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Trial registered on ANZCTR


Registration number
ACTRN12619000829112
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 Metabolic Support (RESPOND-PICU)
Scientific title
Resuscitation in Paediatric Sepsis Using Metabolic Support– A Randomized Controlled Trial to Assess Impact on Survival Free of Organ Dysfunction
Secondary ID [1] 298379 0
University of Queensland: 2019000089
Universal Trial Number (UTN)
N/A
Trial acronym
RESPOND- PICU
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Sepsis 313053 0
Septic Shock 313054 0
Condition category
Condition code
Infection 311549 311549 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Early Metabolic Resuscitation: After initial shock treatment including fluids and a first intravenous inotrope patients receive concomitant treatment with Hydrocortisone, Vitamin C, and Thiamine:
1. Ascorbic acid (Vitamin C). The dosing schedule is 30mg/kg intravenously every 6 hours for the duration of study treatment and will be infused over 1 hour.
2. Thiamine (Vitamin B1): The dosing schedule is 4mg/kg intravenously every 12 hours for the duration of study treatment and will be infused over 1 hour.
3. Hydrocortisone: The dosing schedule is 1mg/kg intravenously every 6 hours for the duration of study treatment given as a slow bolus.
Study drugs will be given through an existing intravenous line using. Drug delivery will occur through guardrails or similar system to ensure safe delivery of applied standardized drug concentrations.
Study treatments will be given for a duration of 7 days, or until resolution of shock, discharge from intensive care unit, death, 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] 314622 0
Treatment: Drugs
Comparator / control treatment
Standard care: Patients in the standard treatment arm of the study can receive Hydrocortisone or Thiamine only if clinically indicated at the discretion of the attending ICU staff specialist.
Control group
Active

Outcomes
Primary outcome [1] 320258 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] 320258 0
28 days after randomisation
Primary outcome [2] 320259 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] 320259 0
28 days after randomisation
Secondary outcome [1] 371006 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] 371006 0
28 days from randomisation
Secondary outcome [2] 371186 0
Survival free of vasopressor support at 7 and 28 days
Timepoint [2] 371186 0
We will access the prospective hospital charts (including electronic health records and paper-based charts) and the study case report form
Secondary outcome [3] 371187 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] 371187 0
28 days from randomization
Secondary outcome [4] 371198 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] 371198 0
28 days from randomisation
Secondary outcome [5] 371199 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] 371199 0
28 days from randomisation
Secondary outcome [6] 371200 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] 371200 0
6 months from randomisation
Secondary outcome [7] 371201 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] 371201 0
28 days from randomisation
Secondary outcome [8] 371202 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] 371202 0
28 days from randomisation
Secondary outcome [9] 371203 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] 371203 0
28 days from randomisation
Secondary outcome [10] 371320 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] 371320 0
6 months post randomization
Secondary outcome [11] 377053 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] 377053 0
28 days from randomisation
Secondary outcome [12] 377054 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] 377054 0
For the duration of hospitalisation

Eligibility
Key inclusion criteria
Children age =>28 days and <18 years which are admitted to the Paediatric Intensive Care Unit with a diagnosis of suspected septic shock requiring vasopressors/inotropes for >2hours (i.e. fluid-refractory shock).
Minimum age
28 Days
Maximum age
17 Years
Gender
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
- Known chronic renal failure not related to sepsis
- Known chronic hepatic failure not related to sepsis
- Known diseases affecting the steroid axis, including pituitary disease, congenital adrenal hypoplasia, Cushing or Addison’s disease
- 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
- Major bleeding with haemorrhagic shock
- Sepsis is not likely to be the cause of shock
- Known glucose-6 phosphate dehydrogenase (G-6PD) deficiency
- Patients with sepsis/septic shock transferred form another ICU or hospital who have been treated with inotropes for septic shock for >24 hours
- Patients with known history of oxalate nephropathy
- Patients with acute beri-beri disease
- Patients with acute Wernike’s encephalopathy
- Patients with known malaria
- Patients with known of suspected scurvy
- Patient is receiving treatment for systemic fungal infection or has documented strongyloides infection at the time of randomization
- Patient undergoing active chemotherapy for cancer treatment (incl. all administration routes)
- 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 total of three medications 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 and stratified by site 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 early metabolic resuscitation versus standard shock 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
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 hospital [1] 13878 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 13879 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 26650 0
4101 - South Brisbane
Recruitment postcode(s) [2] 26651 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 302915 0
Charities/Societies/Foundations
Name [1] 302915 0
Emergency Medicine Foundation
Address [1] 302915 0
Suite 1b, Terraces, 19 Lang Parade Milton, QLD, 4064
Country [1] 302915 0
New Zealand
Funding source category [2] 302916 0
Charities/Societies/Foundations
Name [2] 302916 0
Gold Coast Hospital Foundation
Address [2] 302916 0
Gold Coast University Hospital 1 Hospital Boulevard Southport, QLD 4215. Australia PO Box 23
Country [2] 302916 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
St Lucia, Brisbane, Qld. 4072
Australia
Country
Australia
Secondary sponsor category [1] 302878 0
None
Name [1] 302878 0
N/A
Address [1] 302878 0
N/A
Country [1] 302878 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303486 0
Children's Health Queensland Hospital and Health Human Research Ethics Committee
Ethics committee address [1] 303486 0
62 Graham St, South Brisbane, QLD. 4101
Ethics committee country [1] 303486 0
Australia
Date submitted for ethics approval [1] 303486 0
26/11/2018
Approval date [1] 303486 0
18/12/2018
Ethics approval number [1] 303486 0
HREC/18/QCHQ/49168

Summary
Brief summary
This multicentre pilot pragmatic open label randomized controlled Trial (RCT) compares early metabolic resuscitation treatment with Hydrocortisone, Vitamin C, and Thiamine in comparison to standard care defined as no treatment with Hydrocortisone, Vitamin C, and Thiamine. We hypothesize that in children presenting with sepsis and septic shock early intravenous administration of Vitamin C (30mg/kg iv q6h), Thiamine (4mg/kg q12h) and Hydrocortisone (1mg/kg q6h) delivered early during resuscitation is feasible. We hypothesize that these interventions will lead to a more rapid resolution of shock, reduced duration of organ dysfunction, leading to reduced intensive care resource utilisation.
The study can provide the urgently needed evidence on currently used sepsis resuscitation bundles.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes
N/A

Contacts
Principal investigator
Name 93822 0
A/Prof Luregn Schlapbach
Address 93822 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93822 0
Australia
Phone 93822 0
+61 401054017
Fax 93822 0
N/A
Email 93822 0
l.schlapbach@uq.edu.au
Contact person for public queries
Name 93823 0
A/Prof Luregn Schlapbach
Address 93823 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93823 0
Australia
Phone 93823 0
+61 401054017
Fax 93823 0
N/A
Email 93823 0
l.schlapbach@uq.edu.au
Contact person for scientific queries
Name 93824 0
A/Prof Luregn Schlapbach
Address 93824 0
Level 4, Queensland Children's Hospital
Stanley Street
South Brisbane, QLD 4101
Country 93824 0
Australia
Phone 93824 0
+61 401054017
Fax 93824 0
N/A
Email 93824 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