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Trial registered on ANZCTR


Registration number
ACTRN12619000828123
Ethics application status
Approved
Date submitted
30/05/2019
Date registered
7/06/2019
Date last updated
20/11/2019
Date data sharing statement initially provided
7/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Resuscitation in Paediatric Sepsis Using Early Inotropes (RESPOND-ED)
Scientific title
Resuscitation in Paediatric Sepsis Using Early Inotropes– – A Randomized Controlled Trial to Assess Impact on Survival Free of Organ Dysfunction
Secondary ID [1] 298377 0
University of Queensland: 2019000089
Universal Trial Number (UTN)
Trial acronym
RESPOND-ED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 313047 0
Septic Shock 313048 0
Condition category
Condition code
Infection 311545 311545 0 0
Studies of infection and infectious agents
Emergency medicine 311546 311546 0 0
Resuscitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Early Inotropes:
Early Inotropes: Goal-Directed Therapy with initiation of intravenous inotropes after the initial fluid bolus (20ml/kg, minimal amount 10-20ml/kg fluid bolus; (or 500-1000ml fluid bolus in patients >50kg). The inotrope used is diluted adrenaline initiated at 0.05 to 0.1 (up to 0.3) mcg/kg/min. Dilution is used to fasten drug delivery and response to drug rate changes, to reduce risks with extravasation, and to facilitate peripheral application. Adrenaline will be prepared in 50ml syringes in 5% Dextrose solution that will be connected to peripheral, intraosseus, or central vascular access device. Drug delivery will occur through guardrails or similar system to ensure safe delivery of applied standardized drug concentrations.

The study treatment will be given as continuous infusion for the duration of resuscitation until resolution of shock, discharge from intensive care unit, death, decision of the treating physician to stop or replace with other inotrope, or occurrence of major side effects, whichever occurs first.
Compliance with protocol will be assessed through the prospective institutional drug charts, and the prospective study case report form
Intervention code [1] 314617 0
Treatment: Drugs
Comparator / control treatment
Standard Care:
Early Goal-Directed Therapy as per the institutional practice aligned with the most recent edition of the ACCCM recommendations for management of paediatric septic shock. Specifically, 40-60ml/kg of fluid will be administered prior to initating inotropes (>2-3L for patients >50kg). The inotrope used is diluted adrenaline initiated at 0.05 to 0.1 (up to 0.3) mcg/kg/min.
Control group
Active

Outcomes
Primary outcome [1] 320251 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] 320251 0
28 days after randomisation
Primary outcome [2] 320252 0
The primary outcome is defined as survival free of organ dysfunction, censored at 28 days.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form to assess organ dysfunction as defined by established organ dysfunction scoring using laboratory and clinical variables. Organ dysfunction will be defined as per the 2005 International Pediatric Sepsis Consensus Definition Conference criteria.
Timepoint [2] 320252 0
28 days after randomisation
Secondary outcome [1] 370987 0

PICU free survival at 7 and 28 days.

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [1] 370987 0
28 days from randomisation
Secondary outcome [2] 371204 0
Survival free of vasopressor support at 7 and 28 days

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [2] 371204 0
28 days from randomisation
Secondary outcome [3] 371205 0
Survival free of multiorgan dysfunction at 7 and 28 days

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [3] 371205 0
28 days from randomization
Secondary outcome [4] 371206 0
28-day mortality

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [4] 371206 0
28 days from randomization
Secondary outcome [5] 371207 0
Hospital length of stay

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [5] 371207 0
28 days from randomisation
Secondary outcome [6] 371208 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 [6] 371208 0

6 months from randomisation
Secondary outcome [7] 371209 0

Time to normalisation of lactate

We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [7] 371209 0
28 days from randomisation
Secondary outcome [8] 371210 0
Time to reversal of shock
We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [8] 371210 0
28 days from randomisation
Secondary outcome [9] 371211 0
Time to reversal of tachycardia
We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [9] 371211 0
28 days from randomisation
Secondary outcome [10] 371319 0
Functional Status 6 months post enrolment. Parents will be sent questionnaires by the study team. The questionnaires will be built using validated tools (Functional Status Score and age specific assessment).
Timepoint [10] 371319 0
6 months post randomisation
Secondary outcome [11] 377055 0
PICU length of stay. We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Timepoint [11] 377055 0
28 days from randomisation
Secondary outcome [12] 377056 0
Economic evaluation.
Evaluation will be undertaken from the health system perspective to compare the cost of providing the study interventions to that of usual care.
Resources to be measured and costed will include the number of length of stay (in PICU and/or non-intensive stay), and the length of hospital treatment.
Timepoint [12] 377056 0
For the duration of hospitalisation

Eligibility
Key inclusion criteria
Reword to:
Children age =>28days and <18 years where the decision is made by the treating physician to launch the institutional paediatric sepsis bundle treating for sepsis or septic shock. To be eligible, the child must have received at least 20ml/kg of intravenous fluid bolus(es) in the past four hours with the clinician deciding to continue treating for signs of shock.
Minimum age
28 Days
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Preterm babies born <34 weeks gestation that have a corrected age of <28 days
- Children who received =>40ml/kg of fluid during the 4 hours pre enrolment
- Children on Inotrope infusion
- Lack of access (intraosseus, central venous, peripheral) to administer fluids and/or inotropes after 60minutes of enrolment.
- Known cardiomyopathy or chronic cardiac failure
- Chronic hypertension due to cardiovascular or renal disease, requiring regular antihypertensive treatment.
- Known chronic renal failure
- Known chronic hepatic failure
- Palliative care patient/patient with limitation of treatment (not for inotropes, CPR, ECLS, intubation and ventilation)
- Cardiopulmonary arrest in the past two hours requiring CPR >2 min, or death is deemed to be imminent or inevitable during this admission.
- Major bleeding with haemorrhagic shock
- Sepsis is not likely to be the cause of shock
- Enrolment in RESPOND study <6 months ago (except for RESPOND ED randomization prior to RESPOND PICU within the same sepsis episode)

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)
No blinding 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 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 randomizsation. A permuted block randomizsation method with variable block sizes of 2, 4 and 6 and stratified by site will be used to allocate eligible patients to the treatment groups.
All eligible patients will be enrolled as soon as possible after fulfilling the criteria for randomizsation. Patients will be allocated in a 1:1 ratio to the treatment group (Intervention 1, receiving early inotropes versus standard fluid management).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
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 organ dysfunction 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 for the primary outcomes. Post-hoc power analyses may be undertaken to determine if results found in sub-group analyses are reliable.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
12/06/2019
Actual
21/07/2019
Date of last participant enrolment
Anticipated
30/11/2020
Actual
Date of last data collection
Anticipated
31/07/2021
Actual
Sample size
Target
80
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13860 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 13861 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 26631 0
4101 - South Brisbane
Recruitment postcode(s) [2] 26632 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 302912 0
Charities/Societies/Foundations
Name [1] 302912 0
Emergency Medicine Foundation
Country [1] 302912 0
Australia
Funding source category [2] 302913 0
Charities/Societies/Foundations
Name [2] 302913 0
Gold Coast Hospital Foundation
Country [2] 302913 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
St Lucia, Brisbane, Qld. 4072
Australia
Country
Australia
Secondary sponsor category [1] 302876 0
None
Name [1] 302876 0
Address [1] 302876 0
Country [1] 302876 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303484 0
Children's Health Queensland Hospital and Health Human Research Ethics Committee.
Ethics committee address [1] 303484 0
Ethics committee country [1] 303484 0
Australia
Date submitted for ethics approval [1] 303484 0
26/11/2018
Approval date [1] 303484 0
18/12/2018
Ethics approval number [1] 303484 0
HREC/18/QCHQ/49168

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

Contacts
Principal investigator
Name 93814 0
A/Prof Luregn Schlapbach
Address 93814 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93814 0
Australia
Phone 93814 0
+61 401054017
Fax 93814 0
n/a
Email 93814 0
l.schlapbach@uq.edu.au
Contact person for public queries
Name 93815 0
Luregn Schlapbach
Address 93815 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93815 0
Australia
Phone 93815 0
+61 401054017
Fax 93815 0
Email 93815 0
l.schlapbach@uq.edu.au
Contact person for scientific queries
Name 93816 0
Luregn Schlapbach
Address 93816 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93816 0
Australia
Phone 93816 0
+61 401054017
Fax 93816 0
Email 93816 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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Not available yet

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEarly Resuscitation in Paediatric Sepsis Using Inotropes - A Randomised Controlled Pilot Study in the Emergency Department (RESPOND ED): Study Protocol and Analysis Plan.2021https://dx.doi.org/10.3389/fped.2021.663028
EmbaseResuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan.2021https://dx.doi.org/10.3389/fped.2021.663435
N.B. These documents automatically identified may not have been verified by the study sponsor.