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Trial registered on ANZCTR


Registration number
ACTRN12618001984280
Ethics application status
Approved
Date submitted
4/12/2018
Date registered
11/12/2018
Date last updated
11/12/2018
Date data sharing statement initially provided
11/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Perampanel for the prevention of post-stroke epilepsy- efficacy and safety
Scientific title
Perampanel for the prevention of post-stroke epilepsy- efficacy and safety: a pilot phase II randomised controlled trial
Secondary ID [1] 296741 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PEPSTEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 310614 0
Epilepsy 310615 0
Condition category
Condition code
Stroke 309327 309327 0 0
Ischaemic
Stroke 309328 309328 0 0
Haemorrhagic
Neurological 309329 309329 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The interventional treatment to be used in this trial is the oral anti-epileptic drug, perampanel. Perampanel is an AMPA-receptor antagonist. A comparator (placebo) medication indistinguishable from the active drug will also be used.

Patients with acute cortical ischaemic or haemorrhagic stroke will be recruited within 7 days of stroke onset. A subset will undergo a 7T MRI scan. Patients will be randomised to receive perampanel or placebo for 16 weeks and be observed for a further 36 weeks, until the study ends at 52 weeks.

For patients randomised to the active arm, perampanel will be started at 2mg at night and increased after 2 weeks to 4mg at night. At the start of the assessment phase (week 5-16), perampanel will be increased to 6mg. Participants will remain on 6mg from week 5 until the end of week 16 unless seizures or side effects occur.

At the end of the assessment phase all medications will be ceased and patients will enter the observation phase (week 17-52).

Participants will have 6 visits after randomisation over the 52-week study period, during which post-stroke seizures, compliance and side effects will be assessed by investigators. In escalation and assessment phases, participants will be questioned regarding their medication adherence, and tablet/bottle counting will be performed to aid in compliance assessment. Visits will occur at 2, 4, 8 and 16 weeks, and again at 6 and 12 months.

If a post-stroke seizure occurs during the escalation phase, then after assessment by a study neurologist, standard titration will continue to occur if clinically appropriate. If multiple seizures occur during this period, additional anti-epileptic drugs may be prescribed at the discretion of the treating neurologist. If seizures occur during the assessment or observation phase, then the endpoint will be reached and the blind broken. The patient will be withdrawn from the study at this point and managed as per their treating physician.

If side effects develop and are intolerable, one dose reduction of 2mg can occur.
Intervention code [1] 313052 0
Prevention
Intervention code [2] 313053 0
Treatment: Drugs
Comparator / control treatment
The comparator group will receive a placebo as seizure prophylaxis. There is currently no evidence to support anti-epileptic drug treatment for prophylaxis after stroke. Placebo tablets will be indistinguishable from the active drug. The placebo tablet will be composed of lactose monohydrate, low substituted hydroxypropyl, cellulose, povidone, magnesium stearate and purified water.
Control group
Placebo

Outcomes
Primary outcome [1] 308290 0
Proportion of patients seizure free during observation phase. This will be assessed by a study-specific questionnaire administered at all clinic and phone visits after the commencement of treatment.
Timepoint [1] 308290 0
12 months after randomisation
Secondary outcome [1] 354545 0
Time to first seizure during observation phase. This will be assessed by a study-specific questionnaire administered at all clinic and phone visits after the commencement of treatment.
Timepoint [1] 354545 0
12 months after randomisation
Secondary outcome [2] 354546 0
Modified Rankin Scale (mRS) score
Timepoint [2] 354546 0
90 days after randomisation
Secondary outcome [3] 354547 0
Proportion of patients who continue on allocated treatment. This will be assessed by a Medication Adherence Questionnaire performed during study visits as well as by counting number of dispensed tablets remaining.
Timepoint [3] 354547 0
16 weeks after randomisation
Secondary outcome [4] 354548 0
Proportion of patients who show improvement in Quality of Life scores (SS-QOL) over study period
Timepoint [4] 354548 0
16 weeks and 12 months after randomisation
Secondary outcome [5] 354549 0
Safety assessment: frequency and type of adverse effects. Known adverse effects from perampanel treatment include drowsiness, dizziness, fatigue and less commonly behavioural or psychiatric disturbance. These will be assessed by regular performance of the Liverpool Adverse Events Profile (LAEP) and the Columbia Suicide Severity Rating Scale (C-SSRS).
Timepoint [5] 354549 0
2, 4, 8 and 16 weeks and 6 and 12 months after randomisation

Eligibility
Key inclusion criteria
1. Radiological (CT, CT perfusion or MRI) evidence of acute cortical ischaemic stroke or lobar haemorrhage within 7 days of symptom onset
If enrolment is feasible prior to obtaining MRI (or MRI is contraindicated), cortical involvement can be inferred by either (1) evidence of large vessel (ICA, M1/M2) occlusion on CT angiography at admission or (2) clinical evidence of a cortical syndrome such as aphasia, neglect/inattention or visual field defect
2. No previous anti-epileptic drug use
3. Able to give informed consent or proxy consent
4. Pre-admission mRS<4
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Preadmission Modified Rankin Scale (mRS) > 3
2. Acute stroke more than 7 days from onset
3. Previous ischaemic or haemorrhagic stroke within preceding 12 months
4. Significant risk factors for non stroke-related epilepsy
5. Previously diagnosed epilepsy (excluding benign childhood epilepsies)
6. Additional epileptogenic intra-cranial pathology
7. Previous intracranial surgery
8. History of major psychiatric morbidity (such as psychiatric illness requiring hospitalisation or history of psychosis, major depression or suicidality) within the last 2 years
9. Pregnant or breast-feeding
10. Excessive alcohol or recreational drug use
11. Unable to obtain informed consent from patient or substitute decision maker

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment by central computer based randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software

Participants will be randomised in a 1:1 fashion, according to stroke subtype (ischaemic vs haemorrhagic). A computer generated randomisation method will be used with an allocation table uploaded to a Redcap database program. An independent clinical researcher will be given access to randomise patients using the Redcap database, keeping all other researchers blinded.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is primarily a hypothesis-generating pilot RCT, the results of which will aid study design and power calculations in a subsequent phase III trial. Regardless, power calculations have been performed for planned sample size. An adaptive increase in sample size will be performed if the results of interim analysis using data from the first 82 patients are promising as per the methodology of Mehta and Pocock (Statistics in medicine 2011;30:3267-84). The maximum sample size is capped at 328 patients.

Based on the seizure risk identified in high risk populations studied by Galovic et al (Lancet Neurology 2018;17:143-52), we anticipate approximately 20% of patients in the untreated cohort will develop seizures within 12 months. Given a sample size of 82 in each group, allocation ratio 1:1, two-sided significance level of 0.05 and assumed 5% incidence of seizures in the perampanel group, Fisher’s exact test has a power of 0.8 to detect a relative decrease of 75% in the incidence of seizures.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12628 0
The Alfred - Prahran
Recruitment hospital [2] 12629 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 12630 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 12631 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 25051 0
3004 - Prahran
Recruitment postcode(s) [2] 25052 0
3050 - Parkville
Recruitment postcode(s) [3] 25053 0
3168 - Clayton
Recruitment postcode(s) [4] 25054 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 301321 0
Hospital
Name [1] 301321 0
Alfred Health
Address [1] 301321 0
55 Commercial Road
Melbourne VIC 3004
Country [1] 301321 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health
Address
55 Commercial Road
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 300987 0
None
Name [1] 300987 0
Address [1] 300987 0
Country [1] 300987 0
Other collaborator category [1] 280453 0
University
Name [1] 280453 0
Monash University, Department of Neuroscience
Address [1] 280453 0
Central Clinical School, Monash University
The Alfred Centre, Level 6
99 Commercial Road
Melbourne VIC 3004
Country [1] 280453 0
Australia
Other collaborator category [2] 280454 0
University
Name [2] 280454 0
University of Melbourne
Address [2] 280454 0
757 Swanston Street
Parkville, Victoria, 3050
Country [2] 280454 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302063 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 302063 0
Alfred Health
Alfred Hospital
55 Commercial Road
Melbourne VIC 3004
Ethics committee country [1] 302063 0
Australia
Date submitted for ethics approval [1] 302063 0
05/09/2018
Approval date [1] 302063 0
23/11/2018
Ethics approval number [1] 302063 0
44336 Local Reference: Project 287/18

Summary
Brief summary
The aim of this study is to examine the effectiveness of perampanel in the prevention of post-stroke seizures.

Patients will be randomised to receive perampanel or placebo for 16 weeks. Doses will be escalated over the first four weeks before patients enter an assessment phase for the remainder of the trial. Patients will be followed up for 52 weeks. The primary outcome is the proportion of patients seizure free at the conclusion of the 52 week period. Secondary endpoints include measures of drug safety, tolerability and quality of life. In a subset of participants glutamate concentrations in the brain will be measured by MRI to assess whether they can be used to predict development of post-stroke seizures.

This will be the third randomised trial examining the prevention of seizures after stroke. A positive study would support a larger randomised phase III trial of perampanel for prevention of post-stroke seizures. The novel use of 7T MRI to quantify glutamate offers the opportunity to assess if a non-invasive biomarker can help stratify seizure risk so that at-risk patients can be targeted for preventative treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88998 0
Prof Patrick Kwan
Address 88998 0
Centre Block, Level 4
Alfred Hospital
55 Commercial Road, Melbourne VIC 3004
Country 88998 0
Australia
Phone 88998 0
+61 3 9903 0900
Fax 88998 0
Email 88998 0
patrick.kwan@monash.edu
Contact person for public queries
Name 88999 0
Mr Jack Germaine
Address 88999 0
Epilepsy Research Unit – 4 Centre Block, Level 4
The Alfred Hospital
55 Commercial Rd, Melbourne VIC 3004
Country 88999 0
Australia
Phone 88999 0
+61 3 9076 2029
Fax 88999 0
Email 88999 0
J.Germaine@alfred.org.au
Contact person for scientific queries
Name 89000 0
Dr John-Paul Nicolo
Address 89000 0
Level 4, Neurosciences
Royal Melbourne Hospital
300 Grattan Street, Parkville VIC 3050
Country 89000 0
Australia
Phone 89000 0
+61 3 9342 7722
Fax 89000 0
Email 89000 0
JohnPaul.Nicolo@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All individual participant data, after de-identification.
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following article publication.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
To achieve aims in the approved proposal.
How or where can data be obtained?
This will be arranged on request by contacting the corresponding author.
What supporting documents are/will be available?
No other documents available
Summary results
No Results