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Trial registered on ANZCTR


Registration number
ACTRN12618001444279
Ethics application status
Approved
Date submitted
11/08/2018
Date registered
28/08/2018
Date last updated
4/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Genomic sequencing for Refractory EPilepsy (GREP)
Scientific title
Clinical utility and cost-effectiveness of immediate vs delayed whole genome sequencing for refractory epilepsy in children and adults: a multicentre randomised controlled trial.
Secondary ID [1] 295603 0
Nil known
Universal Trial Number (UTN)
U1111-1218-0937
Trial acronym
GREP
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 308932 0
Condition category
Condition code
Neurological 307833 307833 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Whole genome sequencing - immediate vs. delayed
After a consultation with a genetics counsellor patients who consent to participation in the trial will have blood drawn for whole genome sequencing.
Patients will attend clinic twice for a discussion of genetic testing results - 3 months ( for immediate testing group) and 15 months ( delayed testing group) after whole genome sequencing. First visit will be dedicated to discussion of epilepsy related pathogenic or likely pathogenic variants and pharmacogenomic variants. Patients who chose to receive secondary results of genetic testing will then attend a second visit at 6 months ( immediate group) and 18 months ( delayed group).
Intervention code [1] 301908 0
Diagnosis / Prognosis
Comparator / control treatment
Participants will be randomised 1:1 to an immediate testing (intervention) or a delayed testing (control) group. Participants in the former group will undergo whole genome sequencing (WGS) immediately while WGS will be delayed in the latter group for 12 months, during which they will continue to be investigated and treated as per standard of care. Participants from the same Clinical Centre will be grouped into one strata. Within each stratum, randomisation will be stratified by age group with children (1 month to 17 years) to adults (18 years or above) in 1:2 ratio. The randomisation, in which 20-25 patients per centre will be enrolled into the study, will be done electronically.
Standard of care for the purpose of study is defined as continuing management including : magnetic resonance imaging (MRI), fluorodeoxyglucose - positron emission tomography (FDG-PET), single-photon emission computed tomography (SPECT), electroencephalogram (EEG), video EEG monitoring, medication trials, vagal nerve stimulation ( VNS), deep brain stimulation ( DBS), dietary therapies.
Control group
Active

Outcomes
Primary outcome [1] 306811 0
Diagnostic efficiency of WGS, defined as the proportion of patients found to have causal variants (pathogenic or likely pathogenic) for their epilepsy in the immediate testing group compared with the delayed testing group at 6 months after randomisation.
Timepoint [1] 306811 0
6 months
Secondary outcome [1] 350571 0
Clinical impact of whole genome sequencing - assessed as :
1) change in clinical management compared to delayed testing group.
2) identification of pharmacogenomic variants related to anti epileptic drugs and/or Identification of secondary genetic findings, including disease specific variants, and pharmacogenomic variants unrelated to anti epileptic drugs.
3) identification of further pathogenic or likely pathogenic variants.
Timepoint [1] 350571 0
12 months
Secondary outcome [2] 350572 0
Psychosocial impact of whole genome sequencing assessed via:
1) Quality of life of patient (by EQ-5D/ED-5D-Y, QOLIE-31/PedsQL)
2)Ca rer quality of life (by CES)
3) Emotional impact of patient and carer (HADS, IES)
Timepoint [2] 350572 0
12 months
Secondary outcome [3] 350573 0
Patient preferences in relation to receiving primary and secondary genetic testing information - assessed via discrete choice experiment (DCE) compared to baseline DCE.
Timepoint [3] 350573 0
12 months
Secondary outcome [4] 350574 0
Direct healthcare costs
Assessed via data linkage to PBS and MBS to determine cost of outpatient and emergency department visits, hospital admissions and investigations in comparison to delayed testing group.
Timepoint [4] 350574 0
12 months
Secondary outcome [5] 350575 0
Indirect healthcare costs assessed via Work Productivity and Activity Impairment Questionnaire - General Health version ( WPAI:GH)
Timepoint [5] 350575 0
12 months
Secondary outcome [6] 350576 0
Cost effectiveness analysis assessed via cost effectiveness incremental ratio.
Timepoint [6] 350576 0
12 months

Eligibility
Key inclusion criteria
1. Age at recruitment 1 month to 65 years.
2. Age of onset of epilepsy less or equal to 18 years.
3. Medically refractory epilepsy (persistent seizures despite trials of 2 or more antiepileptic drugs)
4. Suspected but unknown genetic cause of epilepsy demonstrated by (any of):
• At least one first and/or second degree relatives with epilepsy or febrile seizures.
• MRI evidence of malformation of cortical development (e.g. focal cortical dysplasia, polymicrogyria).
• Suspected genetic epilepsy syndrome.
Minimum age
1 Months
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with a recognised idiopathic generalised epilepsy (also called genetic generalised epilepsy) syndrome, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, or generalised tonic-clonic seizures alone.
2. Diagnosis of a known single gene syndrome (e.g. Dravet syndrome, tuberous sclerosis complex, lissencephaly, double cortex, familial cavernomas).
3. Epilepsy related to an acquired brain insult or lesion, e.g. trauma, stroke, tumour, encephalitis (bacterial/viral/autoimmune). Hippocampal sclerosis is not excluded.
4. Patients who had previous next generation sequencing (single gene acceptable).
5. Patients with only psychogenic non-epileptic seizures.
6. Patients requiring early/urgent genetic testing with results available in less than 9 months.
7. Patients who had drug-resistant epilepsy but have become seizure-free after resective epilepsy surgery.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment - yes.
Patients who may be eligible for the study will be referred to study investigators. Patient suitability will be discussed in a trial meeting.
Participants determined to be eligible for the study by treating clinician and principle investigator team will be accepted into the trial. At the time of the acceptance neither the treating clinician nor the principle investigators will be aware of the allocation. Patients will be randomised centrally by computer to an immediate testing (intervention) or a delayed testing (control) group using computer generated randomisation. Participants in the former group will undergo WGS immediately while WGS will be delayed in the latter group for 12 months, during which they will continue to be investigated and treated as per standard of care.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants from the same Clinical Centre will be grouped into one strata. Within each stratum, randomisation will be stratified by age group with children (1 month to 17 years) to adults (18 years or above) in 1:2 ratio. The randomisation, in which 20-25 patients per centre will be enrolled into the study, will be done electronically.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This trial will include an immediate testing and delayed testing groups as follows.
Participants will be randomised 1:1 to the immediate testing (intervention) group and the delayed testing (control) group. In the immediate testing group, WGS will commence immediately, while in the delayed testing group, WGS will commence after 12 months. Participants in both groups will be followed for another 12 months. This will allow comparison of outcomes with the pre-testing period to evaluate any “catching up” effect, i.e. each participant will be followed up for a total of 24 months after randomization.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Aim (1): Fisher Exact Test.
Aim (2): Mann-Whitney test.
Aim (3): cost-utility analysis based on Quality Adjusted Life Years (QALYs).

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)
NSW,VIC
Recruitment hospital [1] 11504 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 11505 0
The Alfred - Prahran
Recruitment hospital [3] 11506 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 11507 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 11508 0
The Northern Hospital - Epping
Recruitment hospital [6] 11509 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [7] 11510 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 23530 0
3050 - Parkville
Recruitment postcode(s) [2] 23531 0
3004 - Prahran
Recruitment postcode(s) [3] 23532 0
3084 - Heidelberg
Recruitment postcode(s) [4] 23533 0
3128 - Box Hill
Recruitment postcode(s) [5] 23534 0
3076 - Epping
Recruitment postcode(s) [6] 23535 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 300178 0
Government body
Name [1] 300178 0
National Health and Medical Research Council
Address [1] 300178 0
GHD Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601
Country [1] 300178 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Department of Neuroscience, Central Clinical School, Monash University
Level 6, The Alfred Centre
99 Commercial Road
Melbourne, VIC 3004
Country
Australia
Secondary sponsor category [1] 299589 0
University
Name [1] 299589 0
University of Melbourne
Address [1] 299589 0
Genetic Medicine, Royal Melbourne Hospital, Grattan Street, Parkville 3050 VIC
Country [1] 299589 0
Australia
Secondary sponsor category [2] 299828 0
University
Name [2] 299828 0
University of South Australia
Address [2] 299828 0
Institute for Choice, School of Commerce, UniSA Business School
Level 13, 140 Arthur Street, North Sydney, NSW 2060
Country [2] 299828 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301010 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 301010 0
Office for Research
The Royal Melbourne Hospital Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 301010 0
Australia
Date submitted for ethics approval [1] 301010 0
01/03/2018
Approval date [1] 301010 0
26/06/2018
Ethics approval number [1] 301010 0
HREC/18/MH/19

Summary
Brief summary
GREP is a clinical trial that will study if performing a comprehensive genetic test called whole genome sequencing (WGS) will find out the genetic cause of drug-resistant epilepsy in more patients than usual investigations. It will also look at other ways whole genome sequencing may influence patients' life and healthcare needs, and whether it is good value for money. We plan to enrol children and adults who suffer from drug-resistant epilepsy and are likely to have a genetic cause of their illness. Suitable patients who agree to take part in the trial will have their blood collected. Whole genome sequencing will be performed immediately in half of the patients and delayed by 12 months in the other half. We will compare how earlier genetic testing results influence diagnosis, care and well-being of the patients, and overall cost-effectiveness.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 85590 0
Prof Patrick Kwan
Address 85590 0
Department of Neurology, Royal Melbourne Hospital, 300 Grattan Street, Parkville, VIC 3050
Country 85590 0
Australia
Phone 85590 0
+61 3 9342 7722
Fax 85590 0
Email 85590 0
patrick.kwan@monash.edu
Contact person for public queries
Name 85591 0
Dr Loretta Piccenna
Address 85591 0
Department of Neuroscience
Central Clinical School
Level 6, The Alfred Centre
99 Commercial Road
Melbourne, VIC 3004
Country 85591 0
Australia
Phone 85591 0
+61 3 99030879
Fax 85591 0
Email 85591 0
loretta.piccenna@monash.edu
Contact person for scientific queries
Name 85592 0
Prof Patrick Kwan
Address 85592 0
Department of Neurology, Royal Melbourne Hospital, 300 Grattan Street, Parkville, VIC 3050
Country 85592 0
Australia
Phone 85592 0
+61 3 9342 7722
Fax 85592 0
Email 85592 0
patrick.kwan@monash.edu

No data has been provided for results reporting
Summary results
Not applicable