Pharmacological Management of Seizures Post Traumatic Brain Injury (MAST)

Pharmacological Management of Seizures Post Traumatic Brain Injury (MAST)

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Traumatic Brain Injury; Post Traumatic Seizures
• Intervention / Treatment: Drug: Phenytoin Sodium; Drug: Levetiracetam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1649
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Samantha Lawes, PhD; Phone Number: 07891 432226; Email: samantha.lawes@addenbrookes.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MAST DURATION - <3 months; 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; Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.; Drug: Levetiracetam; Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.; Other Names: Keppra
Experimental: MAST DURATION - >6 months; 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; Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.; Drug: Levetiracetam; Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.; Other Names: Keppra
Experimental: MAST PROPHYLAXIS - Phenytoin Sodium; TBI patients, without an acute symptomatic seizure, will receive a 7-day course of Phenytoin Sodium as seizure prophylaxis.	Drug: Phenytoin Sodium; Dosing will be as prescribed clinically by the treating physician. Phenytoin Sodium may be administered orally, intravenously or via nasogastric tube.
Experimental: MAST PROPHYLAXIS - Levetiracetam; 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; Dosing will be as prescribed clinically by the treating physician.Levetiracetam may be administered orally, intravenously or via nasogastric tube.; Other Names: Keppra
No Intervention: MAST PROPHYLAXIS - no treatment; TBI patients, without an acute symptomatic seizure, will not receive any anti-epileptic drug.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: University of Cambridge
• Investigators: Principal Investigator: Peter Hutchinson, PhD, University of Cambridge

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2021
• Primary Completion (Anticipated): March 1, 2026
• Study Completion (Anticipated): March 1, 2028

Study Registration Dates

• First Submitted: September 7, 2020
• First Submitted That Met QC Criteria: September 28, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): November 3, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Traumatic brain injury; Levetiracetam; Phenytoin; Post-traumatic seizure
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Seizures; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Nootropic Agents; Levetiracetam; Phenytoin
• Other Study ID Numbers: A095460

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No