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Trial registered on ANZCTR

Registration number

ACTRN12611000327987

Ethics application status

Approved

Date submitted

16/03/2011

Date registered

28/03/2011

Date last updated

14/02/2022

Date data sharing statement initially provided

14/02/2022

Date results provided

14/02/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

A study of the impact of treating seizures that can be seen and those that can be seen only on a brain monitor in newborn babies, who are having seizures or at high risk of seizures.

Scientific title

A randomised controlled trial comparing the treatment of electrographic seizures and clinical seizures, to the treatment of clinical seizures alone, in term or near-term infants and measuring the impact on death and neurodevelopment at 2 years.

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-111914884

Trial acronym

NEST (Neonatal Electrographic Seizure Trial)

Linked study record

Health condition

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

Neonatal Encephalopathy

Neonatal seizures

Hypoxic-ischemic encephalopathy (HIE)

Condition category

Condition code

Neurological

Other neurological disorders

Reproductive Health and Childbirth

Complications of newborn

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Amplitude integrated electroencephalography monitoring will be applied to consented newborn infants admitted to participating Neonatal Intensive Care Units. Infants will be randomized into two groups:

(1) Clinical seizure group (CSG) - infants who will recieve treatment of clinical seizures alone - this is standard treatment (electrographic seizures will not be revealed to the treating physician).

(2) Electrographic seizure group (ESG) - infants who will be treated for both clinical and electrographic seizures. Electrographic seizures will be detected by a bedside amplitude integrated EEG (aEEG) monitor. Monitoring will be applied for five days.

Treatment of seizures in both groups will follow a strict alogrithim based on current standard practice. Anticonvulsants used will include phenobarbitone, phenytoin and midazolam at standard clinical dosage.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Standard Treatment (Clinical seizure group) - The comparator used is the treatment of seizures detected on clinical seizure activity alone which is the standard of care in most Neonatal Intensive Care Units.
A conventional EEG(electroencephologram) will be taken for one hour at the first available opportunity to ensure infants are not in non-convulsive status epilepticus (infant will be withdrawn from the study if status is verified) and decisions to obtain further EEG's will be at the discretion of the primary medical team as per standard care.

Control group

Active

Outcomes

Primary outcome [1]

All cause mortality as assessed by data linkage to medical records.

Timepoint [1]

At 2 years of age of participant unless death occurs during the intervention phase.

Primary outcome [2]

Severe disability as defined as motor and/or cognitive delay more than two standard deviations (2sd = 30) below the Australian population mean (ie 108 - 30 = 78) measure with the Bayley Scales of Infant Development, 3rd Edition.

Timepoint [2]

At 2 years of age of participant.

Secondary outcome [1]

MRI injury was scored with a modification of the scoring system published by Weeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, van Haastert IC, Benders MJ, Hallberg B and de Vries LS. A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. The Journal of Pediatrics 2018; 192: 33-40.

Timepoint [1]

10-14 days days of life.

Secondary outcome [2]

Seizure burden - will be measured as the total duration of electrographic seizures for the duration of the intervention phase. Accumulative total number of seizure seconds will be calculated from the aEEG and recorded on the appropriate CRF.

Timepoint [2]

10 - 14 days of life

Secondary outcome [3]

Anti-convulsant use - throughout the inpatient period, anti-convulsant use will be entered daily into the CRF. Data verification will be performed using the participants medical records. Total dosage in mg/kg of each anticonvulsant used during initial inpatient stay will be recorded.

At 2 year follow up, anti-convulsant use will be assessed from parent recall/reporting and through access to the participants medical record. This data will be entered into the appropriate CRF.

Timepoint [3]

Two time points:

1. During in-patient period
2. At 2 year follow up

Secondary outcome [4]

Length of inpatient stay during initial admission- will be calculated from recorded time of admission to recorded time of discharge (Hours/Days) as per the participants medical record. This figure will be entered into the appropriate CRF.

Timepoint [4]

Discharge from hospital

Secondary outcome [5]

Development of epilepsy - will be assessed from parent reporting and medical record data. This outcome will be dependent upon the participant fulfilling the clinical diagnosis of epilepsy ascribed by the treating paediatrician or neurologist. This diagnosis will be recorded on the appropriate CRF.

Timepoint [5]

At 2 year follow up

Secondary outcome [6]

Time to full suck feeds - will be assessed and verified from the participants medical record and clinical medical/nursing team. Participants will be assessed as having achieved full suck feeds when they are able to suck all of their feeds for a full 24 hour period, without supplemental feeds via a nasogastric tube.

Timepoint [6]

During in-patient period

Eligibility

Key inclusion criteria

Infants greater than or equal to 35 weeks' gestation (term or near term) admitted to a participating Neonatal Intensive Care Unit.
Less than or equal to 48 hours old:
A diagnosis of either:
-Neonatal encephalopathy including coma, stupor or depressed mental state (based on modified Sarnat classification II-III).
-Hypoxic-ischaemic encephalopathy or at risk for hypoxic-ischaemic encephalopathy (ie. 2 of the following - Apgar score less than 5 at 5 minutes); cord blood gas or postnatal blood gas within 1 hour of birth with a pH less than 7.1 or base excess < -12 within 1 hour of birth; need for ongoing respiratory support at 10 minutes after birth)
-suspected neonatal seizures

Minimum age

1 Hours

Maximum age

48 Hours

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Infants less than 35 weeks gestation;

Greater than 48 hours old;

Infants in non-convulsive status (as confirmed by conventional electroencephalography taken for one hour as soon as practical);

Infants diagnosed with Cerebral dysgenesis

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)

Potential subjects will be identified by study staff located at participating sites and the parents will be approached to determine their interest in participation in the project. Those parents who express interest will be provided with an information statement and consent form. All ethical and ICH/GCP procedures will be adhered to in respect to the consent process.

Once informed consent has been obtained by the Principal Investigator or his/her delegate, the infant will be randomized by the site via a web based randomisation procedure available 24 hours per day. Should access to the internet be disrupted for any reason, investigators will be able to call the Coorodinating centre on a mobile number for manual randomisation.

Investigators will be required to enter basic subject data such as age, gender, diagnosis at the time of randomisation. Treatment allocation will then be computer generated. Investigators will not be able to influence treatment allocation.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation has been stratified by diagnosis - Hypoxic-ischemic encephalopathy or other. Therefore, there will be 2 strata.

Treatment allocation is then computer generated using block randomisation with variable block sizes by an independent statistician.

Masking / blinding

Who is / are masked / blinded?

The people assessing the outcomes

Intervention assignment

Parallel

Other design features

Due to the design of this study it is not possible to conceal treatment allocation from the parents or the treating clinicians as it will be obvious which infants have their monitor covered.

However, at the 2 year follow up the psychologist conducting the assessment of the primary outcome, will effectively be blinded to treatment allocations as they will not have been involved in the inpatient care of the participating infants and parents will be asked not to reveal their treatment allocation to the psychologist.

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Participant recruitment difficulties

Date of first participant enrolment

Anticipated

20/09/2011

Actual

20/09/2011

Date of last participant enrolment

Anticipated

18/12/2015

Actual

12/02/2016

Date of last data collection

Anticipated

30/05/2018

Actual

30/05/2018

Sample size

Target

630

Accrual to date

Final

212

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,TAS,WA,VIC

Recruitment postcode(s) [1]

3052

Recruitment postcode(s) [2]

2310

Recruitment postcode(s) [3]

2050

Recruitment postcode(s) [4]

2145

Recruitment postcode(s) [5]

2031

Recruitment postcode(s) [6]

2605

Recruitment postcode(s) [7]

4101

Recruitment postcode(s) [8]

4029

Recruitment postcode(s) [9]

5006

Recruitment postcode(s) [10]

7001

Recruitment postcode(s) [11]

6008

Recruitment postcode(s) [12]

3168 - Clayton

Recruitment postcode(s) [13]

4870 - Cairns

Recruitment outside Australia

Country [1]

Austria

State/province [1]

Vienna

Country [2]

Singapore

State/province [2]

Singapore

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Charities/Societies/Foundations

Name

Murdoch Childrens Research Institute

Address

Flemington Road
Parkville Victoria 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Children's Hospital, Melbourne

Ethics committee address [1]

50 Flemington Road
PARKVILLE Victoria 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/04/2011

Approval date [1]

22/06/2011

Ethics approval number [1]

EC00238

Summary

Brief summary

Doctors know that seizures occur more often in babies than older children. Seizures in babies may result in damage to their brain that may lead to epilepsy or affect their learning, thinking and memory. There is not a lot of research as to the best way to treat seizures in babies and to protect their brain function.

The aim of this research project is to compare the treatment of seizures that are physically seen by doctors and nurses (standard clinical care) to when seizures are detected using an amplitude integrated electroencephalograph monitor (aEEG), to see which method is better at protecting brain function in the longer term.

We hope a total of 630 babies will take part in this study. Half of the babies will receive standard treatment and half will be treated when a seizure is seen on the aEEG monitor. After the babies have been discharged from hospital we will follow them up at 2 years of age to assess their development. 

This research project is important because it may change the way doctors treat seizures in babies in the future, and we want to make sure that our treatment is protecting the babies brain.

Trial website

Trial related presentations / publications

Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, Francis-Pester S, deWaal K, Cheong JYL, Olischar M, Badawi N, Wong FY, Osborn DA, Rajadurai VS, Dargaville PA, Headley B, Wright I, Colditz PB for the Newborn Electrographic Seizure Trial Investigators. Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates: A randomized controlled trial. JAMA Network Open 2021; 4(12): e2139604. DOI: 10.1001/jamanetworkopen.2021.39604

Public notes

Contacts

Principal investigator

Name

A/Prof Rod Hunt

Address

Professor of Neonatal Medicine
Monash University
5th Floor, Monash Children's Hospital
246 Clayton Road
CLAYTON
Victoria 3168

Country

Australia

Phone

+61 417274359

Fax

[email protected]

Contact person for public queries

Name

Samantha Francis-Pester

Address

Neonatal Research
Level 4, West Building
Murdoch Childrens Research Institute
The Royal Children's Hospital
50 Flemington Road
PARKVILLE Victoria 3052

Country

Australia

Phone

+61 3 9936 6684

Fax

[email protected]

Contact person for scientific queries

Name

Rod Hunt

Address

Professor in Neonatal Medicine
Monash University
5th Floor, Monash Children's Hospital
246 Clayton Road
CLAYTON
VIC 3168

Country

Australia

Phone

+61 417274359

Fax

[email protected]

Data sharing statement

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

Yes

What data in particular will be shared?

protocol, de-identified individual participant data of published results only

When will data be available (start and end dates)?

on publication of the primary manuscript - published on 17.12.21; data available for 5 years after publication.

Available to whom?

Relevant researchers conducting systematic reviews.

Available for what types of analyses?

systematic review with meta-analysis, or IPD meta-analysis

How or where can data be obtained?

by contacting the PI, Professor Rod Hunt at
[email protected]

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
15075	Study protocol			[email protected]
15076	Ethical approval			[email protected]

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	Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial.	2021	https://dx.doi.org/10.1001/jamanetworkopen.2021.39604

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

Trial Review

Documents added manually

Documents added automatically