterns and/or Sylvian or interhemipheric fissures or a intraparenchymal hyperdensity consistent with a hematoma from an anterior, a pericallosal, a posterior or a middle cerebral artery aneurysm.
Exclusion Criteria:
- No proficiency of the Dutch or English language
- No loss of consciousness after the hemorrhage with WFNS grade 1 or 2 on admission in combination with a perimesencephalic hemorrhage Definition: on CT examination presence of hyperdensities exclusively in the basal cisterns maximal extending to the proximal part of the Sylvian fissure or posterior part of the interhemispheric fissure, without evidence for intracerebral or intraventricular haemorrhage (except slight sedimentation)
- Bleeding pattern on CT compatible with a traumatic SAH
- Treatment for deep vein thrombosis or pulmonary embolism
- History of a blood coagulation disorder (a hypercoagulability disorder)
- Pregnancy checked with a pregnancy test in women in their childbearing period
- History of severe renal (serum creatinin >150 mmol/L)
- History of severe liver failure (AST > 150 U/l or ALT > 150 U/l or AF > 150 U/l or γ-GT > 150 U/l)
- Imminent death within 24 hours
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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No Intervention: Control
Standard care
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Active Comparator: Tranexamic Acid
Eligible subjects are randomly assigned to immediate administration of TXA (1 g i.v.) after a diagnosis of SAH, as confirmed by CT-scan of the brain, continued by continuous infusion of 1 g per 8 hours to a maximum of 24 hours after start of medication.
A maximum of 4 g TXA (1 g bolus + 3x 1 g continuous infusion) can be administered to one patient.
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Treatment until aneurysm treatment or maximum dosage of 4 gram
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Modified Rankin Scale (mRS)
Time Frame: six months
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Good (mRS 0-3) and Poor (mRS 4-6)
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six months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Date and cause of death
Time Frame: Maximum six month
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Assessment of cause of death by a committee (intensive care/neurosurgeon)
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Maximum six month
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Cause of poor outcome
Time Frame: six months
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Assessment of which events during hospital admission led to a poor outcome defined as mRS 4 and 5 by a committee (intensive care/neurosurgeon)
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six months
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Rebleed and time interval after first hemorrhage
Time Frame: six months
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The time interval between the initial hemorrhage and occurence of a recurrent bleeding will be recorded.
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six months
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Thromboembolic events during endovascular treatment
Time Frame: up to 48 hours
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Complications during endovascular treatment will be recorded (ie occurence of clotting in one of the vessels)
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up to 48 hours
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Ischemic stroke (Dealyed cerebral ischemia)
Time Frame: 14-20 days
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14-20 days
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Extracranial thrombosis
Time Frame: six months
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six months
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Hydrocephalus and treatment modality
Time Frame: six months
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Occurence of a hydrocephalus will be recorded and which treatment modality is used to treat the hydrocephalus
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six months
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Hemorrhagic complications (intra- and extracranial)
Time Frame: six months
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six months
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Time interval from last hemorrhage to first TXA administration
Time Frame: 24 hours
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24 hours
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Discharge location
Time Frame: six months
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six months
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Infarctions on MR imaging at six months after endovascular treatment
Time Frame: six months
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six months
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Health-care costs between discharge and six months after hemorrhage
Time Frame: three and six months
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Questionnaires
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three and six months
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Quality of life at six months after hemorrhage
Time Frame: six months
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Questionnaire (EQ-5D)
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six months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: William P Vandertop, PhD MD, Department of Neurosurgery
Publications and helpful links
General Publications
- Germans MR, Post R, Coert BA, Rinkel GJ, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials. 2013 May 16;14:143. doi: 10.1186/1745-6215-14-143.
- Tjerkstra MA, Post R, Germans MR, Vergouwen MDI, Jellema K, Koot RW, Kruyt ND, Willems PWA, Wolfs JFC, de Beer FC, Kieft H, Nanda D, van der Pol B, Roks G, de Beer F, Halkes PHA, Reichman LJA, Brouwers PJAM, Van den Berg-Vos RM, Kwa VIH, van der Ree TC, Bronner I, Bienfait HP, Boogaarts H, Klijn CJ, van den Berg R, Coert BA, Horn J, Majoie CBLM, Rinkel GJE, Roos YBWM, Vandertop W, Verbaan D. Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial. Neurology. 2022 Oct 20:10.1212/WNL.0000000000201160. doi: 10.1212/WNL.0000000000201160. Online ahead of print.
- Post R, Germans MR, Tjerkstra MA, Vergouwen MDI, Jellema K, Koot RW, Kruyt ND, Willems PWA, Wolfs JFC, de Beer FC, Kieft H, Nanda D, van der Pol B, Roks G, de Beer F, Halkes PHA, Reichman LJA, Brouwers PJAM, van den Berg-Vos RM, Kwa VIH, van der Ree TC, Bronner I, van de Vlekkert J, Bienfait HP, Boogaarts HD, Klijn CJM, van den Berg R, Coert BA, Horn J, Majoie CBLM, Rinkel GJE, Roos YBWEM, Vandertop WP, Verbaan D; ULTRA Investigators. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet. 2021 Jan 9;397(10269):112-118. doi: 10.1016/S0140-6736(20)32518-6. Epub 2020 Dec 23.
- Post R, Germans MR, Coert BA, Rinkel GJE, Vandertop WP, Verbaan D. Update of the ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage (ULTRA) trial: statistical analysis plan. Trials. 2020 Feb 18;21(1):199. doi: 10.1186/s13063-020-4118-5.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Intracranial Hemorrhages
- Hemorrhage
- Subarachnoid Hemorrhage
- Molecular Mechanisms of Pharmacological Action
- Fibrin Modulating Agents
- Antifibrinolytic Agents
- Hemostatics
- Coagulants
- Tranexamic Acid
Other Study ID Numbers
- 2012-000343-26
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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