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).

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%.[ref 14] 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).

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.

TELEPHONE FOR RANDOMISATION
OR PAPER RANDOMISE

TRANEXAMIC ACID

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 will be available in all drug packs in addition to a form for Legal Representative Consent (EU only).

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 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.

Each CRASH 2 treatment pack contains:

• 4 x 500 mg ampoules of Tranexamic Acid or placebo
• 1 x 100mL 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
• Outcome form

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.

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.

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 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.

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.