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Trial registered on ANZCTR


Registration number
ACTRN12621001233819
Ethics application status
Approved
Date submitted
26/07/2021
Date registered
13/09/2021
Date last updated
13/09/2021
Date data sharing statement initially provided
13/09/2021
Date results information initially provided
13/09/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut Phenotype (ESTEL)
Scientific title
Efficacy and safety of deep brain stimulation to thalamic centromedian nucleus in Lennox-Gastaut syndrome (ESTEL): a randomised, double-blind, placebo-controlled epilepsy treatment trial

Secondary ID [1] 304997 0
APP110881
Universal Trial Number (UTN)
Trial acronym
ESTEL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lennox-Gastaut Syndrome 323002 0
Condition category
Condition code
Neurological 320568 320568 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Prospective, double-blind, randomised study of continuous, cycling stimulation of Centromedian nucleus Deep Brain Stimulation (CM-DBS), in patients with Lennox-Gastaut Syndrome (LGS). All participants (n=20) will undergo bilateral CM-DBS insertion by a single neurosurgeon at Austin Health (Austin Health Human Research Ethics approval number HREC/16/Austin/139). Following 3-month pre- and post-implantation periods, half receive 3-months stimulation (blinded phase), then all receive 3-months stimulation (unblinded phase) i.e., early treatment group receives 6-months of stimulation and delayed treatment group receive 3-months of stimulation throughout the study. Randomisation/stimulation adjustments are by a single unblinded programmer, while clinical assessments and data collation are performed by separate clinicians blinded to treatment group and voltage settings. Participants and caregivers are also blinded to stimulation group/settings. Stimulation parameters: Medtronic Activa PC; 3389 leads; duty cycle stimulation, 1 min on/5 mins off; 145Hz, 90usec pulse width, 2.5V or highest tolerated.

Intervention code [1] 321268 0
Treatment: Devices
Comparator / control treatment
Comparator/control are participants assigned to the delayed treatment group who first receive stimulation at the beginning of the unblinded arm of the study (i.e., 6-months post CM-DBS implantation). At the end of the study, the delayed treatment arm will receive a total of 3-months of stimulation, compared with the early treatment group who will receive a total of 6-months of stimulation.

Control group
Active

Outcomes
Primary outcome [1] 328386 0
The primary outcome is the proportion of participants with a >/= 50% reduction in diary-recorded seizures in stimulated versus control participants, measured at the end of the blinded phase.
Timepoint [1] 328386 0
month 6 post implantation = month 3 of blinded phase
Secondary outcome [1] 398858 0
Proportion of participants with a >/= 50% reduction in electrographic seizures on 24-hour ambulatory scalp EEG at the end of blinded phase.
Timepoint [1] 398858 0
Month 6 post-implantation = month 3 blinded phase.
Secondary outcome [2] 398860 0
Seizure frequency (seizure diaries) at study exit relative to baseline. Total seizure counts (type and number) are manually entered by participant caregivers onto a monthly (28-day) seizure diary. Average number of seizures per day are calculated for each month of the study.
Timepoint [2] 398860 0
Month 9 post-implantation = after 3 or 6 months stimulation (depending on whether in treatment or control arms.
Secondary outcome [3] 398861 0
Seizure frequency (electroencephalogram [EEG] recorded seizures) at study exit vs baseline. 24-hour EEG's are recorded for each participant at each phase of the study (i.e., baseline, 3-months post-DBS insertion/pre-randomisation, at the end of the blinded phase and end of the unblinded phase/study exit). EEGs are manually evaluated for electrographic seizures by a single assessor, blinded to study phase and treatment group. EEG seizures are defined as those similar to seizures documented on prior video-EEG monitoring where available, or by the following criteria: (i) a sustained run of generalised, fast epileptiform activity with evolution, causing a change in the background rhythm, and (ii) a duration of greater than 5 sec.

Timepoint [3] 398861 0
3-months post CM-DBS implantation i.e., post-stimulation/pre-stimulation
6-months CM-DBS implantation (=3-months post randomisation) i.e. end of blinded phase
9-months post CM-DBS implantation (=study exit) i.e., after 3 or 3 or 6 months stimulation (depending on whether in treatment or control arms)
Secondary outcome [4] 399400 0
Burden of scalp EEG interictal generalised paroxysmal fast activity (GPFA). This was measured during a 2-hour period of sleep on the 24-hour EEG. GPFA was again manually marked by a single assessor blinded to treatment group and study timepoint.
Timepoint [4] 399400 0
3-months post CM-DBS implantation i.e., post-stimulation/pre-stimulation
6-months CM-DBS implantation (=3-months post randomisation) i.e. end of blinded phase
9-months post CM-DBS implantation (=study exit) i.e., after 3 or 3 or 6 months stimulation (depending on whether in treatment or control arms)
Secondary outcome [5] 399401 0
Global assessment of epilepsy severity (GASE)

Timepoint [5] 399401 0
Baseline (i.e., before implantation/stimulation), end of blinded phase/6-months post CM-DBS implantation (i.e., after either 3-months stimulation or no stimulation) and end of study/9-months post CM-DBS implantation (i.e. after 3 or 6-months stimulation depending on whether in treatment or control arms).

Secondary outcome [6] 400259 0
Global assessment of epilepsy disability (GADS)
Timepoint [6] 400259 0
Baseline (i.e., before implantation/stimulation), end of blinded phase/6-months post CM-DBS implantation (i.e., after either 3-months stimulation or no stimulation) and end of study/9-months post CM-DBS implantation (i.e. after 3 or 6-months stimulation depending on whether in treatment or control arms).
Secondary outcome [7] 400260 0
Adaptive behaviour Assessment system, 3rd edition (ABAS-III)
Timepoint [7] 400260 0
Baseline (i.e., before implantation/stimulation), end of blinded phase/6-months post CM-DBS implantation (i.e., after either 3-months stimulation or no stimulation) and end of study/9-months post CM-DBS implantation (i.e. after 3 or 6-months stimulation depending on whether in treatment or control arms).
Secondary outcome [8] 400261 0
Safety - adverse events
Timepoint [8] 400261 0
Recorded as they are reported (i.e. participant-reported) from implantation to study exit.
Secondary outcome [9] 400262 0
Safety - serious adverse events
Timepoint [9] 400262 0
Recorded as they occur (i.e. participant-reported) from implantation to study exit

Eligibility
Key inclusion criteria
i) an electroclinical diagnosis of LGS; ii) generalised paroxysmal fast activity (GPFA) and slow spike-and-wave (SSW) on interictal EEG; and iii) generalised tonic seizures documented on prior video-EEG monitoring or clearly described by a reliable eyewitness
Minimum age
15 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) participants with elevated risks for bleeding; ii) cerebral anatomical variations precluding safe CM-DBS implantation; iii) predominant seizure type being focal impaired awareness seizures; iv) current or prior psychogenic non-epileptic seizures

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)
Randomisation and stimulation adjustments are conducted by a single, unblinded programmer, not responsible for study assessments. Clinical assessments and data collation are performed by separate clinicians, blinded to treatment group and voltage settings. Excluding the unblinded programmer, all study personnel, participants and carers remain blinded to treatment group until all data collation (all participants) are completed. Data remain locked until the unblinded programmer reveals which group each participant is assigned, once the last subjects has exited the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation occurs after implantation, prior to the stimulation phase, to either immediate stimulation (i.e., starting 3-months after implantation) or delayed-stimulation/control (i.e., starting 6-months after implantation) in a 1:1 ratio, stratified by age (below vs above 30 years of age).
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
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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] 20078 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 34786 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 309250 0
Government body
Name [1] 309250 0
National Health and Medical Research Council of Australia
Address [1] 309250 0
414 La Trobe St, Melbourne VIC 3000
Country [1] 309250 0
Australia
Primary sponsor type
Individual
Name
Associate Professor John ARCHER
Address
The University of Melbourne, Department of Medicine, Austin Health
Melbourne Brain Centre, 245 Burgundy Street, Heidelberg, Victoria 3084
Country
Australia
Secondary sponsor category [1] 310222 0
None
Name [1] 310222 0
Address [1] 310222 0
Country [1] 310222 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309095 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 309095 0
145 Studley Road, Heidelberg, Victoria 3084
Ethics committee country [1] 309095 0
Australia
Date submitted for ethics approval [1] 309095 0
Approval date [1] 309095 0
21/12/2016
Ethics approval number [1] 309095 0
HREC/16/Austin/139

Summary
Brief summary
Lennox-Gastaut syndrome (LGS) is a treatment-resistant form of childhood-onset generalised epilepsy, defined by multiple seizure types including tonic seizures, specific EEG abnormalities, and cognitive impairment. Anti-seizure medications are only partially effective and resective surgery is rarely an option, meaning new treatment approaches are needed. Deep brain stimulation (DBS) is an emerging treatment for drug-resistant epilepsies, which aims to modulate neuronal excitability across the distributed networks that underpin generalised epilepsies. Prior uncontrolled studies have reported seizure reductions following Deep Brain Stimulation (DBS) in patients with Lennox-Gastaut syndrome (LGS), but data from randomised controlled studies are lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for treatment of LGS. Electrical Stimulation of the Thalamus for Epilepsy of Lennox-Gastaut Phenotype (ESTEL) is the first randomised, double-blind, controlled study to evaluate the efficacy and safety of CM-DBS in a carefully characterised group of young adults with LGS. Due to the poor correlation between diary seizure counts and objective seizure frequencies, we also measure electrographic seizures (on 24-hour ambulatory EEG) at key timepoints (baseline, post-implantation/pre-stimulation, and post-stimulation. We perform cognitive assessments at these same timepoints and report safety outcomes in the 20 participants. We hypothesise that the proportion of participants with a 50% or greater reduction in seizures will be higher in those receiving 3-months of CM-DBS, compared to control participants (i.e., no stimulation).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112958 0
A/Prof John ARCHER
Address 112958 0
Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria
Country 112958 0
Australia
Phone 112958 0
+61 3 90357071
Fax 112958 0
Email 112958 0
jarcher@unimelb.edu.au
Contact person for public queries
Name 112959 0
A/Prof John ARCHER
Address 112959 0
Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria
Country 112959 0
Australia
Phone 112959 0
+61 3 90357071
Fax 112959 0
Email 112959 0
jarcher@unimelb.edu.au
Contact person for scientific queries
Name 112960 0
A/Prof John ARCHER
Address 112960 0
Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria
Country 112960 0
Australia
Phone 112960 0
+61 3 90357071
Fax 112960 0
Email 112960 0
jarcher@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
organisational ethics constraints
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 12665 0
Study protocol
Citation [1] 12665 0
Link [1] 12665 0
Email [1] 12665 0
Other [1] 12665 0
Type [2] 12666 0
Informed consent form
Citation [2] 12666 0
Link [2] 12666 0
Email [2] 12666 0
Other [2] 12666 0
Type [3] 12667 0
Ethical approval
Citation [3] 12667 0
Link [3] 12667 0
Email [3] 12667 0
Other [3] 12667 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary