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Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage. (ULTRA)

This study is currently recruiting participants.
Verified February 2016 by R. Post, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02684812
First Posted: February 18, 2016
Last Update Posted: February 18, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Stichting Nuts Ohra
Information provided by (Responsible Party):
R. Post, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  Purpose
This is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation.

Condition Intervention Phase
Subarachnoid Hemorrhage Drug: Tranexamic Acid Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage. A Prospective, Randomized, Multicenter Study.

Resource links provided by NLM:


Further study details as provided by R. Post, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • Modified Rankin Scale (mRS) [ Time Frame: six months ]
    Good (mRS 0-3) and Poor (mRS 4-6)


Secondary Outcome Measures:
  • Date and cause of death [ Time Frame: Maximum six month ]
    Assessment of cause of death by a committee (intensive care/neurosurgeon)

  • Cause of poor outcome [ Time Frame: six months ]
    Assessment of which events during hospital admission led to a poor outcome defined as mRS 4 and 5 by a committee (intensive care/neurosurgeon)

  • Rebleed and time interval after first hemorrhage [ Time Frame: six months ]
    The time interval between the initial hemorrhage and occurence of a recurrent bleeding will be recorded.

  • Thromboembolic events during endovascular treatment [ Time Frame: up to 48 hours ]
    Complications during endovascular treatment will be recorded (ie occurence of clotting in one of the vessels)

  • Ischemic stroke (Dealyed cerebral ischemia) [ Time Frame: 14-20 days ]
  • Extracranial thrombosis [ Time Frame: six months ]
  • Hydrocephalus and treatment modality [ Time Frame: six months ]
    Occurence of a hydrocephalus will be recorded and which treatment modality is used to treat the hydrocephalus

  • Hemorrhagic complications (intra- and extracranial) [ Time Frame: six months ]
  • Time interval from last hemorrhage to first TXA administration [ Time Frame: 24 hours ]
  • Discharge location [ Time Frame: six months ]
  • Infarctions on MR imaging at six months after endovascular treatment [ Time Frame: six months ]
  • Health-care costs between discharge and six months after hemorrhage [ Time Frame: three and six months ]
    Questionnaires

  • Quality of life at six months after hemorrhage [ Time Frame: six months ]
    Questionnaire (EQ-5D)


Estimated Enrollment: 950
Study Start Date: July 2012
Estimated Study Completion Date: January 2020
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Tranexamic Acid
Treatment until aneurysm treatment or maximum dosage of 4 gram
Other Name: Cyklokapron
No Intervention: Control
Standard care

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02684812


Contacts
Contact: Dagmar Verbaan, PhD 020-5669111 d.verbaan@amc.nl
Contact: William P Vandertop, PhD MD 020-5669111 w.p.vandertop@amc.nl

Locations
Netherlands
Academic Medical Centre Recruiting
Amsterdam, Netherlands
Contact: Rene Post, MD       r.post@amc.nl   
Sub-Investigator: Rene Post, MD         
Principal Investigator: Dagmar Verbaan, PhD         
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Stichting Nuts Ohra
Investigators
Principal Investigator: William P Vandertop, PhD MD Department of Neurosurgery
  More Information

Additional Information:
Publications:
Responsible Party: R. Post, Drs., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT02684812     History of Changes
Other Study ID Numbers: 2012-000343-26
First Submitted: February 9, 2016
First Posted: February 18, 2016
Last Update Posted: February 18, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by R. Post, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
antifibrinolytic therapy
recurrent bleeding
tranexamic acid

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Tranexamic Acid
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants