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Trial registered on ANZCTR


Registration number
ACTRN12619001518156
Ethics application status
Approved
Date submitted
15/07/2019
Date registered
4/11/2019
Date last updated
4/11/2019
Date data sharing statement initially provided
4/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Nitric Oxide on ExtraCorporeal Membrane Oxygenation – a randomised Trial in neonates and children (NECTAR trial).
Scientific title
Nitric Oxide on ExtraCorporeal Membrane Oxygenation – a randomised Trial in neonates and children (NECTAR trial).
Secondary ID [1] 297266 0
Nil known
Universal Trial Number (UTN)
NA
Trial acronym
NECTAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular failure requiring Extracorporeal Membrane Oxygenation 311585 0
Respiratory failure requiring Extracorporeal Membrane Oxygenation 311586 0
Condition category
Condition code
Respiratory 310215 310215 0 0
Other respiratory disorders / diseases
Cardiovascular 310216 310216 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients allocated to the study gas arm will receive nitric oxide (NO), which will be blended into the fresh gas flow for the ECMO oxygenator and maintained at 20 ppm.
ECMO specialists and/or Perfusionists will administer the study drug via a Nitric Oxide delivery system (such as SoKinox provided by Air Liquide Healthcare) with continuous sampling of NO and NO2 concentration from an access port just prior to the oxygenator.
NO will be started when the patient is cannulated for ECMO and ceased once patient is off ECMO.
The duration of the intervention should be equal to the duration of ECMO (i.e. several days). ECMO specialists and/or Perfusionists will record electronically the start time and stop time of the study drug.
Patients allocated to the intervention arm will receive standard respiratory gases (oxygen-air mix) during ECMO as per institutional practice.
Compliance with protocol will be assessed through the prospective institutional drug charts, and the prospective study case report form.
Intervention code [1] 313664 0
Treatment: Drugs
Comparator / control treatment
Patients allocated to the control arm will receive standard respiratory gases (oxygen-air mix) without Nitric Oxide during ECMO as per institutional practice.
Control group
Active

Outcomes
Primary outcome [1] 319099 0
The main feasibility outcome is compliance with study protocol during the pilot.

We will assess the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form to assess compliance with the study protocol.
Timepoint [1] 319099 0
30 days after randomisation.
Primary outcome [2] 320721 0
The primary outcome is defined as survival free of ECMO, censored at 90 days post randomisation. Patients dying within 90 days of presentation will be considered as zero days to correct for the competing effect of mortality on ECMO free survival.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form to assess ECMO use and survival status.
Timepoint [2] 320721 0
90 days after randomisation.
Secondary outcome [1] 366972 0
Survival free of ECMO, censored at 30 days post randomisation. Patients dying within 30 days of presentation will be considered as zero days to correct for the competing effect of mortality on ECMO free survival.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form to assess ECMO use and survival status.
Timepoint [1] 366972 0
30 days after randomisation.
Secondary outcome [2] 372605 0
PICU free survival censored at 90 days

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [2] 372605 0
90 days after randomisation.
Secondary outcome [3] 372606 0
Length of hospital stay post randomization

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [3] 372606 0
For the duration of hospitalization after randomisation.
Secondary outcome [4] 372607 0
Composite outcome of average daily blood product usage (in ml/kg/day) during ECMO, including red blood cells, cryoprecipitate, platelets, and fresh frozen plasma.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form.
Timepoint [4] 372607 0
Duration of the ECMO run
Secondary outcome [5] 372608 0
Bleeding complications during the ECMO run.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form.
Timepoint [5] 372608 0
Daily assessment during the duration of the ECMO run post randomization
Secondary outcome [6] 372609 0
Exploratory analyses will investigate host systemic inflammation measured by cytokine levels post cannulation at 0, 12, and 24hours using blood stored at each of the time points.
Timepoint [6] 372609 0
The first 24hours of cannulation
Secondary outcome [7] 372610 0
Quality of life 6 months post enrolment

Parents will be sent questionnaires by the study team. The questionnaires will be built using validated tools (Pediatric Quality of Life).
Timepoint [7] 372610 0
6 months from randomisation
Secondary outcome [8] 372611 0
Functional Status 6 months post enrolment.

Parents will be sent questionnaires by the study team.
Timepoint [8] 372611 0
6 months post randomization
Secondary outcome [9] 372612 0
Direct health care costs.

Health care costs will be extracted from the hospital financial records for each of the ECMO-related admissions.
Timepoint [9] 372612 0
Duration of hospital stay from randomization

The outcome will be censured 90d after recruitment of the last patient into the study.
Secondary outcome [10] 376302 0
Clotting complications during the ECMO run.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form.
Timepoint [10] 376302 0
Daily for the duration of the ECMO run post randomization

Eligibility
Key inclusion criteria
1. All neonates and children < 18 years requiring ECMO for respiratory or cardiovascular dysfunction including extracorporeal cardiopulmonary resuscitation (eCPR)
2. Ability to obtain prospective consent or consent to continue from parents/guardian.
Minimum age
0 Days
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients retrieved to PICU on ECMO who did not undergo randomisation during cannulation
2. Pre-existing methaemoglobinemia (MetHb>3%)
3. Anticipated inability to obtain parental consent (prospective consent or consent to continue)
4. Patients managed on ventricular assist device (VAD) only without an oxygenator present in the ECMO circuit

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)
Allocation concealement will be done by sealed envelopes containing the intervention allocation information.

No blinding of the intervention will be performed, intervention will be open labelled. The main aim of this pilot study is to define the feasibility of treatment. To ensure preliminary evidence of safety can be provided, and reduce the logistic challenges with blinding of a medical gas in an acute care situation, it is acceptable to perform this pilot open label.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be enrolled as soon as possible after fulfilling the criteria for randomisation. A permuted block randomisation method with variable block sizes of 2, 4 and 6 will be used to allocate eligible patients to the treatment group.
All eligible patients will be enrolled as soon as possible after fulfilling the criteria for randomisation. Patients will be allocated in a 1:1 ratio to the treatment group (receiving NO on ECMO versus standard ECMO management).
The randomisation will be stratified into two arms, with patients requiring veno-venous ECMO support being randomised in one strata, and patients requiring veno-venous ECMO support being randomised in the other.
Where conversion of VV to VA and VA to VV occurs patients will remain in the initial randomisation arm. Where a second ECMO run is commenced after decannulation the patient is randomised again.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive statistics will be utilised to report on the baseline characteristics of the total study cohort and each subgroup, as well as by site. The primary outcome measure investigating days free of ECMO will be analysed using a Mann-Whitney test (assuming the data is non-normally distributed). Analysis of secondary outcomes includes both comparisons of measurements and proportions, using confidence intervals of differences as the major method of presentation where possible, otherwise standard techniques such as Mann-Whitney U tests, t-tests and chi-squared tests will be utilised. Main analyses will be by intention-to-treat. Per-protocol analyses will be performed as well and compared to intention-to-treat. Statistical significance will be set at the 0.05 level. Post-hoc power analyses may be undertaken to determine if results found in sub-group analyses are reliable.

Recruitment
Recruitment status
Not yet recruiting
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)
QLD
Recruitment postcode(s) [1] 27214 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 301826 0
Charities/Societies/Foundations
Name [1] 301826 0
Children`s Hospital Foundation
Address [1] 301826 0
Children’s Hospital Foundation
494 Stanley St,
South Brisbane QLD 4101
Country [1] 301826 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
St Lucia, Brisbane, Qld. 4072
Australia
Country
Australia
Secondary sponsor category [1] 303313 0
None
Name [1] 303313 0
Address [1] 303313 0
Country [1] 303313 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302529 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 302529 0
CHILDREN’S HEALTH QUEENSLAND HOSPITAL AND HEALTH SERVICE HUMAN RESEARCH ETHICS COMMITTEE
Level 7, Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
62 Graham Street, South Brisbane QLD 4101
Telephone (07) 3069 7002
Ethics committee country [1] 302529 0
Australia
Date submitted for ethics approval [1] 302529 0
26/11/2018
Approval date [1] 302529 0
19/12/2018
Ethics approval number [1] 302529 0
St Lucia, Brisbane, Qld. 4072 Australia

Summary
Brief summary
This pilot pragmatic open label randomized controlled Trial (RCT) compares the use of Nitric Oxide (NO) treatment blended into the oxygenator of the Extracorporeal Membrane Oxygenation (ECMO) circuit in comparison to standard care defined as no treatment with NO into the ECMO circuit. We hypothesize that in children treated with ECMO, a randomized trial investigating the use of NO during ECMO is feasible. We hypothesize that neonates and children on ECMO exposed to NO on ECMO have a reduced rate of clotting and bleeding complication and reduced inflammatory response measured by various clotting markers as well as serum cytokine levels in comparison to controls, leading to shorter ECMO run duration and reduced health care costs.
The findings could have major potential to improve patient-centered outcomes and reduce health care costs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90534 0
A/Prof Luregn Schlapbach
Address 90534 0
Paediatric Intensive Care Unit,
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 90534 0
Australia
Phone 90534 0
+61 7 3068 11 11
Fax 90534 0
N/A
Email 90534 0
l.schlapbach@uq.edu.au
Contact person for public queries
Name 90535 0
Dr Adrian Mattke
Address 90535 0
Paediatric Intensive Care Unit,
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 90535 0
Australia
Phone 90535 0
+61 7 3068 11 11
Fax 90535 0
N/A
Email 90535 0
adrian.mattke@health.qld.gov.au
Contact person for scientific queries
Name 90536 0
A/Prof Luregn Schlapbach
Address 90536 0
Paediatric Intensive Care Unit,
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 90536 0
Australia
Phone 90536 0
+61 7 3068 11 11
Fax 90536 0
N/A
Email 90536 0
l.schlapbach@uq.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
Not available at present, review once recruiting commenced and feasibility is confirmed
What supporting documents are/will be available?
No other documents available
Summary results
No Results