Title: Pharmacological management of seizures post traumatic brain injury (MAST trial)
Funder: Department of Health and Social Care

Abstract: Background and study aims_x000D_ _x000D_ The majority of patients who suffer a traumatic brain injury (TBI) do not need to stay in hospital overnight. However, some require admission to a specialist hospital, as their injury is more serious. Seizures can be harmful or even fatal, if not treated appropriately. Medications that reduce the risk of seizures are called anti-epileptic drugs (AEDs). However, AEDs have side effects, which can affect patients’ quality of life, memory, concentration and general health._x000D_ _x000D_ Patients with seizures after TBI are typically prescribed an AED to prevent further seizures, most commonly Phenytoin or Levetiracetam. Some doctors favour a short course, whereas others favour a longer course. The first part of the trial aims to answer if one approach is better than the other (MAST-DURATION). The second part of the trial aims to answer if a 7-day course of either Phenytoin or Levetiracetam should be used for patients with a serious TBI to prevent seizures from happening (MAST- PROPHYLAXIS)._x000D_ _x000D_ Who can participate?_x000D_ _x000D_ MAST-DURATION:_x000D_ _x000D_ Patients aged 10 years and over, with a traumatic brain injury, managed in a neurosurgical unit, who have started on phenytoin or levetiracetam due to an acute symptomatic seizure during acute hospitalisation._x000D_ _x000D_ MAST-PROPHYLAXIS:_x000D_ _x000D_ Patients aged 10 years and over, with a traumatic brain injury, managed in a neurosurgical unit, without an acute symptomatic seizure._x000D_ _x000D_ What does the study involve?_x000D_ _x000D_ MAST-DURATION:_x000D_ _x000D_ Patients will be randomised to receive to a maximum of 3 months or a minimum of 6 months course of phenytoin or levetiracetam._x000D_ _x000D_ MAST-PROPHYLAXIS:_x000D_ _x000D_ Patients will be randomised to receive either phenytoin, levetiracetam or no anti-epileptic drug for a period of 7 days._x000D_ _x000D_ Current international guidelines for traumatic brain injury recommend the use of phenytoin for the prevention of early post traumatic seizures, when the benefits are thought to outweigh the risks. In practice alternative anti-epileptic drugs such as levetiracetam are being used clinically as they are associated with fewer risks._x000D_ _x000D_ Patients will be assessed for seizures during hospital admission and will also be asked to complete follow-up questionnaires at 6,12, 18 and 24 months._x000D_ _x000D_ What are the possible benefits and risks of participating?_x000D_ _x000D_ MAST-DURATION:_x000D_ _x000D_ The study drugs patients will be provided with are standard anti-epileptic drugs, used to control seizures. We expect seizures to be reduced as a result of taking the study drug._x000D_ _x000D_ MAST-PROPHYLAXIS:_x000D_ _x000D_ There is no guarantee that patients will benefit from taking part in this trial._x000D_ _x000D_ Apart from the potential side effects from the study drug, there are no additional risks or disadvantages involved with taking part in this study. Patients will continue to receive the standard care for their condition._x000D_ _x000D_ Who is funding the study?_x000D_ _x000D_ The National Institute of Health Research

Lay abstract: Post-traumatic seizures (PTS) can lead to derangement of brain physiology, which can lead to brain herniation and death. The incidence of early PTS (within 7 days post-TBI) is as high as 14% and prevention of seizures can limit these outcomes and may prevent the development of late PTS (after 7 days). This is the rationale for seizure prophylaxis with an anti-epileptic drug (AED). Late PTS within 24 months can have a negative impact of quality of life, return to work, return to driving, and can even result in death. However, there is no high-quality evidence regarding the optimal duration of treatment for patients who have been started on an AED for acute PTS. AEDs are associated with various side effects. The trial aims to define best practice in the use of AED for TBI patients. We will achieve this by conducting two closely related clinical trials (PROPHYLAXIS and DURATION), which will run in parallel but independently of each other. MAST PROPHYLAXIS will compare the clinical effectiveness (absolute difference in the rate of PTS within the first 2 weeks post-TBI) of a 7-day course of phenytoin or levetiracetam, used as seizure prophylaxis, versus no AED for TBI patients. MAST DURATION will compare the clinical effectiveness (absolute difference in the rate of late PTS within 24 months post-TBI) of a longer course of phenytoin or levetiracetam (at least 6 months) versus a shorter course (up to 3 months) for TBI patients with early PTS._x000D_ _x000D_ Eligibility criteria_x000D_ _x000D_ MAST-PROPHYLAXIS_x000D_ _x000D_ Inclusion Criteria:_x000D_ _x000D_ Patients aged =10 years, with TBI managed in a neurosurgical unit without an acute symptomatic seizure_x000D_ Patient or Legal Representative is willing and able to provide informed consent or in the absence of a legal representative, an Independent Healthcare Professional provides authorisation for patient enrolment_x000D_ Exclusion Criteria:_x000D_ _x000D_ Post-traumatic seizures_x000D_ Un-survivable injury_x000D_ Previous history of epilepsy_x000D_ Patients who are on an AED pre-TBI_x000D_ Pregnancy or breastfeeding_x000D_ Any hypersensitivity to study drug (or hydantoins or pyrrolidone derivatives) or any of its excipients_x000D_ Time interval from the time of admission to NSU to randomisation exceeds 48 hours_x000D_ MAST-DURATION_x000D_ _x000D_ Inclusion Criteria:_x000D_ _x000D_ Patients aged =10 years with TBI managed in a neurosurgical unit who have started on phenytoin or levetiracetam due to an acute symptomatic seizure during acute hospitalisation_x000D_ Patient or Legal Representative is willing and able to provide informed consent or in the absence of a legal representative, an Independent Healthcare Professional provides authorisation for patient enrolment_x000D_ Exclusion Criteria:_x000D_ _x000D_ Un-survivable injury_x000D_ Previous history of epilepsy_x000D_ Patients who are on an AED pre-TBI_x000D_ Patient who has been clinically prescribed an AED to treat PTS (other than phenytoin or levetiracetam) since current admission_x000D_ Any hypersensitivity to study drug selected or any of its excipients_x000D_ Primary outcome measures:_x000D_ _x000D_ MAST-DURATION: Occurrence of late PTS within 24 months after TBI._x000D_ MAST-PROPHYLAXIS: Occurrence of PTS within 2 weeks after TBI._x000D_ Secondary outcome measures:_x000D_ _x000D_ PTS up to 2 years (MAST-PROPHYLAXIS only)_x000D_ Extended Glasgow Outcome Scale at 6, 12, 18 and 24 months_x000D_ Neurobehavioural Symptom Inventory at 6, 12, 18 and 24 months_x000D_ Quality of life (EQ-5D-5L) at 6, 12, 18 and 24 months_x000D_ Liverpool Adverse Events Profile at 6, 12, 18 and 24 months_x000D_ Economic evaluation_x000D_ Frequency of PTS_x000D_ Mortality_x000D_ Adverse events of special interest during treatment_x000D_ Sample size_x000D_ _x000D_ MAST-PROPHYLAXIS: 1221 patients in total (130 in an internal pilot)_x000D_ _x000D_ MAST-DURATION: 428 patients in total (50 in an internal pilot)_x000D_ _x000D_ Funding Acknowledgement:_x000D_ _x000D_ This project is funded by the National Institute for Health Research Health Technology Assessment programme (NIHR128226)

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS