Chester Clinic

 

Instructions for use ‘template research protocol'

ULTRA-EARLY TRANEXAMIC ACID AFTER
SUBARACHNOID HEMORRHAGE
A prospective, randomized, multicenter study M.R. Germans*, M.D. D. Verbaan*, Ph.D. G.J.E. Rinkel#, prof., M.D., Ph.D. W.P. Vandertop*, prof., M.D., Ph.D. *,Neurosurgical Center Amsterdam, Academic Medical Center # Department of Neurology, University Medical Center Utrecht PROTOCOL TITLE Ultra-early tranexamic acid after subarachnoid hemorrhage
Protocol ID
Short title
10/11/2015
Project leader
Prof.dr. W.P. Vandertop
Dr. D. Verbaan, Academic Medical Center,
Coordinating investigator
Amsterdam
Principal investigator(s) (in
Dr. D. Verbaan, Academic Medical Center,
Amsterdam
Prof.dr. W.P. Vandertop, VU University Medical
Multicenter research: per site
Center, Amsterdam
Prof. dr. G.J.E. Rinkel, University Medical Center
Drs. R. Post, Academic Medical Center,
Amsterdam
Drs. M.R. Germans, Academic Medical Center,
Amsterdam
Dr. B.A. Coert, Academic Medical Center,
Amsterdam
D. Verbaan, Ph.D. (AMC)
W.P. Vandertop, prof., M.D., Ph.D (AMC, VUMC)
Steering committee
M.R. Germans, M.D. (AMC)
B.A. Coert, M.D., Ph.D. (AMC)
Y.B.W.E.M. Roos, M.D., Ph.D. (AMC)
R. v.d. Berg, M.D., Ph.D. (AMC)
C.B.L.M. Majoie, M.D., Ph.D. (AMC)
J. Horn, M.D., Ph.D. (AMC)
G.J.E. Rinkel, prof., M.D., Ph.D. (UMCU)
Sponsor (in Dutch:
Academic Medical Center
Independent physician(s)
Dr. P. v.d. Munckhof, M.D., Ph.D., Academic
Medical Center, Amsterdam
Laboratory sites
Pharmacy
None involved
PROTOCOL SIGNATURE SHEET
Signature
For non-commercial research,
Head of Department:
Prof.dr. W.P. Vandertop
Principal Investigator:
Dr. D. Verbaan
Site investigator:
TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS . 7 2. SUMMARY . 8 3. INTRODUCTION AND RATIONALE . 9 4. OBJECTIVES .10 5. STUDY DESIGN .11 6. POPULATION .12 Population (base) .12 Inclusion criteria .13 Exclusion criteria .13 Sample size calculation .14 7. TREATMENT OF SUBJECTS .15 Investigational product/treatment .15 Escape medication .15 8. INVESTIGATIONAL MEDICINAL PRODUCT .15 Name and description of investigational medicinal product .15 Summary of findings from clinical studies .16 Summary of known and potential risks and benefits .16 Description and justification of route of administration and dosage .16 Dosages, dosage modifications and method of administration .16 Drug accountability and logistics .17 Study parameters/endpoints .17 Main study parameter/endpoint .17 Secondary study parameters/endpoints .17 Other study parameters .18 Randomisation, blinding and treatment allocation .19 Study procedures .20 Withdrawal of individual subjects .20 Replacement of individual subjects after withdrawal .21 SAFETY REPORTING .21 10.1 Temporary halt for reasons of subject safety .21 10.2 Adverse and serious adverse events .22 10.2.1 Suspected unexpected serious adverse reactions (SUSAR) .23 10.2.2 Annual safety report .23 10.3 Follow-up of adverse events .24 10.4 Data Safety Monitoring Board (DSMB) .24 10.5 Monitoring .24 STATISTICAL ANALYSIS .25 11.1 Descriptive statistics and analysis between randomization groups .25 11.2 Interim analysis .25 11.3 Analyses on primary and secondary outcomes .26 ETHICAL CONSIDERATIONS .26 12.1 Regulation statement .26 12.2 Recruitment and consent.26 12.3 Objection by minors or incapacitated subjects .28 12.4 Benefits and risks assessment, group relatedness .28 12.5 Compensation for injury .29 12.6 Incentives .29 ADMINISTRATIVE ASPECTS AND PUBLICATION .29 13.1 Handling and storage of data and documents .29 13.2 Amendments .30 13.3 Annual progress report .30 13.4 End of study report .30 13.5 Public disclosure and publication policy .31 APPENDIX: Dutch Flowchart SAE and SUSAR procedures .34 1. LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR form (General Assessment and Registration form) is required for submission to the accredited Ethics Committee (ABR = Algemene Beoordeling en Registratie) Adverse Reaction Central Committee on Research Involving Human Subjects Computed tomography Computed tomography angiography Curriculum Vitae Digital subtraction angiography Data Safety Monitoring Board Delayed cerebral ischemia EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice Glasgow Coma Scale Investigator's Brochure Informed Consent Investigational Medicinal Product Investigational Medicinal Product Dossier Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing commissie (METC) Serious Adverse Event Subarachnoid hemorrhage Substitute decision maker Summary of Product Characteristics (in Dutch: officiële productinformatie IB1- The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising Suspected Unexpected Serious Adverse Reaction Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) Medical Research Involving Human Subjects Act (Wet Medisch-wetenschappelijk Onderzoek met Mensen) Version number: 10 2. SUMMARY
Rationale: 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 rebleeding 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. Objective: Primary: 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. Secondary: 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. Study design: Multicenter, prospective, randomized, open label treatment with blind
endpoint assessment. Study population: Adult patients (18 years and older) included within 24 hours after SAH.
Intervention: 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. Main study parameters/endpoints:
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 Version number: 10 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. 3. INTRODUCTION AND RATIONALE
Subarachnoid hemorrhage (SAH) accounts for 5% of all strokes, and has an incidence of 6-7 per 100.000 person-years1. In 85% an intracranial aneurysm is found which is responsible for the hemorrhage, in 10% a perimesencephalic hemorrage is diagnosed and the remaining group includes other or unknown causes2, 3. SAH occurs at a fairly young age and carries a worse prognosis than other types of stroke.4 Approximately 25% of all patients with aneurysmal SAH have a favourable outcome5. Nevertheless, these patients still have severe cognitive and functional dysfunctions6. The case fatality in SAH is 50% due to the initial hemorrhage or subsequent complications1. A frequent complication in patients with SAH is a recurrent bleeding from the aneurysm ("rebleed") which occurs in 4-12%7-11 of patients that reach the hospital within the first 24 hours. The percentage of rebleeds increases to 21.5%12 if the rebleeds presenting within the first six hours after the primary hemorrhage9, 11 ("ultra- early rebleed") are also counted in. A rebleed is, next to the primary hemorrhage, still one of the major causes of death and disability in patients with SAH13. Functional dependency in this patient group is related to a lower quality of life and higher healthcare costs14. The prognosis of patients with SAH can be improved by decreasing the amount of rebleeds which can be accomplished by early aneurysm occlusion15, 16. However, in daily clinical practice, treatment can be delayed by a delay in diagnosis and transfer to a tertiary center. Therefore, despite several efforts to improve the logistic processes, ultra-early rebleeds still occur before the aneurysm is secured15. An alternative to reduce the number of rebleeds, other than by early aneurysm occlusion, is treatment with antifibrinolytic agents prior to aneurysm occlusion17. Long-term administration of antifibrinolytics has been extensively studied in the previous century. A Cochrane review Version number: 10 concerning antifibrinolytic therapy for aneurysmal SAH found a reduction in rebleeds of approximately 40% with administration of antifibrinolytic therapy17. Nevertheless, no significant difference was seen in outcome, due to a concurrent increase in ischemic stroke as a result of the antifibrinolytic treatment. A limitation of the included studies is that the majority was performed over a decade ago when overall outcome after SAH was worse because of less accurate diagnostic methods, lack of nimodipine treatment and a minor role for endovascular treatment1, 18. Nowadays, diagnosis and treatment are performed earlier after the initial hemorrhage and administration of nimodipin, a calcium antagonist which is proven to reduce ischemic stroke, is standard. Recent studies combining these up-to-date treatment protocols with early, short-term antifibrinolytic therapy show better results compared to the earlier performed studies8, 9, 19, with a tendency for improved functional outcome without an increase in ischemic stroke, as shown in a recent meta-analysis20. Although results from previous studies are promising, a randomized clinical trial in which TXA is administrated ultra-early (as soon as possible and at least within the first 24 hours after the primary hemorrhage) and for a short time period has not been performed yet. Ultra-early TXA treatment is expected to reduce the amount of rebleeds as much as possible whilst the short- term administration in combination with early aneurysm occlusion might reduce the risk for the occurrence of ischemic stroke20. This should result in a better outcome for patients with SAH. Therefore, the goal of this study is to evaluate whether patients with ultra-early and short-term administration of tranexamic acid (TXA), as add-on to standard, state-of-the-art SAH management have a significantly better functional outcome at six months compared to patients treated by standard, state-of-the-art SAH management without additional TXA 4. OBJECTIVES
Primary Objective: • To evaluate whether a group of patients with SAH treated by standard, state-of-the-art SAH management with additional ultra-early and short-term TXA administration (TXA group) has a significantly higher percentage of patients with a favourable outcome after six months (score 0-3 on the Modified Rankin Scale21; mRS) compared to a group treated by standard, state-of-the-art SAH management without TXA administration (control group). Secondary Objective(s): • To evaluate whether there is a significant difference in case fatality rate between the TXA group and the control group at discharge and at six months after SAH • To evaluate the cause of poor outcome Version number: 10 • To evaluate whether there is a significant difference in rebleed rate before or during aneurysm treatment between the TXA group and the control group • To evaluate whether there is a difference in thromboembolic events during endovascular treatment between the TXA group and the control group • To evaluate whether there is a difference in ischemic stroke rate between the TXA group and the control group • To evaluate whether there is a difference in complications, such as hydrocephalus, extracranial thrombosis or hemorrhagic complications, during admission and after six months, between the TXA group and the control group • To evaluate whether there is an association between favourable outcome and time from last hemorrhage to first TXA administration • To evaluate whether there is a difference in discharge location, between the TXA group and the control group • To evaluate whether there is a difference in (micro)infarctions on MR imaging at six months after endovascular treatment between the TXA group and the control group • To evaluate whether there is a difference in health-care costs from discharge until six months after hemorrhage between the TXA group and the control group • To evaluate whether there is a difference in quality of life at six months after hemorrhage between the TXA group and the the control group • To evaluate whether there is a significant difference in rebleed rate and favourable outcome between females and males and between groups with different World Federation of Neurological Surgeons (WFNS) scores at admission 5. STUDY DESIGN
A multicenter, prospective, randomized, open-label with blinded endpoint, trial will be performed in patients with a SAH (PROBE design: Prospective, Randomized, Open label
treatment with Blind Endpoint assessment). With the calculated amount of included
patients (950), the expected duration will be three years if all centers start inclusion at start of study. The following procedures will be performed during the study: Version number: 10 TXA GROUP
CONTROL GROUP
Administer 1 g TXA i.v. immediately No additional intervention Continue with 1 g per 8 hours i.v. After CT-a and/or DSA: aneurysm After CT-a and/or DSA: aneurysm responsible for SAH? responsible for SAH? Endovascular or surgical treatment Endovascular, surgical or no treatment < 24 hours > 24 hours or no treatment Stop TXA at time-out procedure Stop TXA 24 hours after start If endovascular treatment: MR imaging If endovascular treatment: MR imaging at at six months after hemorrhage six months after hemorrhage Outcome assessment, survey for Outcome assessment, survey for healthcare costs and quality of life healthcare costs and quality of life at six months after hemorrhage at six months after hemorrhage * if recent laboratory investigations revealed severe renal (serum creatinin >150 mmol/L) or liver failure (AST > 150 U/l or ALT > 150 U/l or AF > 150 U/l or γ-GT > 150 U/l), study medication will also be stopped immediately
6. POPULATION
6.1 Population (base)
The research population are adult patients admitted with the diagnosis subarachnoid hemorrhage (SAH) as proven by computed tomography (CT) within 24 hours after the primary hemorrhage. The incidence of this type of hemorrhage is about 6-7 per Version number: 10 100.000 person-years3. It is expected that in the population admitted in The Netherlands about 80% of SAH is a result of a ruptured intracranial aneurysm22. Approximately 90% of SAH patients are admitted to a hospital within 24 hours after the hemorrhage (own data, not published). A bolus of the study medication will be administered as soon as possible after the diagnosis. The continuous infusion of the study medication will be cancelled immediately if after inclusion 1) no aneurysm appears to be present on CT-angiography (CT-a) or Digital Subtraction Angiography (DSA), 2) other intracranial pathology is responsible for the SAH, or 3) the aneurysm which is visualised is probably not responsible for the hemorrhage based on the bleeding pattern on CT. Patients, or their legally-appropriate substitute decision maker (SDM), will be approached to ask for the patients' participation in the study. Due to the emergent intervention and the need to administer the medication as soon as possible an emergency procedure will be applied where consent is obtained after the administration of the medication (see 12.2). Patients or their legally-appropriate SDM will be informed about the rationale of this study, possible risks and study burden as soon as possible after the emergency intervention. A member of the research team will provide the study information and will give eligible candidates, or their legally-appropriate SDM, the study information letter. After the reflection period, patients or they SDM's will be asked to provide informed consent. If patients are primarily enrolled in the study after consent of an SDM and have become adequate enough to judge for joining the study, they will be informed by a study information letter as well with an additional question for informed consent. 6.2 Inclusion criteria
• Admission to one of the participating study centers or the participating referring • 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. • Age 18 years and older 6.3 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 Version number: 10 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 Since a majority of the patients arrive at the hospital with decreased consciousness on admittance and the study is being executed based on the emergency procedure, exclusion criteria that cannot be determined on admittance are considered to be absent. These criteria will be checked later and if present, will be acted upon (see 6.4 Sample size calculation
The primary analysis at the end of the study is based on the difference in percentage of patients with good outcome (mRS 0-3) at six months after initial hemorrhage between patients with and without additional TXA intervention. The overall favourable outcome in patients with standard, state-of-the-art SAH management without TXA was calculated by combining the results of the studies mentioned in this paragraph and the results from our own patients (293 consecutive patients, including angiogram-negative SAH, treated between 2008 and 2011) and The total percentage of rebleeds in patients with standard, state-of-the-art SAH management without TXA was determined at 17%. Although two studies and a recent review evaluating ultra-early antifibrinolytic treatment after SAH8, 9 reported a rebleed rate of approximately 12%, our own recent results showed a rebleed rate of 17.1%, which was supported by Guo et al. (rebleed rate of 21.5% in aneurysmal SAH)12. The difference in results may be due to the shorter time interval between primary hemorrhage and diagnosis (the majority of rebleeds namely occurs within the first few hours) in our center compared to the studies reporting a lower rebleed percentage (own data, manuscript in preparation). The percentage of patients with rebleeds who will have a favourable outcome with standard, state-of-the-art SAH management is 20% (0.17*0.20= 3.4% of the total group)9. Consequently, with an overall favourable outcome in 69% of the patients, Version number: 10 the percentage of patients with a favourable outcome in patients without a rebleed is 79% (65.6/83= 0.79). The reduction in rebleeds by ultra-early TXA administration is expected to be 77%, resulting in a rebleed percentage of 3.9% in the patients receiving TXA (0.17*0.77= 13.1%; 17%-13.1%= 3.9%)8, 9. The percentage of patients with a rebleed and a favourable outcome is anticipated to improve from 20% to 30% in patients with TXA9. Summarizing, after TXA administration, 3.9% will have a rebleed, of which 30% will have a favourable outcome (0.039*0.3= 1.2%). The resulting patients without a rebleed will have a favourable outcome in 79%, which contributes 75.9% to the complete group with favourable outcome (0.961*0.79=75.9%). With these premises we calculated an improvement of favourable outcome from 69% to 77.1% (75.9%+1.2%). In conclusion, to be able to detect the difference of 8.1% with a power of 80% and alpha of 5%, approximately 470 patients have to be included in each group (940 patients in total). Taking into account some withdrawals, the amount to be included patients will be 950. 7. TREATMENT OF SUBJECTS
7.1 Investigational product/treatment
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. 7.2 Escape medication
8. INVESTIGATIONAL MEDICINAL PRODUCT
8.1 Name and description of investigational medicinal product
Tranexamic acid (Cyklokapron®) forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. Eligible subjects are randomly assigned to immediate administration of TXA (1 g i.v.) after diagnosis SAH confirmed by CT, as soon as possible continued by continuous infusion of 1 g per 8 hours to a maximum of 24 hours after start of medication. If aneurysm treatment is initiated within 24 hours (approximately 80% of all patients) Version number: 10 the medication infusion will be discontinued at the time-out procedure before start of aneurysm treatment (endovascular or surgical). 8.2 Summary of findings from clinical studies
• Immediate TXA administration after SAH is diagnosed reflects a tendency toward better outcome on the Glasgow Outcome Scale9. • In patients with a rebleed, TXA administration significantly reduces death from rebleed9. • Antifibrinolytic treatment reduces the risk of rebleeding (OR 0,55, 95% CI 0,42- • Short-term TXA administration does not increase DCI significantly9, 19. • Short-term application of epsilon-aminocaproic acid does not result in an increase of ischemic complications, pulmonary emboli, vasospasm, ventriculoperitoneal shunt rates or differences in outcome in angiogram negative 8.3 Summary of known and potential risks and benefits
The most common adverse events occur mainly in a short period after start of medication. During this time subjects are continually monitored so it is expected that adverse events are diagnosed and treated adequately by the attending physician. Standard care to prevent nausea, vomiting or hypotension is a part of the standard SAH protocol because patients with such a hemorrhage also often have such Known adverse events of TXA are described below: • >10%: gastrointestinal: diarrhea, nausea, vomiting • 1% to 10%: cardiovascular: hypotension, thrombosis. Ocular: blurred vision • <1% (limited to important or life-threatening): deep venous thrombosis, pulmonary embolus, renal cortical necrosis, retinal artery obstruction, retinal vein obstruction, unusual menstrual discomfort, ureteral obstruction 8.4 Description and justification of route of administration and dosage
In previously performed studies, safety is warranted with use of TXA intravenously 8.5 Dosages, dosage modifications and method of administration
• Bolus: 10 ml (100 mg/ml) = 1000 mg dissolved in 100 ml NaCl 0,9% and administered intravenously in 10 minutes • Start immediately after diagnosis SAH on CT and randomization Version number: 10 • Followed by continuous infusion of 10 ml (100 mg/ml) = 1000 mg intravenously per 8 hours until a maximum of 24 hours • The Study Drug will be dispensed only to eligible subjects under the supervision of the Investigator or identified sub-Investigator(s). 8.6 Drug accountability and logistics
Cyklokapron is registered in The Netherlands, available on prescription and widely used in different hospitals. If a patient is randomized to the TXA group, the treating physician (electronically) prescribes the TXA in their hospital according to standard procedures. TXA will be given from stock on the emergency department, or neuro (intensive) care unit. Charge numbers and expiry dates from the TXA are documented in the study CRF, as well as the initials from the person who administered the TXA. Each participating center will ensure the availability of cyklokapron in their pharmacy. Accountability for the study drug is in accordance to GCP guidelines, except for stock management. However, for financial purposes, each participating center needs to manage the administered TXA for all patients included in the ULTRA study treatment arm. Yearly, participating centers can send an invoice with respect to costs for TXA to the coordinating center. 9. METHODS
9.1 Study parameters/endpoints
9.1.1 Main study parameter/endpoint
Clinical outcome assessed by the modified Rankin Scale score at six months. 9.1.2 Secondary study parameters/endpoints
1. If patient has deceased: date and cause of death 2. Cause of poor outcome Related to the primary hemorrhage, related to complications of hemorrhage, related to one of the reported adverse events or unrelated to hemorrhage. Assessed by a central reading committee 3. Possible or definite rebleed and time interval with first hemorrhage Definition: sudden neurological deterioration with change in vital parameters suggestive for rebleed (possible rebleed) and presence of more SAH on CT than in a previous investigation (definite rebleed). 4. Rebleed during endovascular or surgical treatment Definition: extravasation of contrast dye outside of the vascular wall or perforation of the microcatheter, microwire or coil through the aneurysm wall with of without a sudden change in vital parameters suggestive for rebleed. Rupture of aneurysm during aneurysm surgery. 5. Thromboembolic events during endovascular treatment Definition: reduced passage or stasis of contrast in an artery or slowed venous outflow without the aspect of vascular spasm. Evaluated by treating neuroradiologist. Version number: 10 6. Ischemic stroke (delayed cerebral ischemia) Definition: The occurrence of focal neurological impairment (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect), or a decrease of at least 2 points on the Glasgow Coma Scale (either on the total score or on one of its individual components [eye, motor on either side, verbal]). This should last for at least 1 hour, is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies23. 7. Extracranial thrombosis Definition: Lower extremity deep venous thrombosis, upper extremity venous thrombosis, upper extremity arterial thrombosis or pulmonary embolism diagnosed after clinical suspicion. 8. Treatment for hydrocephalus (therapeutic lumbar puncture, lumbar or ventricular drainage or definitive shunt) Definition of hydrocephalus: gradual onset of deterioration of consciousness measured on the Glasgow Coma Scale with CT evidence of enlarged ventricles and no other explanation for deterioration. 9. Hemorrhagic complications (intra- and extracranial) Definition: on CT proven intracranial hemorrhage (intracerebral, intraventricular, subdural or epidural), increased or newly developed after the primary hemorrhage; any extracranial hemorrhage for which intervention is necessary; either with neurological deterioration or not. 10. Time interval from last hemorrhage to first TXA administration 11. Discharge location Other hospital, nursing home, rehabiliation center or home 12. Infarctions on MR imaging at six months after endovascular treatment Definition: amount of hyperintensity signals in brain parenchyma on T2 weighted MR imaging. 13. Health-care costs between discharge and six months after hemorrhage Evaluated with a standardized questionnaire 14. Quality of life at six months after hemorrhage Evaluated with the EQ-5D questionnaire 15. WFNS grade at admission Dichotomized into 1-3 and 4-5 9.1.3 Other study parameters
1. Date of birth 2. Modified Rankin Scale score before admittance 3. Medication use (antihypertensives, antiplatelets, anticoagulation) before 4. WFNS grading of SAH 6. Date and time of SAH • if exact time is unknown, then approximation of time of hemorrhage • if patient is discovered with depressed consciousness, then the time of patient last seen well is used 7. Date and time of CT scan for diagnosis SAH Version number: 10 8. Date and time of first administration of TXA 9. Date and time of first continuous administration of TXA 10. Date and time of ending the administration of TXA 11. Total dose of administered TXA 12. Location of aneurysm 13. Type of aneurysm treatment 14. Date and time of time-out procedure for aneurysm treatment 15. If applicable: date and time of rebleed (or approximation of it) and whether this is confirmed by consecutive CT scans or based on a sudden change in vital parameters and neurological deterioration (see also 9.1.2.) 9.2 Randomisation, blinding and treatment allocation
When a patient is admitted directly to the study center, the on-line randomization procedure will be done immediately by the treating physician after confirmation of SAH on CT. When the subject is allocated to administration of TXA, the bolus of TXA is given as soon as possible. After the bolus, continuous infusion of TXA is started as soon as possible. In the majority of cases, about 80%, patients are first admitted to a referring center of the study center(s). In this case, when the diagnosis SAH is confirmed by CT, the treating physician contacts the neurology/neurosurgery resident at the center to which the patient will be transferred to. The resident will perform the on-line randomization as soon as possible. The result of the randomization will be communicated to the treating physician at the referring center and when the subject is allocated to TXA treatment, an order is given by the treating physician to administer the bolus as soon as possible. The continuous infusion is started as soon as possible after the bolus and at least before transport to the study center. In conclusion, when a subject is allocated to TXA treatment, the bolus of study medication will be administered as soon as possible through an already present venous catheter (conform standard protocol for SAH) followed by the start of continuous infusion as soon as possible. Patients will be randomized, using permuted blocks and stratified for study center (i.e. equal number of patients in both trial arms per center), using the on-line randomization module (ALEA), where fictive patient initials, date of birth, date and time of hemorrhage and eligibility based on in- and exclusion criteria is considered before randomization. The study starts after the patient has been randomized. The study nurse who will evaluate the modified Rankin Scale score (mRS) at six months after the SAH will be blinded for treatment allocation. In this way, blinding of the Version number: 10 primary endpoint measurement is established. This evaluation takes place at a later stage, and the data are not used in any way during treatment of the patient. 9.3 Study procedures
Patients are admitted to the intensive care unit, medium care or neurological/ neurosurgical ward in one of the study centers. The necessary data for the study are collected and imported in an on-line database by the treating physician of the study center, supported by the study coordinator. The CT-scan on which the diagnosis SAH was stated is evaluated by a neuroradiologist at the center where the treatment The outcome assessment at six months after the hemorrhage is done by a trial nurse who is blinded for allocation and did not participate in the medical treatment of the included patients. The mRS score at six months is taken by a standardized and validated telephone interview with the patient or the legally appropriate SDM. This score is commonly used for outcome assessment in stroke trials. Additionally, a short questionnaire to assess the health-care costs and quality of life at three and six months after SAH is sent and patients or their legally appropriate SDM will be asked to return this to the study center. If the patient has an unfavourable outcome (mRS 4-6), the most probable cause (i.e. related to the primary hemorrhage, related to complications of hemorrhage, related to one of the reported adverse events or unrelated to hemorrhage) is assessed by a Data Classification Committee (DCC). This committee is composed of the investigators of the coordinating centre and the local investigator. The results of these evaluations will be made available to the DSMB. If the patient has deceased, the primary cause and date of death is recorded. Prof. dr. W.P. Vandertop is, as co-PI with a medical background, responsible for the medical part of this study. 9.4 Withdrawal of individual subjects
Subjects, or their legally appropriate SDM can refuse to participate in the study by not signing the informed consent. If the informed consent is not signed and patients are allocated to TXA administration, TXA will be cancelled immediately if it is still administered. Data from these patients will be destroyed immediately. Subjects, or their legally appropriate SDM who approved the authorization for inclusion in the study, can decide to exit the study at any time for any reason if they wish to do so, without any consequences. In these cases, the patient data are not used for primary or secondary outcome assessments. The investigator can decide to withdraw a Version number: 10 subject from the study for urgent medical reasons. A specific reason for withdrawal would be the occurrence of a Serious Adverse Event. If it is revealed after inclusion, that one of the exclusion criteria was present in a certain patient at admittance, this patient remains included in the study and this is recorded as a protocol violation. Depending on the criterion, actions are undertaken. For instance, TXA may be stopped (perimesencephalic hemorrhage, traumatic SAH, treatment for deep vein thrombosis or pulmonary embolism, history of a blood coagulation disorder, pregnancy, history of severe renal or liver failure). In case of no proficiency of the Dutch or English language, TXA will not be stopped but an interpreter has to be arranged to be able to perform the informed consent procedure (and the patient information has to be translated). In patients who are correctly included and who already received TXA and 1) no aneurysm appears to be present on DSA, 2) other intracranial pathology is responsible for the SAH, 3) the aneurysm which is visualised is probably not responsible for the hemorrhage based on the bleeding pattern on CT, or 4) recent laboratory investigations reveal pregnancy or severe renal (serum creatinin >150 mmol/L) or liver failure (AST > 150 U/l or ALT > 150 U/l or AF > 150 U/l or γ-GT > 150 U/l), the continuous infusion of the medication will be cancelled immediately. These patients will be included for the outcome assessments to ensure an adequate intention-to-treat analysis. 9.5 Replacement of individual subjects after withdrawal
Subjects who are lost to follow-up cannot be included in the analysis of the primary outcome assessment. If possible, they will be included in the secondary endpoint assessment. Individual subjects will not be replaced after withdrawal. Our analysis will be according to the intention-to-treat principle and exclusion of these patients would lead to a selective patient sample. 10. SAFETY REPORTING
10.1 Temporary halt for reasons of subject safety
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardise subject health or safety. The sponsor will notify the accredited METC without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending further review by the accredited METC. The investigator will take care that all subjects are kept informed. Version number: 10 10.2 Adverse and serious adverse events
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational drug. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. A serious adverse event is any untoward medical occurrence or effect that at any is life threatening (at the time of the event); requires hospitalisation or prolongation of existing inpatients' hospitalisation; results in persistent or significant disability or incapacity; is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the treatment of a life threatening disease, major safety finding from a newly completed animal study, etc. For the present study, an AE is defined according to the definition above. Only AEs during hospital admission that are not related to the subarachnoid haemorrhage must be reported. For the present study, an SAE is defined according to the definition above, during hospital admission. The investigator will report all SAEs to the sponsor without undue delay after obtaining knowledge of the events. A life threatening SAE, or SAE with death as a result, must be reported within 7 days after the local investigator has been informed. Other SAEs must be reported within 15 days. The sponsor is responsible for reporting and records SAEs at the internetsite of ToetsingOnline of the CCMO. This instance reports the SAE to the METC. In this study, certain SAEs may occur that are expected in SAH patients. The expected SAEs are rebleed, severe hyponatriaemia, hydrocephalus, cerebral ischemia, pneumonia, nosocomial meningitis, Terson's syndrome, delirium, epilepsy, pneumocephalus, and perprocedural aneurysm rupture. These are recorded and reported to the METC every half year by line listing and not reported at the internetsite as described above. Version number: 10 10.2.1 Suspected unexpected serious adverse reactions (SUSAR)
Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered. Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information (e.g. Investigator's Brochure for an unapproved IMP or Summary of Product Characteristics (SPC) for an authorised medicinal product). The investigator will report expedited the following SUSARs to the METC: − SUSARs that have arisen in the clinical trial that was assessed by the − SUSARs that have arisen in other clinical trial of the same sponsor and with the same medicinal product, and that could have consequences for the safety of the subjects involved in the clinical trial that was assessed by the The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, accompanied by a brief report highlighting the main points of concern. The investigator will report expedited all SUSARs conform protocol of the CCMO to the competent authority, the Medicine Evaluation Board and the competent authorities in other Member States unless it is already reported to the EMEA Eudravigilance database (appendix) . The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report. 10.2.2 Annual safety report
In addition to the expedited reporting of SUSARs, the investigator will submit, once a year throughout the clinical trial, a safety report to the accredited METC, competent authority, Medicine Evaluation Board and competent authorities of the concerned Member States. This safety report consists of: − a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study; Version number: 10 − a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation. 10.3 Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. 10.4 Data Safety Monitoring Board (DSMB)
The Data Safety Monitoring Board (DSMB) is an independent committee of trial experts, who will focus on both safety monitoring and analysis of effectiveness on unblinded data with an interim analysis after half of the patients were included. The DSMB consists of three members: 2 clinicians and 1 statistician/epidemiologist. A DSMB charter will be used with respect to the schedule and format of DSMB meetings and with respect to the format and timing of presenting data. The DSMB will perform ongoing safety surveillances, especially with regard to the occurrence of serious adverse events in terms of increased ischemic events and serious extracranial thombotic events, such as pulmonary embolism. The investigator will report the occurrences of these events to the chairman according to the charter. Each half year, a line listing will be reported to the METC, and a line listing and a safety evaluation will be reported to the DSMB. Based on these documents the DSMB will give an advice with respect to continuation of the trial based on this safety evaluation. The DSMB can recommend the Steering Committee of the ULTRA trial to terminate the trial when there is clear and substantial evidence of harm or to adjust the sample size. 10.5 Monitoring
Based on the guidelines for risk classification from the Dutch Federation of University Medical Centers (NFU) ("Kwaliteitsborging van mensgebonden onderzoek"), the risk analysis performed for this study resulted in a classification of "average risk". This classification is based on the low chance for complications with clinical consequences due to the use of TXA as described in paragraph 6.3, in a vulnerable patient population. Much experience is present with this medication because of many previously performed human-related studies. Additionally, the maximum dose of administered TXA in this study will be lower than the maximum dose in which safety has been warranted (see paragraph 8.4). Other described Version number: 10 complications, such as increase in ischemic events and more thromboembolic events, are not expected to occur because of the short-term and minimal dose administration of TXA. This is supported by previous studies8, 9, 19 and explained in more detail in paragraph 12.4. Monitoring will be performed according to GCP and will be carried out by the Clinical Research Unit of the AMC using a predefined monitoring plan. The monitor will make several visits to the sites during the trial, in order to complete source data verification (SDV). Next to the ‘regular' visits, the sponsor or investigators can ask for extra visits, preformed by the monitor. By signing this protocol the investigators give consent and full cooperation to the monitor during the trial. The final statistical analysis will be performed by the investigators. If inconsistencies are found during the monitoring, such as missing informed consents or protocol violations, this is reported back to the investigators. They will restore the inconsistencies if possible and report this to the monitor within one month after the monitoring. 11. STATISTICAL ANALYSIS
11.1 Descriptive statistics and analysis between randomization groups
Continuous data with a parametric distribution will be presented as mean with its standard deviation and continuous data with a non-parametric distribution will be presented as median with its interquartile range. Categorical data will be presented Group differences for continuous variables will be calculated by a mean difference with a 95% CI, using an independent t-test for continuous variables with a parametric distribution or Wilcoxon rank sum test for continuous variables with a non-parametric distribution. Group differences for categorical variables will be calculated using chi-square statistics. A 2 sided p-value < 0.05 will be considered 11.2 Interim analysis
The DSMB will perform an unblinded interim analysis on the primary outcome to assess the strength of the efficacy data when half of the patients are enrolled. The DSMB will also check the assumptions for sample size calculations. The DSMB can recommend the Steering Committee of the ULTRA trial to: • adjust the sample size • early terminate the study when there is clear and substantial evidence of benefit, based on a significant (with alpha 0.1%) increase in favourable outcome Version number: 10 (according to the Peto approach of interim analysis with alpha 5% at final • early terminate the study when there is evidence of severe harm based on SAE reporting, outcome, and case fatality • early terminate the study in case accrual rates are too low to provide adequate statistical power for identifying the primary endpoint The Steering Committee and the DSMB will agree on the approach to early termination (stopping rules) and the statistical methods used for efficacy evaluation 11.3 Analyses on primary and secondary outcomes
The statistical analysis will be by "intention to treat". The primary outcome analysis is an analysis evaluating the difference between the proportion of patients with favourable outcome (mRS score of 0 to 3 at six months) between the two randomization groups. The secondary outcome analyses compare several variables between randomization groups: case fatality rate, rebleed rate before or during aneurysm treatment, thromboembolic events during endovascular treatment, rate of DCI, rate of complications with subdividing into types of complications, rate of (micro)infarctions at MR imaging, discharge location, health-care costs, quality of life, WFNS grade at admission or gender associated to rebleed rate and favourable outcome. Chi square statistics will be used to calculate an odds ratio, risk ratio, or risk difference. Adjustments for factors that differ at randomization will be made using regression or multi-level models. 12. ETHICAL CONSIDERATIONS
12.1 Regulation statement
This study will be conducted in full accordance with the principles of the "Declaration of Helsinki" (59th WMA General Assembly, Seoul, October 2008 and Medical Research Involving Human Subjects Act (WMO). 12.2 Recruitment and consent
This study evaluates the influence of an acute treatment in an emergency situation concerning a life-threatening disorder. The TXA treatment is intended to be administered as soon as possible after confirmation of the SAH to maximally reduce rebleeds (in our own database of 293 patients from 2008 until 2011, 39% of all rebleeds occur within two hours after the primary hemorrhage (manuscript in Version number: 10 About two thirds of the patients have a decreased consciousness on admittance and are not able to give informed consent, and legally appropriate SDM's are not always present at the ER. Additionally, these patients are more prone for a rebleed because of the higher WFNS grading. By postponing the administration of the study medication until informed consent is given, rebleeds may occur which could be prevented by early treatment. The emergency situation, the vulnerable patient group and the importance of the ultra-early administration allows an emergency procedure with obtaining consent after start of medication in the above mentioned patient group. Approximately one third of the patients arrive fully conscious (or with a legally appropriate SDM) and are theoretically capable of giving informed consent. However, if these patients are asked for consent immediately, the ultra-early administration of TXA will be delayed compared to patients with a decreased consciousness, thus creating a bias between patients with and without the emergency procedure. Furthermore, a possible rebleed in patients who are clinically good after the first hemorrhage will result in a significant worse outcome. Therefore, TXA has to be administered as soon as possible after the diagnosis, and an emergency procedure with obtaining consent after start of medication in this group seems justifiable as well. Therefore in this study, TXA is administered as soon as possible after diagnosing SAH by CT and random allocation. There are no reported adverse events when TXA is administered for a short period9, 20, 24. Afterwards, as soon as possible at the study center, eligible subjects or their legally appropriate SDM will be notified by their treating physician that they have been included in the study. The investigator of the study will explain the rationale of the study and the study burden. An information letter and informed consent with the amendment that the patients' general physician will be informed of participation in the study will be given to eligible candidates or their legally appropriate SDM. The reflection period for signing the informed consent is as long as necessary (during the admission period). Participating patients can withdraw at any time from the study without prior notice or reason, or can refuse participating by not signing the informed consent. In consultation with the legal expert, some exceptions that are possible on the abovementioned procedure are discussed and a solution is chosen based on both ethical and legal considerations as well as methodological considerations (diminishing of bias). If patients die before the informed consent procedure could be discussed and there is no legally appropriate SDM, no consent is necessary and Version number: 10 patients remain included in the study as long as there is no clearly written objection in the chart from the patient against participation in scientific research projects. If patients die and there is a legally appropriate SDM, but there has been no possibility yet to discuss the informed consent procedure, no consent is necessary and patients remain included in the study as long as there is no clearly written objection in the chart from the patient against participation in scientific research projects. In both cases, the reason to deviate from the standard procedure as well as the decision that the patient remains included in the study has to be written clearly in the chart. 12.3 Objection by minors or incapacitated subjects
Due to the nature of the population studied, it is conceivable that in about 70% eligible subjects have a depressed level of consciousness and thus not be able to object themselves. In patients with a depressed level of consciousness, we will inform the SDM about this study and ask the SDM whether the patient would be willing to continue participating and sign the informed consent form on the patients' behalf. When patients are again capable for adequate judging, they will be informed about the study as written in 12.2. 12.4 Benefits and risks assessment, group relatedness
TXA is given by a bolus through an already present intravenous entry site, through which approximately 2 L NaCl 0,9% per 24 hours is administered (conform SAH protocol). Rapid infusion incidentally causes dizziness and hypotension, which is assumed to occur even less than normally because of the crystalloid infusion. If present, it will be rapidly diagnosed because the patient's parameters are continuously monitored. A side effect is nausea, vomiting and diarrhoea, which generally occurs after SAH as well, so patients often receive medication for this purpose. In brief, by following the standard SAH protocol the extra burden by use of this medication is reduced to a minimum. Concerning risk evaluation, it was reported in a Cochrane review17 that use of antifibrinolytic therapy (e.g. tranexamic acid) is associated with a higher incidence of DCI, without benefits in favourable outcome. A major drawback in the included studies is that the long-term administration of TXA caused an increase in DCI which negated the positive effects of a 40% reduction in rebleed rate. In addition, the majority of studies was performed before 1991 when outcome of SAH was worse because of less specialised institutes, lacking the use of nimodipine and less patients treated with endovascular methods18. More recently, studies have been Version number: 10 done with improved treatment protocols and these tend to show better results than experienced in the past with no higher incidence of DCI8, 9, 19. Other risks associated with use of this medication are allergic skin reactions which can be treated adequately and sporadic thromboembolic complications19. At six months patients are invited for a telephone interview to evaluate the primary and secondary outcome assessments. A survey for the health-care costs and quality of life assessment will be sent to the patient with the question to fill it in and return it to the coordinating study center. When patients are unable to complete the telephone interview and/or questionnaire, a proxy will be asked. Weighing carefully the benefits versus the burden and risks, it is assumed that patients will benefit from ultra-early treatment with TXA with minimal burden during 12.5 Compensation for injury
The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 of the WMO. The sponsor (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study. 1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research; 2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all subjects who participate in the Research; 3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organisation for all damage disclosed by scientific research for the Sponsor as ‘verrichter' in the meaning of said Act in each year of insurance coverage. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study. 12.6 Incentives
13. ADMINISTRATIVE ASPECTS AND PUBLICATION
13.1 Handling and storage of data and documents
The data will be handled by the trial nurse who will have access to the source data and CT investigations. Version number: 10 Data are collected patient record forms and stored in a digital Case Record Form (CRF) based on Oracle Clinical. This data entry meets the needs of AMC Good Clinical Practice (GCP) Guidelines with a number and fictional initials for each patient and a double data entry process. Data will be archived for 20 years after end of study conform the directive of GCP. Every essential document will be preserved on paper or digital copies if no paper version is possible. It will be saved in cardboard archive boxes in the Academic Medical Center (AMC), location E2-170, with the name of the study, principal investigator, department, division and duration of archivation perceptible. Electronical data will be saved on a central server as "write once read many" (WORM) in consultation with an ICT administrator. 13.2 Amendments
A ‘substantial amendment' is defined as an amendment to the terms of the METC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: the safety or physical or mental integrity of the subjects of the trial; the scientific value of the trial; the conduct or management of the trial; or the quality or safety of any intervention used in the trial. All substantial amendments will be notified to the METC and to the competent Non-substantial amendments will not be notified to the accredited METC and the competent authority, but will be recorded and filed by the sponsor. 13.3 Annual progress report
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments. 13.4 End of study report
The sponsor will notify the accredited METC and the competent authority of the end of the study within a period of 90 days. The end of the study is defined as the last patient's last visit. In case the study is ended prematurely, the sponsor will notify the accredited METC and the competent authority within 15 days, including the reasons for the premature Version number: 10 Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC and the Competent Authority. 13.5 Public disclosure and publication policy
Conform the CCMO statement on publication, this study will be proposed for publication within a year after the final outcome measurement, regardless of either positive or negative results. Results will be presented in an appropriate international, peer reviewed journal. Authorship will be granted using the Vancouver definitions and depending on personal involvement. The first, second and last author names will be decided by the principal investigator and project leader. After the first and second author, the steering group members, site investigators and additional names are mentioned in alphabetical order. Referral centres recruiting ≥ 30 patients and treatment centers recruiting ≥ 50 patients will be entitled to one name in the author list (site investigators). After the author list there will be added: "and the ULTRA-trial group" and a reference to an appendix with all sites, site investigators and number of patients enrolled. This trial is registered at the international trial registry , EudraCT database and Nederlands Trial Register (www.trialregister.nl) database. 14. REFERENCES
(1) Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review. Neurology 2010 May 11;74(19):1494-501. (2) van Gijn GJ, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (3) van Gijn GJ, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet 2007 January 27;369(9558):306-18. (4) van Gijn GJ. Subarachnoid haemorrhage. Lancet 1992 March 14;339(8794):653-5. (5) Molyneux AJ, Kerr RSC, Yu LM, Clarke M, Sneade M, Yarnold JA, et a. International subarachnoid aneurysm trial (ISAT) of neurological clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366:809-17. (6) Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010 August;41(8):e519-e536. (7) Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med 2006 August 31;355(9):928-39. Version number: 10 (8) Starke RM, Kim GH, Fernandez A, Komotar RJ, Hickman ZL, Otten ML, Ducruet AF, Kellner CP, Hahn DK, Chwajol M, Mayer SA, Connolly ES, Jr. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke 2008 September;39(9):2617-21. (9) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (10) Beck J, Raabe A, Szelenyi A, Berkefeld J, Gerlach R, Setzer M, Seifert V. Sentinel headache and the risk of rebleeding after aneurysmal subarachnoid hemorrhage. Stroke 2006 November;37(11):2733-7. (11) Starke RM, Connolly ES, Jr. Rebleeding After Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2011 October;15(2):241-6. (12) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (13) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (14) Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry 2000 March;68(3):337-41. (15) Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002 August;97(2):250-8. (16) Phillips TJ, Dowling RJ, Yan B, Laidlaw JD, Mitchell PJ. Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? Stroke 2011 July;42(7):1936-45. (17) Roos YB, Rinkel GJ, Vermeulen M, Algra A, van GJ. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2000;(2):CD001245. (18) Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 2009 July;8(7):635-42. (19) Roos Y. Antifibrinolytic treatment in subarachnoid hemorrhage: a randomized placebo-controlled trial. STAR Study Group. Neurology 2000 January 11;54(1):77-82. (20) Gaberel T, Magheru C, Emery E, Derlon JM. Antifibrinolytic therapy in the management of aneurismal subarachnoid hemorrhage revisited. A meta-analysis. Acta Neurochir (Wien ) 2011 October 15. (21) Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957 May;2(5):200-15. Version number: 10 (22) Germans MR, Pennings FA, Sprengers ME, Vandertop WP. Spinal vascular malformations in non-perimesencephalic subarachnoid hemorrhage. J Neurol 2009 (23) Vergouwen MD, Vermeulen M, van GJ, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010 October;41(10):2391-5. (24) Hui FK, Schuette AJ, Lieber M, Spiotta AM, Moskowitz SI, Barrow DL, Cawley CM. Epsilon Aminocaproic Acid In Angiographically Negative Subarachnoid Hemorrhage Patients Is Safe: A Retrospective Review of 83 Consecutive Patients. Neurosurgery 2011 September 5. Version number: 10 APPENDIX: Dutch Flowchart SAE and SUSAR procedures
Version number: 10

Source: http://www.miradi.nl/ultra/documents/protocol/Protocol.pdf