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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

23/12/2021

Date data sharing statement initially provided

13/09/2021

Date results provided

23/12/2021

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]

APP110881

Universal Trial Number (UTN)

Trial acronym

ESTEL

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Lennox-Gastaut Syndrome

Condition category

Condition code

Neurological

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]

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]

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]

month 6 post implantation = month 3 of blinded phase

Secondary outcome [1]

Proportion of participants with a >/= 50% reduction in electrographic seizures on 24-hour ambulatory scalp EEG at the end of blinded phase.

Timepoint [1]

Month 6 post-implantation = month 3 blinded phase.

Secondary outcome [2]

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]

Month 9 post-implantation = after 3 or 6 months stimulation (depending on whether in treatment or control arms.

Secondary outcome [3]

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]

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]

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]

Secondary outcome [5]

Global assessment of epilepsy severity (GASE)

Timepoint [5]

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]

Global assessment of epilepsy disability (GADS)

Timepoint [6]

Secondary outcome [7]

Adaptive behaviour Assessment system, 3rd edition (ABAS-III)

Timepoint [7]

Secondary outcome [8]

Safety - adverse events

Timepoint [8]

Recorded as they are reported (i.e. participant-reported) from implantation to study exit.

Secondary outcome [9]

Safety - serious adverse events

Timepoint [9]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/03/2017

Date of last participant enrolment

Anticipated

Actual

1/09/2019

Date of last data collection

Anticipated

Actual

1/08/2020

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council of Australia

Address [1]

414 La Trobe St, Melbourne VIC 3000

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

145 Studley Road, Heidelberg, Victoria  3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

21/12/2016

Ethics approval number [1]

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

A/Prof John ARCHER

Address

Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria

Country

Australia

Phone

+61 3 90357071

Fax

[email protected]

Contact person for public queries

Name

John ARCHER

Address

Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria

Country

Australia

Phone

+61 3 90357071

Fax

[email protected]

Contact person for scientific queries

Name

John ARCHER

Address

Melbourne Brain Centre, 245 Burgundy Street Heidelberg 3084 Victoria

Country

Australia

Phone

+61 3 90357071

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

organisational ethics constraints

What supporting documents are/will be available?

Doc. No.	Type	Attachment
12665	Study protocol	382475-(Uploaded-09-08-2021-21-05-10)-Study-related document.docx
12666	Informed consent form	382475-(Uploaded-09-08-2021-21-08-18)-Study-related document.docx
12667	Ethical approval	382475-(Uploaded-26-07-2021-12-55-43)-Study-related document.pdf

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	Cognition, adaptive skills and epilepsy disability/severity in patients with Lennox-Gastaut syndrome undergoing deep brain stimulation for epilepsy in the ESTEL trial.	2022	https://dx.doi.org/10.1016/j.seizure.2022.07.014
Embase	DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial).	2022	https://dx.doi.org/10.1002/ana.26280
Embase	Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome.	2022	https://dx.doi.org/10.1111/epi.17414
Embase	The Optimal Target and Connectivity for Deep Brain Stimulation in Lennox-Gastaut Syndrome.	2022	https://dx.doi.org/10.1002/ana.26368

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically