Pharmacological Management of Seizures Post Traumatic Brain Injury (MAST)

• ClinicalTrials.gov Identifier: NCT04573803
• Recruitment Status: Not yet recruiting
• First Posted: October 5, 2020
• Last Update Posted: November 3, 2020
• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborator: University of Cambridge
• Information provided by (Responsible Party): Peter Hutchinson, University of Cambridge

Tracking Information

• First Submitted Date: September 7, 2020
• First Posted Date: October 5, 2020
• Last Update Posted Date: November 3, 2020
• Estimated Study Start Date: March 1, 2021
• Estimated Primary Completion Date: March 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 28, 2020)

• MAST-DURATION: Occurrence of late PTS [ Time Frame: Within 24 months post traumatic brain injury ]
  The primary outcome for MAST-DURATION is the occurrence of late post-traumatic seizure. This will be assessed by follow-up questionnaire.
• MAST-PROPHYLAXIS: Occurrence of PTS [ Time Frame: Within 2 weeks post TBI ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 2, 2020)

• MAST-PROPHYLAXIS: Occurrence of post-traumatic seizures [ Time Frame: Within 24 months post traumatic brain injury ]
  The occurrence of post-traumatic seizures. This will be assessed by follow-up questionnaire.
• MAST-PROPHYLAXIS: Time to post-traumatic seizure [ Time Frame: Within 24 months post traumatic brain injury ]
  The time to post traumatic seizure. This will be assessed by follow-up questionnaire.
• Both trials: Disability [ Time Frame: At 6, 12, 18 and 24 months ]
  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.
• Both trials: Cognitive function [ Time Frame: At 6, 12, 18 and 24 months ]
  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.
• Both trials: Quality of life [ Time Frame: At 6, 12, 18 and 24 months ]
  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.
• Both trials: Adverse events [ Time Frame: At 6, 12, 18 and 24 months ]
  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.
• Both trials: Hospital admissions [ Time Frame: Within 24 months post traumatic brain injury ]
  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.
• Both trials: Frequency of PTS [ Time Frame: Within 24 months post traumatic brain injury ]
  The frequency of post traumatic seizures.
• Both trials: Mortality [ Time Frame: At 6, 12, 18 and 24 months ]
  Death from any cause
• Both trials: Frequency of adverse events of special interest [ Time Frame: Up to 24 months ]
  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.

Original Secondary Outcome Measures (submitted: September 28, 2020)

• MAST-PROPHYLAXIS: Occurrence and time to PTS [ Time Frame: Within 24 months post traumatic brain injury ]
  The occurrence and time to late post-traumatic seizure. This will be assessed by follow-up questionnaire.
• Both trials: Disability [ Time Frame: At 6, 12, 18 and 24 months ]
  Levels of disability will be assessed using the Extended Glasgow Outcome Scale via follow-up questionnaire.
• Both trials: Cognitive function [ Time Frame: At 6, 12, 18 and 24 months ]
  Cognitive function will be assessed using the Neurobehavioural Symptom Inventory via follow-up questionnaire.
• Both trials: Quality of life [ Time Frame: At 6, 12, 18 and 24 months ]
  Quality of life will be assessed using the EQ-5D-5L via follow-up questionnaire.
• Both trials: Adverse events [ Time Frame: At 6, 12, 18 and 24 months ]
  Adverse events will be assessed using the Liverpool Adverse Events Profile via follow-up questionnaire.
• Both trials: Economic evaluation [ Time Frame: At study completion (5 years) ]
  A detailed economic evaluation will be conducted alongside both trials. Costs will be based on an NHS perspective and a standard price year, and include details of all AED treatment and hospital admissions. Hospital admissions will be extracted from the NHS Digital Hospital Episode Statistics (HES) database) and equivalents.
• Both trials: Frequency of PTS [ Time Frame: Within 24 months post traumatic brain injury ]
  The frequency of post traumatic seizures.
• Both trials: Mortality [ Time Frame: At 6, 12, 18 and 24 months ]
  Death from any cause
• Both trials: Adverse events of special interest [ Time Frame: Up to 24 months ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pharmacological Management of Seizures Post Traumatic Brain Injury
• Official Title: Pharmacological Management of Seizures Post Traumatic Brain Injury (MAST)
• Brief Summary: 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

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
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Prevention

Condition

• Traumatic Brain Injury
• Post Traumatic Seizures

Intervention

• 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 Name: Keppra

Study Arms

• 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.
  Interventions:

  • Drug: Phenytoin Sodium
  • Drug: Levetiracetam
• 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.
  Interventions:

  • Drug: Phenytoin Sodium
  • Drug: Levetiracetam
• Experimental: MAST PROPHYLAXIS - Phenytoin Sodium
  TBI patients, without an acute symptomatic seizure, will receive a 7-day course of Phenytoin Sodium as seizure prophylaxis.
  Intervention: Drug: Phenytoin Sodium
• 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.
  Intervention: Drug: Levetiracetam
• No Intervention: MAST PROPHYLAXIS - no treatment
  TBI patients, without an acute symptomatic seizure, will not receive any anti-epileptic drug.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: September 28, 2020): 1649
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 1, 2028
• Estimated Primary Completion Date: March 1, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Samantha Lawes, PhD; 07891 432226; samantha.lawes@addenbrookes.nhs.uk

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04573803
• Other Study ID Numbers: A095460
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Peter Hutchinson, University of Cambridge
• Study Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: University of Cambridge

Investigators

• Principal Investigator: Peter Hutchinson, PhD; University of Cambridge

• PRS Account: Cambridge University Hospitals NHS Foundation Trust
• Verification Date: September 2020