Trial Review

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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] 259792 0
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 261260 0
Neonatal seizures 261261 0
Hypoxic-ischemic encephalopathy (HIE) 261262 0
Condition category
Condition code
Neurological 259415 259415 0 0
Other neurological disorders
Reproductive Health and Childbirth 265617 265617 0 0
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] 258117 0
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] 262222 0
All cause mortality as assessed by data linkage to medical records.
Timepoint [1] 262222 0
At 2 years of age of participant unless death occurs during the intervention phase.
Primary outcome [2] 262223 0
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] 262223 0
At 2 years of age of participant.
Secondary outcome [1] 273574 0
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 [1] 273574 0
At 2 year follow up
Secondary outcome [2] 273573 0
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 [2] 273573 0
Discharge from hospital
Secondary outcome [3] 273350 0
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 [3] 273350 0
10 - 14 days of life
Secondary outcome [4] 273241 0
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 [4] 273241 0
10-14 days days of life.
Secondary outcome [5] 273575 0
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 [5] 273575 0
During in-patient period
Secondary outcome [6] 273572 0
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 [6] 273572 0
Two time points:

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

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?
No
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] 3661 0
3052
Recruitment postcode(s) [2] 3665 0
2031
Recruitment postcode(s) [3] 7783 0
4870 - Cairns
Recruitment postcode(s) [4] 3668 0
4029
Recruitment postcode(s) [5] 3670 0
7001
Recruitment postcode(s) [6] 3663 0
2050
Recruitment postcode(s) [7] 3662 0
2310
Recruitment postcode(s) [8] 3666 0
2605
Recruitment postcode(s) [9] 3669 0
5006
Recruitment postcode(s) [10] 3664 0
2145
Recruitment postcode(s) [11] 3667 0
4101
Recruitment postcode(s) [12] 7782 0
3168 - Clayton
Recruitment postcode(s) [13] 3671 0
6008
Recruitment outside Australia
Country [1] 5835 0
Singapore
State/province [1] 5835 0
Singapore
Country [2] 5834 0
Austria
State/province [2] 5834 0
Vienna

Funding & Sponsors
Funding source category [1] 264676 0
Government body
Name [1] 264676 0
National Health and Medical Research Council
Country [1] 264676 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Murdoch Childrens Research Institute
Address
Flemington Road
Parkville Victoria 3052
Country
Australia
Secondary sponsor category [1] 263810 0
None
Name [1] 263810 0
Address [1] 263810 0
Country [1] 263810 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 266670 0
The Royal Children's Hospital, Melbourne
Ethics committee address [1] 266670 0
Ethics committee country [1] 266670 0
Australia
Date submitted for ethics approval [1] 266670 0
04/04/2011
Approval date [1] 266670 0
22/06/2011
Ethics approval number [1] 266670 0
EC00238

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32234 0
A/Prof Rod Hunt
Address 32234 0
Professor of Neonatal Medicine
Monash University
5th Floor, Monash Children's Hospital
246 Clayton Road
CLAYTON
Victoria 3168
Country 32234 0
Australia
Phone 32234 0
+61 417274359
Fax 32234 0
Email 32234 0
rod.hunt@monash.edu
Contact person for public queries
Name 15481 0
Samantha Francis-Pester
Address 15481 0
Neonatal Research
Level 4, West Building
Murdoch Childrens Research Institute
The Royal Children's Hospital
50 Flemington Road
PARKVILLE Victoria 3052
Country 15481 0
Australia
Phone 15481 0
+61 3 9936 6684
Fax 15481 0
Email 15481 0
s.francispester@mcri.edu.au
Contact person for scientific queries
Name 6409 0
Rod Hunt
Address 6409 0
Professor in Neonatal Medicine
Monash University
5th Floor, Monash Children's Hospital
246 Clayton Road
CLAYTON
VIC 3168
Country 6409 0
Australia
Phone 6409 0
+61 417274359
Fax 6409 0
Email 6409 0
rod.hunt@monash.edu

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
rod.hunt@monash.edu


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15075Study protocol  rod.hunt@monash.edu
15076Ethical approval  rod.hunt@monash.edu


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial.2021https://dx.doi.org/10.1001/jamanetworkopen.2021.39604
N.B. These documents automatically identified may not have been verified by the study sponsor.