Pharmacological Management of Seizures Post Traumatic Brain Injury

Study Overview
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Brief Summary
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The overall aim of the MAST trial is to define best practice in the use of anti-epileptic drugs (AEDs) for patients following a traumatic brain injury (TBI). The trial will consist of two parts. The first part aims to answer whether a shorter or a longer course of AEDs is better to prevent further seizures in patients who have started having seizures following TBI (MAST - duration). The second part aims to answer whether a 7-day course of either Phenytoin or Levetiracetam should be used for patients with a serious TBI to prevent seizures from starting (MAST- prophylaxis).

Detailed Description
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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 antiepileptic drugs (AEDs). However, AEDs have side effects, which can affect patients' quality of life, memory, concentration and general health. 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). All patients admitted to a neurosurgical unit (NSU) within the UK, with a serious TBI, will be considered for the trial. Patients who have been started on either Phenytoin or Levetiracteam by their clinical team due to seizures will be randomised to either up to 3 months or at least 6 months of treatment. In an independent, parallel trial, TBI patients who have not had a seizure will be randomised to phenytoin, levetiracetam or no treatment. All patients will be managed as per usual NHS practice and followed up for 24 months.

Official Title
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Pharmacological Management of Seizures Post Traumatic Brain Injury (MAST)

Conditions
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Traumatic Brain Injury, Post Traumatic Seizures

Intervention / Treatment
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* Drug: Phenytoin Sodium
* Drug: Levetiracetam


Participation Criteria
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Eligibility Criteria
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MAST DURATION Inclusion Criteria: Patients aged ≥10 years with TBI managed in an NSU who have started on an phenytoin or levetiracetam due to an acute symptomatic seizure during acute hospitalisation 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 Exclusion Criteria: Unsurvivable injury Previous history of epilepsy Patients who are on an AED pre-TBI Patient who has been clinically prescribed an AED other than phenytoin or levetiracetam Unwillingness to take products containing gelatin (animal products) Severe lactose intolerance or any known hypersensitivity to study drug or any of its excipients MAST-PROPHYLAXIS Inclusion Criteria: Patients aged ≥10 years, with TBI managed in an NSU without an acute symptomatic seizure 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 within 48 hours of admittance. Exclusion Criteria: Post-traumatic seizures Unsurvivable injury Previous history of epilepsy Patients who are on an AED pre-TBI Pregnancy or breastfeeding Unwillingness to take products containing gelatin (animal products) Severe lactose intolerance or any known hypersensitivity to study drug or any of its excipients Time interval from the time of admission to NSU to randomisation exceeds 48 hours

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The MAST trial consists of two pragmatic, open-label, multi-centre, independent, parallel, randomised trials. MAST-DURATION consists of two arms and MAST-PROPHYLAXIS consists of three arms.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MAST DURATION - <3 months<br>TBI patients with early seizures (within first 7 days following trauma) will receive a short course of up to 3 months of either Phenytoin Sodium or Levetiracetam. | Drug: Phenytoin Sodium<br>* Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.<br>Drug: Levetiracetam<br>* Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.<br>* Other names: Keppra;|
| Experimental: MAST DURATION - >6 months<br>TBI patients with early seizures (within first 7 days following trauma) will receive a longer course of at least 6 months of either Phenytoin Sodium or Levetiracetam. | Drug: Phenytoin Sodium<br>* Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.<br>Drug: Levetiracetam<br>* Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.<br>* Other names: Keppra;|
| Experimental: MAST PROPHYLAXIS - Phenytoin Sodium<br>TBI patients, without an acute symptomatic seizure, will receive a 7-day course of Phenytoin Sodium as seizure prophylaxis. | Drug: Phenytoin Sodium<br>* Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.<br>|
| Experimental: MAST PROPHYLAXIS - Levetiracetam<br>TBI patients, without an acute symptomatic seizure, will receive a 7-day course of Levetiracetam as seizure prophylaxis. Dosing will be as prescribed clinically by the treating physician. | Drug: Levetiracetam<br>* Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.<br>* Other names: Keppra;|
| No Intervention: MAST PROPHYLAXIS - no treatment<br>TBI patients, without an acute symptomatic seizure, will not receive any anti-epileptic drug. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAST-DURATION: Occurrence of late PTS | The primary outcome for MAST-DURATION is the occurrence of late post-traumatic seizure. This will be assessed by follow-up questionnaire. | Within 24 months post traumatic brain injury | 
| MAST-PROPHYLAXIS: Occurrence of PTS | The primary outcome for MAST-PROPHYLAXIS is the occurrence of an acute symptomatic seizure. This will be assessed in the neurosurgical unit, or by telephone following discharge. | Within 2 weeks post TBI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAST-PROPHYLAXIS: Occurrence of post-traumatic seizures | The occurrence of post-traumatic seizures. This will be assessed by follow-up questionnaire. | Within 24 months post traumatic brain injury | 
| MAST-PROPHYLAXIS: Time to post-traumatic seizure | The time to post traumatic seizure. This will be assessed by follow-up questionnaire. | Within 24 months post traumatic brain injury | 
| Both trials: Disability | Levels of disability will be assessed using the Extended Glasgow Outcome Scale via follow-up questionnaire. The scale is scored from 1 (death) to 8 (upper good recovery) with higher scores reflecting a better outcome. | At 6, 12, 18 and 24 months | 
| Both trials: Cognitive function | Cognitive function will be assessed using the Neurobehavioural Symptom Inventory via follow-up questionnaire. Symptoms are scored from 0 (mild) to 4 (very severe) with higher scores reflecting a worse outcome. | At 6, 12, 18 and 24 months | 
| Both trials: Quality of life | Quality of life will be assessed using the EQ-5D-5L via follow-up questionnaire. The EQ-5D-5L consists of 2 parts - the EQ-5D-5L descriptive system and the EQ Visual Analogue scale. The descriptive system comprises 5 dimensions (mobility, self care, usual activities, pain/discomfort, anxiety/depression) which are scored from 1 (no problems) to 5 (extreme problems) with higher scores reflecting a worse outcome. The EQ Visual Analogue scale is numbered 0 to 100 with higher scores reflecting a better outcome. | At 6, 12, 18 and 24 months | 
| Both trials: Adverse events | Adverse events will be assessed using the Liverpool Adverse Events Profile via follow-up questionnaire. The questionnaire is scored from 1 (never a problem) to 4 (always or often a problem) with higher scores reflecting a worse outcome. | At 6, 12, 18 and 24 months | 
| Both trials: Hospital admissions | Hospital admissions will be extracted from the NHS Digital Hospital Episode Statistics (HES) database) and equivalents. Hospital admissions will be combined with the length of anti-epileptic drug treatment to report an economic evaluation. | Within 24 months post traumatic brain injury | 
| Both trials: Frequency of PTS | The frequency of post traumatic seizures. | Within 24 months post traumatic brain injury | 
| Both trials: Mortality | Death from any cause | At 6, 12, 18 and 24 months | 
| Both trials: Frequency of adverse events of special interest | Frequency of adverse events of special interest (unfavourable and unintended sign, symptom, or disease temporally associated with the use of trial drug, whether or not considered related to the trial drug. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phenytoin, Levetiracetam, Post-traumatic seizure, Traumatic brain injury