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Trial registered on ANZCTR


Registration number
ACTRN12617000073303
Ethics application status
Approved
Date submitted
11/01/2017
Date registered
13/01/2017
Date last updated
23/04/2019
Date data sharing statement initially provided
23/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Perampanel for the prevention of glioma associated seizures – efficacy and safety
Scientific title
Perampanel for the prevention of glioma associated seizures – efficacy and safety: a pilot phase II randomised controlled trial
Secondary ID [1] 289704 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PEGASUS-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tumour associated epilepsy 299518 0
Glioma 301617 0
Condition category
Condition code
Neurological 299495 299495 0 0
Epilepsy
Cancer 299496 299496 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The interventional drug to be utilized in this randomized controlled trial is the oral anti-epileptic drug, perampanel. Perampanel is an AMPA-receptor antagonist. Both intervention and comparator (placebo) medications will be identically encapsulated.
Patients with WHO grade II-III supratentorial gliomas will be recruited pre-operatively and receive a 7T MRI scan. Post-operatively, patients will be randomized to receive perampanel or placebo for 16 weeks and be observed for a further 36 weeks, until at the study ends at 52 weeks.
For patients randomized to the active arm, perampanel will be started at 2mg at night and over the first 4 weeks (escalation phase) will be uptitrated to by 2mg every 2 weeks, eg 2mg for the first 2 weeks, then 4mg for following two weeks.

At the start of the assessment phase 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 8 visits after randomization over the 52-week study period, during which post-operative seizures, compliance and side effects will be assessment 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, 6, 8 weeks and 4, 6, 9, 12 months.
If post-operative seizures occur during the escalation phase, then after assessment by a study neurologist, standard titration will continue to occur if clinically appropriate. If seizures occur during the assessment or observation phase, or multiple seizures occur during escalation phase, then the endpoint will be reached and 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] 295330 0
Prevention
Intervention code [2] 296844 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 tumour surgery. Non-active placebo tablets will be encapsulated to appear identical to intervention tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 298975 0
Time to first seizure after escalation phase (weeks 5-52) - assessed by seizure diary
Timepoint [1] 298975 0
52 weeks after randomization
Primary outcome [2] 298976 0
Proportion of patients seizure free during 12 weeks efficacy assessment phase - assessed by seizure diary
Timepoint [2] 298976 0
16 weeks after randomization
Secondary outcome [1] 325802 0
Proportion of patients seizure free over entire 52 week study period - assessed by seizure diary
Timepoint [1] 325802 0
52 weeks after randomization
Secondary outcome [2] 325803 0
Seizure frequency during observation phase (weeks 17-52).
Seizures per month (total seizures divided by 8), assessed by seizure diary
Timepoint [2] 325803 0
52 weeks after randomization
Secondary outcome [3] 325804 0
Proportion of patients who continue on the allocated treatment at end of assessment phase
Timepoint [3] 325804 0
16 weeks after randomization
Secondary outcome [4] 325805 0
Proportion of patients who show improvement in QOL (Quality of Life) based on QOLIE-89 scores from baseline to 52 weeks.
Improvement defined as baseline score > 52 week score
Timepoint [4] 325805 0
52 weeks after randomization
Secondary outcome [5] 325806 0
Proportion of patients who show improvement in QOL (Quality of Life) based on QOLIE-89 scores from baseline to 16 weeks by treatment group
Improvement defined as baseline score > 16 week score
Timepoint [5] 325806 0
16 weeks after randomization
Secondary outcome [6] 325807 0
Proportion of patients who show improvement in anxiety symptoms (based on HADS score) from baseline to 52 weeks
Improvement defined as baseline score > 52 week score
Timepoint [6] 325807 0
52 weeks after randomization
Secondary outcome [7] 325808 0
Proportion of patients who show improvement in anxiety symptoms (based on HADS score) from baseline to 16 weeks
Improvement defined as baseline score > 16 week score
Timepoint [7] 325808 0
16 weeks after randomization
Secondary outcome [8] 325809 0
Overall survival - time from histological diagnosis to end of follow-up.
Timepoint [8] 325809 0
End of follow-up is 52 weeks after randomization, death or last follow-up if lost to follow-up
Secondary outcome [9] 325810 0
Frequency and type of adverse effects and serious adverse effects - assessed by LAEP questionnaire
Qualitative description of adverse effects which develop over the course of the trial
Timepoint [9] 325810 0
52 weeks after randomization

Eligibility
Key inclusion criteria
Pre-operative phase (ie inclusion for 7T MRI)
1. 18 – 80 years
2. Radiological diagnosis of a supratentorial WHO grade II-III glioma
3. Planned surgical resection or biopsy of lesion
4. 3T MRI performed as clinical standard of care
5. Able to give informed consent
6. No pre-operative seizure

Post-operative phase (ie inclusion for treatment intervention)
1. 18-80 years
2. Diagnosis of WHO grade II-III glioma
3. Less than 3 weeks from date of glioma resection or biopsy
4. No seizures prior to randomisation
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous non-tumour related neurosurgical procedures (excluding biopsy of glioma)
2. Pre-operative chemotherapy or radiotherapy
3. Receiving >1000mg daily of levetiracetam or multiple concurrent anti-epileptic drugs at time of randomization
4. Contraindication to 7T MRI
5. Significant risk factors for non-tumour associated epilepsy
- Previously diagnosed epilepsy (excluding benign childhood epilepsies)
- Additional epileptogenic intra-cranial pathology (including intra-cranial complications from glioma resection)
6. History of major psychiatric morbidity (such as psychiatric illness requiring hospitalisation or history of psychosis, major depression or suicidality) within the last 2 years
7. Pregnant or breast-feeding
8. Excessive alcohol or recreational drug use

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 randomization
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, depending upon both operation (biopsy vs craniotomy and resection) and WHO grade (II vs III). This will ensure approximately equal numbers of each grade glioma are randomized to each treatment arm in study 1 and 2. A computer generated randomisation method will be utilized with an allocation table uploaded to a Redcap database program. An independent clinical researcher will given access randomise patients using the Redcap database, keeping all other researchers blinded.

Stratifying on the basis of WHO grade will help ensure extra homogeneity between study arms. In study 2 (perampanel vs placebo), patients with no pre-operative seizures will be randomised in a 1:1 ratio to either perampanel or placebo. Investigators and patients will be blinded to the assigned treatment until the end of the assessment phase.
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, Power calculations have however been performed for the planned sample size. Given total sample size of 40, allocation ratio 1:1, two-sided significant level of 0.05, and assumed 80% seizure free rate in patients taking placebo, Fisher’s exact test has 0.37 power to detect a 25% increase in seizure free rate in patients taking perampanel. With regards to time to first post-operative seizure analysis, the sample size of 40 has a power of 0.8 detect 61.4% increase in the median time to first post-op seizure
Clinicopathological characteristics will be compared on univariate analysis between intervention (perampanel) and comparison group (placebo). This will be examined using and Fisher’s exact test as appropriate for categorical variables, Independent T-test for continuous, normally distributed variables and Mann-Whiteny U-test for continuous, asymmetric variables. P value <0.05 will indicate a significance difference.
Efficacy to be analysed in both i) intention to treat: randomly assigned to treatment groups and received at least one dose of study treatment and ii) per-protocol: excluded patients who were major protocol violators. Protocol violators will include poor compliance with study drug dosing,

Adaptive statistical analysis:
Adaptive increase in sample size will be performed if the results of interim analysis using data from the first 30 patients in each study are promising as per the methodology of Mehta and Pocock et al (Statistics in medicine 2011;30:3267-84).. For PEGASUS 2, the maximum sample size will be 78 (n = 39 in each group). Sample size was calculated with two-tailed Fisher's Exact Test, assumes perampanel provides superior outcome, assumes 80% seizure free rate on placebo and is able to detect greater than 20% absolute difference (using 80% power and type 1 error set at alpha 0.05).

Recruitment
Recruitment status
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] 6190 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 6191 0
Melbourne Private Hospital - Parkville
Recruitment hospital [3] 6192 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [4] 7269 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 7270 0
St Vincent's Private Hospital - Fitzroy
Recruitment postcode(s) [1] 13633 0
3050 - Parkville
Recruitment postcode(s) [2] 13634 0
3052 - Parkville
Recruitment postcode(s) [3] 13635 0
3065 - Fitzroy
Recruitment postcode(s) [4] 15035 0
3084 - Heidelberg
Recruitment postcode(s) [5] 15036 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 294086 0
Charities/Societies/Foundations
Name [1] 294086 0
Royal Melbourne Hospital Neuroscience Foundation
Address [1] 294086 0
Royal Melbourne Hospital
Grattan St
Parkville, Victoria
3050
Country [1] 294086 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
Melbourne Health
300 Grattan St
Parkville, Victoria
3050
Country
Australia
Secondary sponsor category [1] 292918 0
None
Name [1] 292918 0
Address [1] 292918 0
Country [1] 292918 0
Other collaborator category [1] 279088 0
University
Name [1] 279088 0
The University of Melbourne
Address [1] 279088 0
757 Swanston Street
Parkville, Victoria, 3050
Country [1] 279088 0
Australia
Other collaborator category [2] 279130 0
University
Name [2] 279130 0
University of Pennsylvania
Address [2] 279130 0
University of Pennsylvania
3451 Walnut Street
Philadelphia, PA 19104-6291
Country [2] 279130 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295502 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 295502 0
Melbourne Health
Royal Melbourne Hospital
Grattan St
Parkville, Victoria
3050
Ethics committee country [1] 295502 0
Australia
Date submitted for ethics approval [1] 295502 0
31/08/2016
Approval date [1] 295502 0
12/12/2016
Ethics approval number [1] 295502 0
HREC/16/MH/51

Summary
Brief summary
The aim of this study is to examine effectiveness of perampanel in the prevention of tumour associated epilepsy (TAE) in patients with grade II-III gliomas.

Who is it for?
You may be eligible to join this study if you are aged 18-65 years and have a diagnosis of World Health Organisation grade II-III supratentorial glioma and have not experienced a pre-operative seizure.

Study details
Patients will be randomized (allocated by chance) to receive perampanel, or or placebo for 16 week. Doses will be escalated over the first four week before patients enter an assessment phase for the remainder of the trial. Patients will be followed up for 52 weeks. The primary outcomes are i) time to first seizure after escalation phase (weeks 5-52) and ii) proportion of patients seizure free during 12 week assessment phase. Secondary endpoints include measures of drug safety, tolerability and quality of life. Glutamate concentrations will be measured before drug treatment is commenced to assess whether it can be utilized to predict both post-operative seizure and response to perampanel.

This will be the first monotherapy epilepsy RCT utilizing perampanel. A positive study would support a larger randomized phase III trial examining perampanel monotherapy in tumour associated seizures prophylaxis. The novel use of 7T MRI to quantify glutamate offers the opportunity to assess if a non-invasive biomarker can help stratify seizure risk and perampanel response. This can pave the way for individualised and targeted epilepsy treatment and prevention.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67506 0
Dr Andrew Neal
Address 67506 0
Melbourne Brain Centre
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
Country 67506 0
Australia
Phone 67506 0
+61 3 93427000
Fax 67506 0
Email 67506 0
andrew.neal@mh.org.au
Contact person for public queries
Name 67507 0
Ms Elle Hurley
Address 67507 0
Epilepsy Research Office
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
Country 67507 0
Australia
Phone 67507 0
Change in study coordinator
Fax 67507 0
+61 3 93428628
Email 67507 0
Elle.Hurley@mh.org.au
Contact person for scientific queries
Name 67508 0
Dr Andrew Neal
Address 67508 0
Melbourne Brain Centre
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
Country 67508 0
Australia
Phone 67508 0
+61 3 93427000
Fax 67508 0
Email 67508 0
andrew.neal@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results