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Trial registered on ANZCTR


Registration number
ACTRN12615000556549
Ethics application status
Approved
Date submitted
1/05/2015
Date registered
29/05/2015
Date last updated
28/10/2022
Date data sharing statement initially provided
28/10/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
EpiNet-First Trial 2: Comparison of efficacy of levetiracetam and sodium valproate in people with previously untreated epilepsy who have generalised seizures.
Scientific title
EpiNet First Trial 2: A pragmatic randomised controlled trial comparing the effectiveness of levetiracetam versus sodium valproate in people with previously untreated epilepsy who have generalised seizures.
Secondary ID [1] 286624 0
Nil
Universal Trial Number (UTN)
U1111-1148-2720
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 294943 0
Condition category
Condition code
Neurological 295200 295200 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
EpiNet-First Trial 2: patients with generalised seizures for whom sodium valproate is suitable will be randomised (1:1) to receive levetiracetam or sodium valpoate.

Levetiracetam. Oral medication. Duration of treatment administration = 2 years. Dose to be determined by investigator according to usual clinical practice. The range of doses will vary from 250 mg to 4000 mg (oral tablets) daily in two divided doses and will be determined as considered clinically appropriate by the investigator. Adherence will be assessed by the investigators checking regularly with patients whether they are taking the drug as prescribed. Serum drug levels are not required as part of the study, but will be monitored as determined by the investigator and considered appropriate for good clinical care.
Intervention code [1] 291759 0
Treatment: Drugs
Comparator / control treatment
sodium valproate. Oral medication. Duration of treatment administration = 2 years. Dose to be determined by investigator according to usual clinical practice. The range of doses will vary from 250 mg to 4000 mg (oral tablets) daily in two divided doses and will be determined as considered clinically appropriate by the investigator
Control group
Active

Outcomes
Primary outcome [1] 294955 0
The primary endpoint for the EpiNet-First trial 2 is time to 12 month remission from seizures; The outcome is assessed by self-reporting of seizures by participants
Timepoint [1] 294955 0
The duration of the study is expected to be 5 years, with a 3 year recruitment period and a minimum 2 year follow-up period for each participant.
Secondary outcome [1] 314459 0
Composite secondary outcome. Proportion of patients who achieve a seizure free 12 month remission by 18 months AND who have not changed to a different AED. This outcome is assessed by self-reporting of seizures by participants.
Timepoint [1] 314459 0
From randomisation to 18 months
Secondary outcome [2] 314460 0
Time to treatment failure, due to either inadequate seizure control, or due to unacceptable adverse events. Treatment is deemed to have failed when the investigator changes the randomised anti-epileptic drug to a different anti-epileptic drug. Unacceptable adverse events may be either side effects (e.g. dizziness, fatigue, inablitlity to concentrate) which the participant and investigator agree are sufficiently incapacitating to warrant changing the drug, or abnormalities on examination or laboratory investigation (e.g. blood tests) that the investigator considers are sufficiently severe to terminate treatment.
Timepoint [2] 314460 0
From randomisation to treatment failure. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [3] 314461 0
Time to treatment failure due to inadequate seizure control. Treatment is deemed to have failed when the investigator changes the randomised anti-epileptic drug to a different anti-epileptic drug.
Timepoint [3] 314461 0
From randomisation to treatment failure due to inadequate seizure control. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [4] 314462 0
Time to treatment failure due to unacceptable adverse events. Unacceptable adverse events may be either side effects (e.g. dizziness, fatigue, inablitlity to concentrate) which the participant and investigator agree are sufficiently incapacitating to warrant changing the drug, or abnormalities on examination or laboratory investigation (e.g. blood tests) that the investigator considers are sufficiently severe to terminate treatment. There are no study-specific tests which are mandated in the protocol; tests will be at the clinical discretion of the investigator.
Timepoint [4] 314462 0
From randomisation to treatment failure due to unacceptable adverse events. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [5] 314463 0
Time to first seizure. This outcome is assessed by self-reporting of seizures by participants.
Timepoint [5] 314463 0
From Randomisation to first seizure. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [6] 314464 0
Time to 24 month remission. This outcome is assessed by self-reporting of seizures by participants.
Timepoint [6] 314464 0
From randomisation to 24 month remission. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [7] 314465 0
Serious Adverse events attributed to the trial medication or other anti-epileptic medication. These are as follow: result in death
are life-threatening* (subject at immediate risk of death)
require in-patient hospitalisation or prolongation of existing hospitalisation; **
result in persistent or significant disability or incapacity, or
consist of a congenital anomaly or birth defect
Other important medical events***

*‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures that have not worsened, do not constitute a Serious Adverse Event.
***Other important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event / experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Timepoint [7] 314465 0
From randomisation to onset of SAE. Participants will be followed for a minimum of 2 years up to 5 years post enrolment.
Secondary outcome [8] 314466 0
Quality of life as assessed by the QOLIE31 and QOLIE48 questionnaires. These are validated, and are widely used in epilepsy research.
Timepoint [8] 314466 0
This is assessed at baseline (when the participant is enrolled) and at 3 , 6, 12 and 24 months.

Eligibility
Key inclusion criteria
1-Aged 5 years or older on date of consent

2-The investigator is confident that the patient has epilepsy

3-Two or more spontaneous generalized seizures that require antiepileptic drug treatment (provided all seizures have not been absence seizures);

4-Antiepileptic drug monotherapy considered the most appropriate option

5-Willing to provide consent. For patients younger than the age of consent (usually 16 years), patient's parent/legal representative willing to give consent,
Minimum age
5 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1-Provoked seizures (e.g. alcohol, recreational drugs)

2-Acute symptomatic seizures (e.g. acute brain haemorrhage or acute brain injury)

3- absence seizures as only seizure type

4- Psychogenic non-epileptogenic seizures

5-Has ever been treated with an antiepileptic for more than one week

6-Known progressive neurological disease (e.g. brain tumour)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be approached at emergency departments and outpatient clinics, (including 1st seizure clinics, epilepsy clinics). Once consent has been obtained participants are randomised via the EpiNet database. Block randomisation is being used, with stratification for age (< 18, >=18 yr), sex, and country. Allocation concealment is obtained by means of central randomisation by computer using block randomisation and variable block sizes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This is a pragmatic trial. Guidelines are provided for introduction of drugs, but investigators are free to provide whatever dose they consider clinically appropriate. Generic versions of drugs can be provided.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The EpiNet-First Trial 2 Recruitment rate will be reviewed regularly, and annual progress reports regarding patient recruitment will be prepared and forwarded to the Independent Advisory group and appropriate ethics committees.
No interim analysis is planned.
Statistical analyses will be performed on EpiNet-First Trial 2, using SAS version 9.3 (SAS Institute Inc. Cary NC). Trial data will be collected using the EpiNet web-based database, and extracted into SAS for data quality checks and final statistical analysis when all patients have a minimum two year follow-up data at the end of the trial.
The primary analysis of time to 12 month remission from seizures will be on an intention to treat (ITT) basis including all randomised patients regardless of whether they actually satisfied the entry criteria, the treatment actually received, and subsequent withdrawal or deviation from the protocol. Secondary per protocol (PP) analyses will also be undertaken to assess the robustness of ITT analyses. This analysis will include all randomised patients who have taken the prescribed study drug and who do not have major protocol violations. All statistical tests will be two-sided and a 5% significance level maintained throughout the analyses. Confidence intervals for all point estimates will be two-sided 95% intervals. For EpiNet-First Trial 2, the proposed sample size will provide 90% power at 5% significance level (two-sided) to identify a 10% or greater difference in 12 month disease-free survival at 2 years between the groups, allowing for 10% loss to follow up.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/05/2015
Actual
11/05/2015
Date of last participant enrolment
Anticipated
1/05/2018
Actual
26/09/2019
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
506
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 6849 0
New Zealand
State/province [1] 6849 0
Nationwide
Country [2] 6850 0
United Kingdom
State/province [2] 6850 0
Country [3] 6851 0
Belgium
State/province [3] 6851 0
Country [4] 6852 0
India
State/province [4] 6852 0
Country [5] 6853 0
Slovenia
State/province [5] 6853 0
Country [6] 6854 0
Georgia
State/province [6] 6854 0
Country [7] 6855 0
Mexico
State/province [7] 6855 0
Country [8] 6894 0
Italy
State/province [8] 6894 0

Funding & Sponsors
Funding source category [1] 291192 0
Government body
Name [1] 291192 0
Health Research Council of New Zealand;
Country [1] 291192 0
New Zealand
Funding source category [2] 291193 0
Charities/Societies/Foundations
Name [2] 291193 0
Neurological Foundation of New Zealand
Country [2] 291193 0
New Zealand
Funding source category [3] 291194 0
Charities/Societies/Foundations
Name [3] 291194 0
Julius Brendel Trust
Country [3] 291194 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
EpiNEt Study Group
Address
Neurology Department, Auckland City Hospital, Park Rd, Auckland, New Zealand
Private Bag 92024
Auckland 1142, New Zealand
Country
New Zealand
Secondary sponsor category [1] 289872 0
Government body
Name [1] 289872 0
Auckland District Health Board
Address [1] 289872 0
Auckland City Hospital, Park Rd, Auckland, New Zealand
Private Bag 92024
Auckland 1142, New Zealand
Country [1] 289872 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292765 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 292765 0
PO Box 5013
Wellington 6011
Ethics committee country [1] 292765 0
New Zealand
Date submitted for ethics approval [1] 292765 0
Approval date [1] 292765 0
30/06/2014
Ethics approval number [1] 292765 0
14/NTB/56

Summary
Brief summary
Levetiracetam is being compared with sodium valproate in patients with new-onset epilepsy who have generalised seizures. Four other closely related trials are being conducted, with the entry criteria for each trial determined by the seizure type that the patient experiences. Sustained seizure freedom (at least 12 months seizure free) is the primary endpoint
Trial website
www.epinet.co.nz
Trial related presentations / publications
Public notes
Attachments [1] 429 429 0 0
/AnzctrAttachments/368462-EpiNet protocol V2 - signed June 2014.pdf
Attachments [2] 430 430 0 0
/AnzctrAttachments/368462-HDEC Letter 14NTB56 Approved FULL Application.pdf

Contacts
Principal investigator
Name 56906 0
Dr Peter Bergin
Address 56906 0
Neurology Department, Auckland City Hospital, Park Rd, Grafton,
Private Bag 92024
Auckland 1142
Country 56906 0
New Zealand
Phone 56906 0
+6493074949 x 25563
Fax 56906 0
+6493078912
Email 56906 0
[email protected]
Contact person for public queries
Name 56907 0
Erica Beilharz
Address 56907 0
Neurology Department, Auckland City Hospital, Park Rd, Grafton,
Private Bag 92024
Auckland 1142
Country 56907 0
New Zealand
Phone 56907 0
+6493074949 x 25833
Fax 56907 0
+6493078912
Email 56907 0
[email protected]
Contact person for scientific queries
Name 56908 0
Peter Bergin
Address 56908 0
Neurology Department, Auckland City Hospital, Park Rd, Grafton,
Private Bag 92024
Auckland 1142
Country 56908 0
New Zealand
Phone 56908 0
+6493074949 x 25563
Fax 56908 0
+6493078912
Email 56908 0
[email protected]

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?

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
No additional documents have been identified.