The CRASH-3 Trial: Tranexamic acid for the treatment of significant traumatic brain injury.

There are more deaths each year from injuries than from HIV, TB and malaria combined. Worldwide, about ten million people are killed or hospitalised because of a head injury every year. Most head injuries are caused by road traffic crashes, and because car use is increasing, the number of people suffering a head injury is increasing. Amongst those who survive a head injury, many are left severely disabled for the rest of their lives. For example, there is a high likelihood that Michael Schumacher will be permanently disabled as a result of his recent head injury. Most victims of head injury are young adults living in low and middle income countries. Because many of the victims are also breadwinners for their families, head injuries can also result in loss of income which, along with medical costs, can increase household debt and lead to a fall in living standards for the whole family. When the head is injured there is often bleeding inside the brain, which can continue for some time and worsen after hospital admission. This bleeding increases pressure inside the skull causing further damage to the brain, which can be fatal or result in serious disability for the patient. We think that we can prevent some of these deaths and disability by reducing the amount of bleeding in the brain after head injury. Tranexamic acid is a cheap drug that reduces bleeding in other conditions. A large trial in accident victims (other than those with head injury) found that it reduces the chances of bleeding to death. If this drug also works in patients with head injury and bleeding into the brain, this would be important to know because it could save lives at a very low cost.

We have already done two preparatory studies to see if tranexamic acid can help people who have bleeding inside the brain because of a head injury. Together, the results of the studies suggest that tranexamic acid should reduce the amount of bleeding inside the brain and could reduce their chances of dying or being disabled. However, because these studies were small, we are not very certain about the accuracy of their results. Also, they were not designed to find out whether tranexamic acid reduces disability. Because doctors are still unsure about whether tranexamic acid works, it is not given to patients with traumatic brain injury. But if a new clinical trial showed that it worked, this would change very quickly. We want to find out if tranexamic acid saves lives and reduces disability in people with traumatic brain injury.

We plan to study 10,000 patients with traumatic brain injury in countries throughout the world. We will give half of them tranexamic acid and the other half a dummy medicine called a placebo. To make sure that the two groups are the same apart from tranexamic acid, we will decide who gets tranexamic acid and who gets placebo using the modern equivalent of the toss of a coin (this is called randomisation). Everyone will of course get all the treatments that doctors usually give to traumatically brain injured patients. At the end of the trial we will see if giving tranexamic acid on top of all the usual treatments improves survival and other patient outcomes. The study will be carried out by a team of researchers with lots of experience in doing clinical trials. In fact, it will be the same team that did the successful study of tranexamic acid in accident victims. The trial will cost several million pounds but if it shows (as we hope it will) that tranexamic acid works, we will have a very cheap way of reducing the number of people who die and are disabled after a head injury. The start up phase of trial is underway and over a thousand patients have been recruited. The trial procedures work well. This application is for funds to continue recruitment to 10,000 patients.

The CRASH-3 trial is a multi-centre, randomised placebo controlled trial of the effects of the early administration (within 8 hours of injury) of tranexamic acid on death, disability and vascular occlusive events in patients with acute traumatic brain injury. A total of 10,000 adult TBI patients who fulfil the eligibility criteria will be randomised to receive either TXA or matching placebo. All adults with TBI who are within eight hours of injury, with any intracranial bleeding on CT scan or who have a Glasgow Coma Score (GCS) of 12 or less, and do not require immediate blood transfusion for extra-cranial bleeding, will be eligible for inclusion. The main criterion is the doctor's 'uncertainty' as to whether or not to use TXA in a particular patient. This pragmatic approach allows us to see whether TXA works in real-life conditions.

The primary outcome is death in hospital within one month of injury (cause of death will be described). Secondary outcomes are disability and other patient orientated outcomes; vascular occlusive events (myocardial infarction, pulmonary embolism, deep vein thrombosis); stroke; seizures; neurosurgical intervention and days in intensive care.

We are working with an established network of hospitals that has successfully delivered many global trauma trials (CRASH-1 and CRASH-2 trials). Nigeria and Pakistan were major contributors to these trials and a research partnership has been established with them to help co-ordinate the CRASH-3 trial. LSHTM will build clinical trials research capacity in these settings by providing oversight, training and guidance in conducting clinical trials to the highest global standards.

The main beneficiaries of the results of the CRASH-3 trial will be trauma patients and their families in low and middle income countries where the burden of TBI is greatest. Traumatic brain injury mostly affects economically active young adults and many will experience permanent disability. Michael Schumacher is a well known example of someone in the prime of life who might well be permanently disabled as a result of intracranial bleeding following a TBI. However, in low and middle income countries traumatic brain injury is an important cause of family poverty. Many households are made destitute when a family member sustains a traumatic brain injury. Medical costs and the loss of income can lead to decreased food consumption, a fall in living standards and increased indebtedness.

With growing motorisation, the incidence of traumatic brain injury is increasing rapidly in low and middle income countries. There are now more deaths from traumatic brain injury each year than from HIV. Tranexamic acid is inexpensive and simple to administer and, if shown to be effective in the treatment of traumatic brain injury, is likely to be highly cost effective. It is widely available in generic form in most countries. On the basis of the results of the CRASH-2 trial, tranexamic acid was included on the World Health Organization list of essential medicines which should further increase its availability in low and middle income countries. Tranexamic acid is potentially a simple, inexpensive, widely practicable treatment for a common cause of mortality and morbidity in low and middle income countries. If shown to be effective as a treatment for traumatic brain injury it could be rapidly implemented in global clinical practice.

Civilians and soldiers injured in conflict situations are also potential research beneficiaries. The use of improvised explosive devices in Afghanistan and Iraq has resulted in large increases in blast injuries to the brain. These cause significant mortality and disability in both civilian and military personnel. Although tranexamic acid is not a patented medicine, the findings from this trial could have important implications for new drug discovery. The results of the CRASH-2 trial have already stimulated many studies to understand the physiological role of plasmin in fibrinolysis and inflammation and could stimulate the development of new anti-plasmin medications.

If tranexamic acid is shown to be safe and effective as a treatment of traumatic intracranial bleeding it would almost certainly have implications for the management of haemorrhagic stroke, which is a major cause of death and disability worldwide. Our research team is already working with stroke researchers and a clinical trial of tranexamic acid in stroke is now underway.