Dose Selection

The systematic review of randomised controlled trials of antifibrinolytic agents in surgery showed that dose regimens of tranexamic acid vary widely.⁶ Loading doses range from 2.5 mg/kg to 100 mg/kg and maintenance doses from 0.25 mg/kg/hr to 4 mg/kg/hr delivered over time periods of one to twelve hours. Studies examining the impact of different doses of tranexamic acid on bleeding and transfusion requirements showed no significant difference between a high dose and a low dose.

Studies in cardiac surgery have shown that a 10 mg/kg initial dose of tranexamic acid followed by an infusion of 1 mg/kg/hour produces plasma concentrations sufficient to inhibit fibrinolysis in vitro.¹³ The dose-response relationship of tranexamic acid was examined by Horrow et al (1995) who concluded that 10 mg/kg followed by 1 mg/kg/hour decreases bleeding after extracorporeal circulation and that larger doses did not provide any additional haemostatic benefit.¹⁴

In this emergency situation, administration of a fixed dose would be more practicable as determining the weight of a patient would be impossible. Therefore, a fixed dose within the dose range which has been shown to inhibit fibrinolysis and provide haemostatic benefit is being used for this trial. The fixed dose chosen would be efficacious for larger patients (> 100 kgs) but also safe in smaller patients (< 50 kgs), as the estimated dose/kg the latter group would receive has been applied in other trials without adverse effects. The planned duration of administration allows for the full effect of tranexamic acid on the immediate risk of haemorrhage without extending too far into the acute phase response seen after surgery and trauma.

SUMMARY

CRASH 2 is a large pragmatic randomised placebo controlled trial of the effects of the early administration of the antifibrinolytic agent tranexamic acid on death, vascular events and transfusion requirements. Adults with trauma who are within 8 hours of injury and have either significant haemorrhage, or who are considered to be at risk of significant haemorrhage, are eligible if the responsible doctor is for any reason substantially uncertain whether or not to use an antifibrinolytic agent. Numbered drug or placebo packs will be available in each participating emergency department. Randomisation will involve calling a 24-hour freecall randomisation service. The call should last only a minute or two and at the end of it the randomisation service will specify which numbered treatment pack to use. For hospitals where telephone randomisation is not feasible, randomisation will be by taking the next consecutively numbered treatment pack. No extra tests are required but a short form must be completed one month later or on discharge or on death (whichever occurs first).

NUMBER OF PATIENTS NEEDED

Two main factors determine the number of patients needed in a trial. These are the estimated event rate and size of the treatment effect.

Estimated event rate: In the Medical Research Council (MRC) CRASH trial of corticosteroids in head injury, the overall risk of death was 20%.⁶² The MRC CRASH trial was the largest international randomised controlled trial in trauma patients and it would be reasonable to expect a similar risk of death in CRASH 2.

Size of treatment effect that should be detectable: Because even a 2% survival advantage for an intervention as simple and widely practicable as tranexamic acid would represent a worthwhile benefit, the current trial has been planned to be able to detect a benefit of this size.

Sample size: If the real mortality difference is 20% versus 18% then there is about an 85% chance that a trial involving 20,000 patients will achieve 2P < 0.01 (and a 95% chance that it will achieve 2P < 0.05). If however, the trial were only half as big then there would be a 50% chance of failing to achieve 2P < 0.01 (and a 28% chance of failing to achieve 2p < 0.05), which is not good enough.

Effects on other outcomes: With such large numbers randomised, even moderate effects on the numbers needing transfusion or on the mean volume per transfusion will be determined very accurately, as will any substantial effects on non-fatal vascular events (haemorrhagic or occlusive).

ELIGIBILITY

Adult trauma patients with ongoing significant haemorrhage or at risk of significant haemorrhage, within 8 hours of injury, except those for whom antifibrinolytic agents are thought to be clearly indicated or clearly contra-indicated.

Inclusion criteria: All trauma patients with ongoing significant haemorrhage (systolic blood pressure less than 90 mmHg and/or heart rate more than 110 beats per minute), or who are considered to be at risk of significant haemorrhage, and are within 8 hours of the injury, are eligible for trial entry if they appear to be at least 16 years old. Although entry is allowed up to 8 hours from injury, the earlier that patients can be treated the better.

Exclusion criteria: The fundamental eligibility criterion is the responsible doctor's ‘uncertainty’ as to whether or not to use an antifibrinolytic agent in a particular adult with traumatic haemorrhage. Patients for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapy should not be randomised. Likewise, patients for whom there is considered to be a clear contraindication to antifibrinolytic therapy (such as, perhaps, those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomised. Where the responsible doctor is substantially uncertain as to whether or not to use an antifibrinolytic, all these patients are eligible for randomisation and should be considered for the trial. There are no other pre-specified exclusion criteria.

Heterogeneity of the patients entering such a trial is a particular strength in terms of the analysis. If a wide range of patients are randomised then it may be possible for a really big trial such as this one to help determine which (if any) particular types of patient are most likely to benefit from treatment.

Special eligibility considerations: None. In the setting of acute severe haemorrhage the routine exclusion of patients with a history of thrombo-embolic disease is unnecessary, unless the responsible doctor considers these to be a definite contraindication. Brief details of patients assessed but not randomised in the trial will be recorded on a Patient Screening Log at each collaborating unit.

CONSENT

Patients with significant trauma may have impaired consciousness and may be unable to give properly informed consent. In this emergency situation it may not be medically appropriate to delay the start of treatment. Consent will be obtained from either a personal legal representative or a professional legal representative where relevant. The requirements of the relevant ethics committee will be adhered to at all times. An information leaflet on the study for patients (Protocol Appendix 1a) will be available in all drug packs in addition to a form for Legal Representative Consent (Protocol Appendix 1b).

RANDOMISATION

Patients eligible for inclusion should be randomised, and the study treatment started, as soon as possible. Randomisation is done by telephoning a 24-hour freecall service and takes only about two minutes. The patient entry form (Protocol Appendix 2) shows the questions that will be asked by the telephone operator prior to allocation of the treatment pack. The study computer will then randomly assign a treatment pack number that will identify one of the CRASH 2 treatment packs stored in the emergency department. If telephone randomisation is not feasible a local pack system will be used. At such hospitals, baseline information will be collected on the trial entry form and the next consecutively numbered treatment pack taken from a box of eight packs. Once a patient has been randomised, we will definitely wish to learn the outcome in hospital, even if the trial treatment is interrupted or is not actually given.

TREATMENT

Each CRASH 2 treatment pack contains:

• 4 x 500 mg ampoules of Tranexamic Acid or placebo
• 1 x 100 mL bag of 0.9% NaCl (for use with loading dose)
• Stickers (for attaching to infusion bags and patient notes)
• Patient information leaflet and Consent forms
• Patient entry form and Outcome form

TREATMENT

SERIOUS UNEXPECTED SUSPECTED ADVERSE EVENTS

If a “SUSAR” (Serious Unexpected Suspected Adverse Reaction) occurs and is believed to be related to the study medicine, this should be logged by calling the 24-hour randomisation service, who will inform the Co-ordinating Centre in London. The Co-ordinating Centre will then contact you within 24 hours so that a written SUSAR report can be completed.

EXPECTED SIDE EFFECTS

In general, vascular events such as pulmonary embolism, deep vain thrombosis, stroke, myocardial infarction, gastrointestinal bleeding and multiorgan failure, do not need to be reported in this way because some increase in their incidence might be expected with antifibrinolytic agents. Likewise, the various medical events that are to be expected in severely injured patients do not need to be reported by telephone. However, all such events are routinely monitored among all patients on the outcome form (Protocol Appendix 3).

UNBLINDING

In general there should be no need to unblind the allocated treatment. If some contra-indication to antifibrinolytic therapy develops after randomisation (e.g. clinical evidence of thrombosis), the trial treatment should simply be stopped. Unblinding should be done only in those rare cases when the doctor believes that clinical management depends importantly upon knowledge of whether the patient received antifibrinolytic or placebo. In those few cases when urgent unblinding is considered necessary, the randomisation service should be telephoned, giving the name of the doctor authorising unblinding and the treatment pack number. The caller will then be told whether the patient received antifibrinolytic or placebo.

MEASURES OF OUTCOME

The primary outcome measure is death in hospital within four weeks of injury (causes of death will be described to assess whether deaths were due to haemorrhage or vascular occlusion). Secondary outcome measures are receipt of a blood products transfusion, the number of units of blood products transfused, surgical intervention, and the occurrence of thrombo-embolic episodes (stroke, myocardial infarction, pulmonary embolism, clinical evidence of deep vein thrombosis).

Data collection: In-hospital deaths, transfusion requirement, complications and short-term recovery are to be recorded on the outcome form (Protocol Appendix 3) which can be completed entirely from the hospital notes – no extra tests are needed. The outcome form should be completed at death, discharge or four weeks post randomisation whichever occurs first.

End of trial for patients: Death, discharge or four weeks post randomisation whichever occurs first.

ANALYSIS

Comparisons will be made of the primary outcome measure, comparing all those allocated antifibrinolytic treatment versus those allocated placebo, on an ‘intention to treat’ basis. Analyses will be stratified on time from injury to the initiation of treatment (less than one hour, one to three hours, more than three hours), on severity of haemorrhage as assessed by capillary refill time (0–2, 3–4, ≥ 5 seconds) and systolic blood pressure (< 75, 76–89, > 89 mmHg). Comparisons will also be made of the risks of blood product transfusion, need for operation and thrombo-embolic complications.

DATA MONITORING COMMITTEE

Professor Rory Collins, chair; Professor Adrian Grant; Professor John A Myburgh

Standard Operating Procedures: The Data Monitoring and Ethics Committee (DMEC) has the responsibility for deciding whether, while randomisation is in progress, the unblinded results (or the unblinded results for a particular subgroup), should be revealed to the Trial Steering Committee (TSC). The DMEC terms of reference state that they will do this if, and only if, two conditions are satisfied: (1) the results provide proof beyond reasonable doubt that treatment is on balance either definitely harmful or definitely favourable for all, or for a particular category of patients, in terms of the major outcome; (2) the results would, if revealed, be expected to substantially change the prescribing patterns of doctors who are already familiar with any other trial results that exist. Exact criteria for “proof beyond reasonable doubt” are not, and cannot be, specified by a purely mathematical stopping rule, but they are strongly influenced by such rules. DMEC members have expressed sympathy with the stopping rule proposed in Part I of the 1976 report to the MRC Leukaemia Committee, whereby an interim analysis of major endpoint would generally need to involve a difference between treatment and control of at least three standard errors to justify premature disclosure. An interim subgroup analysis would, of course, have to be even more extreme to justify disclosure. This rule has the advantage that the exact number and timing of interim analyses need not be pre-specified. In summary, the stopping rules (as successfully applied in other trials including the MRC International Stroke Trial, which randomised 19,436 acute stroke patients) require extreme differences to justify premature disclosure and involve an appropriate combination of mathematical stopping rules and scientific judgement.

STEERING COMMITTEE

Professor Ian Franklin (chair), University of Glasgow and Scottish Blood Transfusion Service

Ms Brigitte Chaudhry, RoadPeace

Professor Tim Coats, University of Leicester

Dr Charles Deakin, Southampton General Hospital

Dr Steve Goodacre, University of Sheffield

Dr Beverley J Hunt, Guy's & St Thomas' Hospital NHS Trust

Dr David Meddings, World Health Organization

Professor Sir Richard Peto, University of Oxford

Professor Ian Roberts, London School of Hygiene & Tropical Medicine

Professor Peter Sandercock, University of Edinburgh

The steering committee consists of respected and experienced trauma and haematology experts, clinical triallists as well as a lay representative. Face to face meetings will be held at regular intervals determined by need but not less than once a year. Routine business is conducted by e-mail and post.

Standard Operating Procedures: The Steering Committee, in the development of this protocol and throughout the trial, will take responsibility for:

• major decisions such as a need to change the protocol for any reason
• monitoring and supervising the progress of the trial
• reviewing relevant information from other sources
• considering recommendations from the DMEC
• informing and advising the management group on all aspects of the trial

COLLABORATORS' RESPONSIBILITIES

Co-ordination within each participating hospital will be through a local collaborator who will:

• Discuss the trial with medical and nursing staff who see trauma patients and ensure that they remain aware of the state of the current knowledge, the trial and its procedures (there are wall charts, pocket summaries and a set of slides to assist with this)
• Ensure that adults with trauma are considered promptly for the trial
• Ensure that the patient entry forms (in non-telephone randomising centres) and single sided outcome forms are completed
• Ensure the trial is conducted in accordance with ICH GCP and fulfils all national and local regulatory requirements
• Allow access to source data for audit and verification

CO-ORDINATING CENTRE RESPONSIBILITIES

• Provide study materials and a 24-hour randomisation (and unblinding) service
• Give collaborators regular information about the progress of the study
• Help ensure complete data collection at discharge
• Respond to any questions (e.g. from collaborators) about the trial
• Assure data security and quality and observe data protection laws
• Ensure trial is conducted in accordance with ICH GCP

PUBLICATION

The success of CRASH 2 will be dependent entirely upon the collaboration of nurses and doctors in the participating hospitals. Hence, the chief credit for the study will be assigned to the collaborators from each participating centre and they will be named personally in the main publications. The results of the trial will be reported first to trial collaborators. Dissemination of results to patients will take place via the media, trial website (www.crash2@Lshtm.ac.uk) and relevant patient organisations.

INDEMNITY

CRASH 2 is funded by the London School of Hygiene & Tropical Medicine (LSHTM) and the World Health Organization (WHO) and not the manufacturers of tranexamic acid. LSHTM as the Co-ordinating Centre for the trial accepts responsibility attached to its sponsorship of the trial and, as such, would be responsible for claims for any non-negligent harm suffered by anyone as a result of participating in this trial.

FINANCIAL SUPPORT

LSHTM and WHO funding covers meetings and central organisational costs only. The design, management and finance of the study are entirely independent of the manufacturers of tranexamic acid, which is not a new product. Large trials of such drugs, involving many hospitals, are important for future patients but are practicable only if those collaborating in them do so without payment (except for recompense of any minor local costs that may arise).

INFORMATION FOR PATIENTS, INTERNATIONAL STUDY OF BLEEDING AFTER INJURY

This hospital is taking part in a research study to find ways to reduce severe bleeding after serious injury. You have been included in this study.

PATIENT CONSENT FORM, INTERNATIONAL STUDY OF BLEEDING AFTER INJURY

1. I confirm that I have read and understood the information sheet Version 2, dated 9 December 2004, for the above study and have had the opportunity to ask questions.
2. I understand that my participation is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.
3. I understand that sections of any of my medical notes may be looked at by responsible individuals from The London School of Hygiene & Tropical Medicine or from regulatory authorities where it is relevant to my taking part in research. I give permission for these individuals to have access to my records.
4. I agree to take part in the above study/for my information to be used in this trial.
5. I understand that I can withdraw my consent at any time and my medical care will not be affected in anyway by my withdrawal.

INFORMATION FOR LEGAL REPRESENTATIVE (PERSONAL/PROFESSIONAL)

LEGAL REPRESENTATIVE CONSENT FORM