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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
5/11/2021
Date data sharing statement initially provided
23/04/2019
Date results information initially provided
5/11/2021
Type of registration
Prospectively registered
Titles & IDs
Public title
Perampanel for the prevention of glioma associated seizures – efficacy and safety
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Scientific title
Perampanel for the prevention of glioma associated seizures – efficacy and safety: a pilot phase II randomised controlled trial
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Secondary ID [1]
289704
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Nil known
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Universal Trial Number (UTN)
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Trial acronym
PEGASUS-2
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Tumour associated epilepsy
299518
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Glioma
301617
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Condition category
Condition code
Neurological
299495
299495
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0
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Epilepsy
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Cancer
299496
299496
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0
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Brain
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
295330
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Prevention
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Intervention code [2]
296844
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Treatment: Drugs
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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.
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Control group
Placebo
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Outcomes
Primary outcome [1]
298975
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Time to first seizure after escalation phase (weeks 5-52) - assessed by seizure diary
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Assessment method [1]
298975
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Timepoint [1]
298975
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52 weeks after randomization
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Primary outcome [2]
298976
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Proportion of patients seizure free during 12 weeks efficacy assessment phase - assessed by seizure diary
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Assessment method [2]
298976
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Timepoint [2]
298976
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16 weeks after randomization
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Secondary outcome [1]
325802
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Proportion of patients seizure free over entire 52 week study period - assessed by seizure diary
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Assessment method [1]
325802
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Timepoint [1]
325802
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52 weeks after randomization
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Secondary outcome [2]
325803
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Seizure frequency during observation phase (weeks 17-52).
Seizures per month (total seizures divided by 8), assessed by seizure diary
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Assessment method [2]
325803
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Timepoint [2]
325803
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52 weeks after randomization
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Secondary outcome [3]
325804
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Proportion of patients who continue on the allocated treatment at end of assessment phase
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Assessment method [3]
325804
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Timepoint [3]
325804
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16 weeks after randomization
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Secondary outcome [4]
325805
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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
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Assessment method [4]
325805
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Timepoint [4]
325805
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52 weeks after randomization
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Secondary outcome [5]
325806
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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
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Assessment method [5]
325806
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Timepoint [5]
325806
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16 weeks after randomization
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Secondary outcome [6]
325807
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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
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Assessment method [6]
325807
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Timepoint [6]
325807
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52 weeks after randomization
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Secondary outcome [7]
325808
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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
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Assessment method [7]
325808
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Timepoint [7]
325808
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16 weeks after randomization
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Secondary outcome [8]
325809
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Overall survival - time from histological diagnosis to end of follow-up.
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Assessment method [8]
325809
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Timepoint [8]
325809
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End of follow-up is 52 weeks after randomization, death or last follow-up if lost to follow-up
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Secondary outcome [9]
325810
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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
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Assessment method [9]
325810
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Timepoint [9]
325810
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52 weeks after randomization
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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
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Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
allocation concealment by central computer based randomization
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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.
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Safety/efficacy
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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).
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Recruitment
Recruitment status
Stopped early
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Data analysis
Data collected is being analysed
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Reason for early stopping/withdrawal
Participant recruitment difficulties
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Date of first participant enrolment
Anticipated
31/05/2018
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Actual
2/11/2018
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Date of last participant enrolment
Anticipated
22/04/2021
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Actual
22/07/2019
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Date of last data collection
Anticipated
22/04/2022
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Actual
20/07/2020
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Sample size
Target
40
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Accrual to date
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Final
2
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
6190
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Royal Melbourne Hospital - City campus - Parkville
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Recruitment hospital [2]
6191
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Melbourne Private Hospital - Parkville
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Recruitment hospital [3]
6192
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St Vincent's Hospital (Melbourne) Ltd - Fitzroy
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Recruitment hospital [4]
7269
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Austin Health - Austin Hospital - Heidelberg
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Recruitment hospital [5]
7270
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St Vincent's Private Hospital - Fitzroy
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Recruitment postcode(s) [1]
13633
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3050 - Parkville
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Recruitment postcode(s) [2]
13634
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3052 - Parkville
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Recruitment postcode(s) [3]
13635
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3065 - Fitzroy
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Recruitment postcode(s) [4]
15035
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3084 - Heidelberg
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Recruitment postcode(s) [5]
15036
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3065 - Fitzroy
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Funding & Sponsors
Funding source category [1]
294086
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Charities/Societies/Foundations
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Name [1]
294086
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Royal Melbourne Hospital Neuroscience Foundation
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Address [1]
294086
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Royal Melbourne Hospital
Grattan St
Parkville, Victoria
3050
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Country [1]
294086
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Australia
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Primary sponsor type
Hospital
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Name
Melbourne Health
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Address
Melbourne Health
300 Grattan St
Parkville, Victoria
3050
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Country
Australia
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Secondary sponsor category [1]
292918
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None
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Name [1]
292918
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Address [1]
292918
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Country [1]
292918
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Other collaborator category [1]
279088
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University
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Name [1]
279088
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The University of Melbourne
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Address [1]
279088
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757 Swanston Street
Parkville, Victoria, 3050
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Country [1]
279088
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Australia
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Other collaborator category [2]
279130
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University
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Name [2]
279130
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University of Pennsylvania
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Address [2]
279130
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University of Pennsylvania
3451 Walnut Street
Philadelphia, PA 19104-6291
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Country [2]
279130
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United States of America
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
295502
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Melbourne Health Human Research Ethics Committee
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Ethics committee address [1]
295502
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Melbourne Health
Royal Melbourne Hospital
Grattan St
Parkville, Victoria
3050
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Ethics committee country [1]
295502
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Australia
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Date submitted for ethics approval [1]
295502
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31/08/2016
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Approval date [1]
295502
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12/12/2016
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Ethics approval number [1]
295502
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HREC/16/MH/51
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
67506
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Dr Andrew Neal
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Address
67506
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Melbourne Brain Centre
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
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Country
67506
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Australia
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Phone
67506
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+61 3 93427000
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Fax
67506
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Email
67506
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[email protected]
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Contact person for public queries
Name
67507
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Dr Andrew Neal
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Address
67507
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Epilepsy Research Office
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
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Country
67507
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Australia
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Phone
67507
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Change in study coordinator
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Fax
67507
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+61 3 93428628
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Email
67507
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[email protected]
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Contact person for scientific queries
Name
67508
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Dr Andrew Neal
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Address
67508
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Melbourne Brain Centre
Level 4, Neurosciences
300 Grattan St
Royal Melbourne Hospital
Parkville, VIC, 3050
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Country
67508
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Australia
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Phone
67508
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+61 3 93427000
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Fax
67508
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Email
67508
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Post-operative seizure prophylaxis in gliomas.
2017
https://dx.doi.org/10.21037/tcr.2017.06.51
Dimensions AI
Glutamate weighted imaging contrast in gliomas with 7?Tesla magnetic resonance imaging
2019
https://doi.org/10.1016/j.nicl.2019.101694
N.B. These documents automatically identified may not have been verified by the study sponsor.
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