• This is an international trial. An updated list of collaborators will soon be found on this website.

• CRASH-2 is funded by National Institute for Health Research Health Technology Assessment programme (NIHR HTA) and the London School of Hygiene & Tropical Medicine (LSHTM) and not the manufacturers of tranexamic acid. The funding covers meetings and central organisational costs only. Tranexamic Acid is not a new product. Really 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).

• The most important requirement is that you first obtain local research ethics committee approval. The trial has UK Research Ethics Committee approval, so UK hospitals need to apply for a Site Specific Assessment. CRASH Trials Co-ordinating Centre can help you with your application.
• If you are outside the UK the Co-ordinating Centre will send you materials to submit to your local research ethics committee. We will also send you a Principal Investigator Agreement to sign.
• You will also need to find out if you need approval from any other national organisations in your country.

• Please send a copy of the ethics committee approval to CRASH Trials Co-ordinating Centre. We will send you all trial materials and treatment drugs. Your hospital will then be ready to start randomising patients.

• Because the doctors and nurses collaborating in the CRASH-2 trial are busy and working in emergency situations, the trial involves them in almost no extra work: no special investigations or changes to usual management are required and data collection is absolutely minimal. In-hospital deaths, complications and short term recovery are recorded on a single-sided Outcome Form which can be completed entirely from the hospital notes.

• 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. Currently the only country not included in the indemnity cover is USA.

• The CRASH2 Trial involves patients who have suffered serious injuries and are at risk of life threatening haemorrhage. In this situation, most patients will have some impairment in their level of consciousness caused either by blood loss or coexisting head injury. In this emergency situation patients may not be able to provide written informed consent. In addition, the trial treatment has to be administered as soon as possible after injury. We will need to comply with your local regulations.

• The patient randomisation is planned to start in May 2005 with the aim to recruit approximately 20,000 patients over the next five years.

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• In general there should be no need to unblind the allocated treatment. If some contra-indication to tranexamic acid develops after randomisation (e.g. any clotting disorders), 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 tranexamic acid or placebo (e.g. anaphylaxis). In those few cases when urgent unblinding is considered necessary, the randomisation service should be telephoned, giving the name of the doctor requesting unblinding and the CRASH-2 treatment pack number. The caller will then be put in contact with a member of the trial team who will assist with unblinding.

• There have been three case reports of clot colic and ureteric obstruction in haematology patients who have been given tranexamic acid over several days. All had spontaneous resolution on stopping therapy (B J Haematol 1995: 89(3); 663-4). The short course of tranexamic acid given in the CRASH-2 Trial is unlikely to have the same effect, and if it occurs reversal is likely on stopping the infusion at 8 hours (as per the trial protocol).
• Haematuria is very common in the multiply injured patient. Clot obstruction of the ureter is not a recognised complication of renal trauma - although there seems to be no theoretical reason why it could not occur. Any association between tranexamic acid and clot colic is likely to be weak - this is known as for many years TXA was used as a treatment for haematuria. Putting this all together it was felt that haematuria should not be a contraindication to the entry of an injured patient into the CRASH-2 Trial

• Cirrhosis of the liver affects clotting a number of ways. One effect is to increase fibrinolytic potential ie the ability of the blood to break down clots. Normally the liver breaks down tissue plasminogen activator (t-PA), the main activator of fibrinolysis, but when it is failing this does not occur. So there is increased fibrinolysis in patients with liver disease, and this is one of the reasons why patients bleed so profusely in liver disease - they break down the clots as they are making them. Antifibrinolytic therapy is standard management in liver transplantation and liver failure. The patients with previously undiagnosed liver disease, may be the ones in particular that may benefit from the use of tranexamic acid.

• Many anatomical severity scores, such as the Injury Severity Score, are applied in retrospect. These are therefore not useful in the CRASH-2 trial, where the treatment may be given before all the injuries are defined. The type of injury itself does not necessarily tell us how much bleeding has occured - a fractured pelvis may or may not be associated with significant haemorrhage depending on the amount of damage to pelvic blood vessels.
• Physiological severity scores, such as the Revised Trauma Score, give a heavy weight to level of consciousness, so they do not define the group that has significant bleeding. All forms of scoring require training and add a level of complexity to the patient entry process. For these reasons a severity score has not been used in the CRASH2 trial.

• Apply firm pressure with your fingertips to the selected area, e.g. chest for about 5 seconds. Timing starts on release of pressure and is counted in seconds. Timing stops when the blanched area of the skin returns to its normal colour. If skin is dark or there is injury to the chest, CRT can be measured by applying pressure to another area such as the base of the thumb, nail bed or gums.

• We randomise so that each participant has a known, usually equal, chance of being allocated to either group and importantly the allocation cannot be predicted. This ensures that both groups will be equal for all the variables (patients characteristics, other interventions received, etc) except for the intervention under study (tranexamic acid).

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• The trial co-ordinating team will monitor your stock level via the database and will ensure that adequate supplies of treatment packs are maintained at all times. However, if trial materials appear to be running low then additional stock can be obtained by contacting the CRASH Trials Co-ordinating Centre.

• Any unused trial treatment should be destroyed. If a patient has been randomised and none of the treatment used, all the drug in the allocated pack should be destroyed and not used for another patient.

• Resume as soon as possible.

• In the first instance please ensure that the trial treatment is entered into the patient record. Please ensure the allocated treatment pack accompanies the patient to the ward. This contains all the instructions for administration of the trial drug and trial procedures.

3.5 What if the patient is transferred to another hospital after being randomised but before 28 days?

• Only your hospital has the ethics approval to take part in the trial. Therefore, the trial ends when the patient leaves your hospital. Please complete the Outcome Form based on the information at that time.

3.6 CRASH-2 trial treatment pack

Each 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)
• Syringe and needle
• Stickers (for attaching to infusion bags and patient notes)
• Patient information leaflet and Consent forms in your language
• Patient entry form and Outcome form

• As the patient is randomised in an emergency situation, all materials required to make up the 'loading dose' of the trial treatment are contained in the treatment pack. This is infused over 10 minutes. For maintenance dose two 1g ampoules are added to a 500mL bag of 0.9% NaCl or any other compatible solution. This is infused at 60mL/hour for about 8 hours. The treatment pack does not contain the saline required for the maintenance dose. You will need to take this from your own hospital stocks.
  

3.7 Exclusion criteria

• The fundamental eligibility criterion is the responsible doctor's 'uncertainty' whether or not to use antifibrinolytic agents in a particular adult trauma patient with or at risk of on-going significant haemorrhage. Patients for whom there is considered by the responsible doctor to be a clear indication for antifibrinolytic agents should not be randomised. Likewise, any patients for whom there is considered to be a clear contraindication to antifibrinolytic agents (such as perhaps those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomised. This criterion should be used when assessing any patient suitable for the trial, taking into consideration any other known disease the patient may have. There are no special eligibility considerations.

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