ANZCTR - Registration

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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]

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

Septic Shock

Condition category

Condition code

Infection

Studies of infection and infectious agents

Emergency medicine

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]

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]

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]

28 days after randomisation

Primary outcome [2]

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]

28 days after randomisation

Secondary outcome [1]

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]

28 days from randomisation

Secondary outcome [2]

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]

28 days from randomisation

Secondary outcome [3]

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]

28 days from randomization

Secondary outcome [4]

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]

28 days from randomization

Secondary outcome [5]

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]

28 days from randomisation

Secondary outcome [6]

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]

6 months from randomisation

Secondary outcome [7]

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]

28 days from randomisation

Secondary outcome [8]

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]

28 days from randomisation

Secondary outcome [9]

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]

28 days from randomisation

Secondary outcome [10]

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]

6 months post randomisation

Secondary outcome [11]

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]

28 days from randomisation

Secondary outcome [12]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Queensland Children's Hospital - South Brisbane

Recruitment hospital [2]

Gold Coast University Hospital - Southport

Recruitment postcode(s) [1]

4101 - South Brisbane

Recruitment postcode(s) [2]

4215 - Southport

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Emergency Medicine Foundation

Address [1]

Suite 1b, Terraces, 19 Lang Parade Milton, QLD, 4064

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Gold Coast Hospital Foundation

Address [2]

Gold Coast University Hospital 1 Hospital Boulevard Southport, QLD 4215. Australia PO Box 23

Country [2]

Australia

Primary sponsor type

University

Name

University of Queensland

Address

St Lucia, Brisbane, Qld. 4072
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Children's Health Queensland Hospital and Health Human Research Ethics Committee.

Ethics committee address [1]

62 Graham St, South Brisbane, QLD. 4101

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/11/2018

Approval date [1]

18/12/2018

Ethics approval number [1]

HREC/18/QCHQ/49168

Summary

Brief summary

 In view of the potential harm related to high volume fluid administration in septic shock, fluid-sparing algorithms using early intravenous inotropes to treat shock have been proposed as an alternative strategy. This multicentre pilot pragmatic open label randomized controlled Trial (RCT) compares early inotropes started after 20ml/kg fluid resuscitation with standard care defined as providing up to 40-60ml/kg fluid resuscitation prior to initiation of inotropes as per the American College of Critical Care Medicine recommendations.
We hypothesize that in children presenting with sepsis and septic shock, a fluid-sparing algorithm using early inotropes delivered early during resuscitation is feasible and will lead to a more rapid resolution of shock and reduced duration of organ  dysfunction.

Trial website

N/A

Trial related presentations / publications

N/A

Public notes

N/A

Contacts

Principal investigator

Name

A/Prof Luregn Schlapbach

Address

Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101

Country

Australia

Phone

+61 401054017

Fax

n/a

[email protected]

Contact person for public queries

Name

Luregn Schlapbach

Address

Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101

Country

Australia

Phone

+61 401054017

Fax

[email protected]

Contact person for scientific queries

Name

Luregn Schlapbach

Address

Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101

Country

Australia

Phone

+61 401054017

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

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Plain language summary	No		Not available yet

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Early Resuscitation in Paediatric Sepsis Using Inotropes - A Randomised Controlled Pilot Study in the Emergency Department (RESPOND ED): Study Protocol and Analysis Plan.	2021	https://dx.doi.org/10.3389/fped.2021.663028
Embase	Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan.	2021	https://dx.doi.org/10.3389/fped.2021.663435

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

Trial Review

Documents added manually

Documents added automatically