Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000247875
Ethics application status
Approved
Date submitted
13/01/2021
Date registered
8/03/2021
Date last updated
21/04/2025
Date data sharing statement initially provided
8/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the Efficacy of Treatment with Vitamin C and Hydrocortisone in Children Admitted to Intensive Care Unit with Septic Shock.
Scientific title
Resuscitation in Paediatric Sepsis using Vitamin C and Hydrocortisone - A Randomized Controlled Multicentre Trial - assessing the effect on time alive and free of vasopressors
Secondary ID [1] 303154 0
None
Universal Trial Number (UTN)
The Universal Trial Number (UTN) is U1111-1263-7736
Trial acronym
RESPOND Study
Linked study record
ACTRN12619000829112 was a the pilot study. The current RESPOND study is the full multi-centre RCT.

Health condition
Health condition(s) or problem(s) studied:
Sepsis 320272 0
Septic Shock 320273 0
Condition category
Condition code
Infection 318200 318200 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be allocated in a 1:1:1 ratio to the RESPOND treatment groups.
Arm 1 - Intervention 1 - Early intravenous resuscitation with Vitamin C and Hydrocortisone.
After initial shock treatment including fluids and a first intravenous inotrope, patients then receive concomitant treatment with Vitamin C and Hydrocortisone.
Ascorbic acid (Vitamin C): the dosing schedule is 100 mg/kg (maximum 5,000 mg per dose) intravenously every 6 hours for the duration of study treatment and will be infused over 60 minutes.

Hydrocortisone: The dosing schedule is 1 mg/kg (maximum 50 mg per dose) intravenously infused over 5 minutes every 6 hours for the duration of study treatment given as a slow bolus.

Arm 2 - Intervention 2 - Hydrocortisone only.
Hydrocortisone: the dosing schedule is 1mg/kg (maximum 50 mg per dose) intravenously infused over 5 minutes every 6 hours for the duration of study treatment given as a slow bolus.

All three arms will be monitored for adherence to interventions by a formal data monitoring and audit of the medication records.

Duration of treatment
After shock resolution - defined as cessation of inotropes for at least 4 hours - or after a maximum of 72hours study drugs should be ceased. The treatment will continue until (whichever occurs first):
- Septic shock resolves defined as ability to cease inotropes for less than 4 hours with good perfusion and no signs of shock.
- 72 hours of treatment has been administered
- The patient is discharged from ICU
- Contraindications to Vitamin C or Hydrocortisone therapy arise
- Death occurs
- Serious adverse events suspected to be secondary to the intervention therapy develop
Intervention code [1] 319462 0
Treatment: Drugs
Comparator / control treatment
Arm 3 - Standard care: Patients in the standard treatment arm of the study can receive Hydrocortisone only if clinically indicated at the discretion of the attending ICU staff specialist.
The dose and duration of hydrocortisone in the standard care arm will be decided by the clinician, usually this would be a dose of 1mg/kg 6 hourly administered intravenously over 5 minutes.
Control group
Active

Outcomes
Primary outcome [1] 326182 0
Time alive and free of vasopressors. Assessed by manual data collection from patient clinical records.
Timepoint [1] 326182 0
Time alive and free of vasopressors, censored at 7 days (168 hours). Patients dying within 7 days of presentation will be censored as zero to correct for the competing effect of mortality.
Secondary outcome [1] 390404 0
Survival free of organ support (defined as free of ventilation, inotropes, Extracorporeal Membrane Oxygenation, and Renal Replacement Therapy). Assessed by manual data collection from patient clinical records.
Timepoint [1] 390404 0
Censored at 28 days. Patients still requiring organ support at 28 days after admission to PICU will be censored as zero days.
Secondary outcome [2] 390405 0
Survival free of cardiovascular support (defined as free inotropes and ECMO)
Timepoint [2] 390405 0
Censored at 28 days. Patients still requiring cardiovascular support at 28 days after admission to PICU will be censored as zero days. Assessed by manual data collection from patient clinical records.
Secondary outcome [3] 390406 0
Survival free of ventilation (defined as free of invasive ventilation)
Timepoint [3] 390406 0
Censored at 28 days. Patients still requiring ventilatory support at 28 days after admission to PICU will be censored as zero days. Assessed by manual data collection from patient clinical records.
Secondary outcome [4] 390407 0
Mortality
Timepoint [4] 390407 0
Censored at 28 days
Secondary outcome [5] 390408 0
Hospital length of stay
Timepoint [5] 390408 0
Until discharge from hospital. Assessed using data-linkage to integrated medical records.
Secondary outcome [6] 390409 0
Quality of life post enrolment assessed using PedsQL and EQ-5D-Y.
Timepoint [6] 390409 0
Assessment will be performed at 6 months from date of index admission to PICU
Secondary outcome [7] 390410 0
Functional status post enrolment assessed using Functional Status Score and pediatric overall performance score (POPC).
Timepoint [7] 390410 0
Assessment will be performed at 6 months from date of index admission to PICU
Secondary outcome [8] 390411 0
Direct hospitalization-related costs
Timepoint [8] 390411 0
At hospital discharge censored at 6 months post randomisation. Assessed by an audit of hospital financial records.
Secondary outcome [9] 390412 0
Proportion with major adverse events defined as death, hyperglycaemia, hypoglycaemia hospital-acquired microbiologically confirmed infection, oxalate nephropathy, hypernatremia, haemolysis, and worsening of liver function. Assessed by manual data collection from patient clinical records.
Timepoint [9] 390412 0
Censored at 28 days after randomisation
Secondary outcome [10] 405911 0
Neurodevelopmental vulnerability post sepsis. Assessed formal follow-up survey and questionnaire.
Timepoint [10] 405911 0
6 months post sepsis index admission, defined as a score in each developmental domain > 1 SD below the normative mean or specified impairment cut-offs. These domains include health and physical development, cognitive skills and emotional wellbeing and social competence.
Secondary outcome [11] 405912 0
Multiple organ dysfunction measured by a paediatric Sequential organ Failure Assessment score change in organ-specific sub score of >0 in at least two organs withing 72 hours. Assessed by manual data collection from patient clinical records.
Timepoint [11] 405912 0
Censored at 72 hours after randomisation
Secondary outcome [12] 405913 0
PICU-free survival. Patients dying within 28 days of presentation will be censored as zero days to correct for the competing effect of mortality on PICU length of stay. Assessed by manual data collection from patient clinical records.
Timepoint [12] 405913 0
Censored at 28 days.
Secondary outcome [13] 446604 0
Length of stay in PICU
Timepoint [13] 446604 0
Until discharge from PICU. Assessed using medical records

Eligibility
Key inclusion criteria
Criterion 1: Child aged >=7 days and <18 years and admitted to PICU.
Criterion 2: Treatment of septic shock with vasopressor/inotrope therapy for >1 hour
Minimum age
7 Days
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Corrected age of <7 days
- 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
- Receiving ongoing treatment with inotropes/vasopressors for confirmed or suspected sepsis/septic shock for >24 hours
- Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency
- Patients with known history of oxalate nephropathy
- Patients with known malaria
- Patients receiving cyanocobalamin or deferoxamine
- Enrolment in RESPOND study within the past 6 months

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, all three interventions will be open labelled. The main aim of this study is investigate the effect of vitamin c and hydrocortisone while being cognisant of safety of the interventions. To ensure evidence of safety can be provided and reduce the logistic challenges with blinding three arms, it is acceptable to perform this study as a open label format.
Allocation concealment will occur by central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed by the site investigator or research coordinator opening the next sequential sealed opaque envelope which are prepared using a randomization sequence provided by The University of Queensland, Child Health Research Centre.
Variable block randomisation will be used to allocate children in a 1:1:1 ratio stratified by administration of steroids prior to enrolment, and site
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 used to report on the baseline characteristics of the total study cohort and each group. The primary outcome will be analysed using quantile regression. Stratification variables (administration of steroids prior to enrolment, and site) will be accounted for in the model. Analysis of secondary outcomes will be undertaken using a similar approach using appropriate regression models for the outcome under investigation. 95% confidence intervals will be used as the major method of presentation. Main analyses will be performed according to the intention-to-treat principle; per-protocol analyses will be performed as well. An exploratory analysis will compare the two intervention groups to each other, as well as the vitamin C and hydrocortisone group with the hydrocortisone and standard care groups combined. Pre-defined subgroup analyses will focus on severity upon presentation measured by PELOD-2, age, previously healthy children versus children with comorbidity, community-acquired versus hospital-acquired sepsis, oncologic children, pre-treatment with hydrocortisone, country of recruitment, and formulation used.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
19/12/2021
Actual
19/12/2021
Date of last participant enrolment
Anticipated
30/11/2025
Actual
Date of last data collection
Anticipated
31/08/2026
Actual
Sample size
Target
384
Accrual to date
228
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 18401 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 18402 0
Gold Coast University Hospital - Southport
Recruitment hospital [3] 18403 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [4] 18406 0
Perth Children's Hospital - Nedlands
Recruitment hospital [5] 18407 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [6] 18408 0
Sydney Children's Hospital - Randwick
Recruitment hospital [7] 18409 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [8] 18410 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 32495 0
4101 - South Brisbane
Recruitment postcode(s) [2] 32496 0
4215 - Southport
Recruitment postcode(s) [3] 32497 0
4575 - Birtinya
Recruitment postcode(s) [4] 32500 0
6009 - Nedlands
Recruitment postcode(s) [5] 32501 0
5006 - North Adelaide
Recruitment postcode(s) [6] 32502 0
2031 - Randwick
Recruitment postcode(s) [7] 32503 0
2145 - Westmead
Recruitment postcode(s) [8] 32504 0
3052 - Parkville
Recruitment outside Australia
Country [1] 23372 0
New Zealand
State/province [1] 23372 0
Auckland
Country [2] 23374 0
Korea, Republic Of
State/province [2] 23374 0
Chonnan
Country [3] 24540 0
Brazil
State/province [3] 24540 0
São Paulo
Country [4] 24541 0
Brazil
State/province [4] 24541 0
Porto Alegre
Country [5] 26989 0
India
State/province [5] 26989 0
Chandigarh
Country [6] 26990 0
India
State/province [6] 26990 0
Vellore
Country [7] 26991 0
India
State/province [7] 26991 0
Bangalore

Funding & Sponsors
Funding source category [1] 307560 0
University
Name [1] 307560 0
University of Queensland
Country [1] 307560 0
Australia
Funding source category [2] 307562 0
Charities/Societies/Foundations
Name [2] 307562 0
Financial Markets Foundation for childreem-The Children's Hospital Foundation Queensland
Country [2] 307562 0
Australia
Funding source category [3] 307563 0
Government body
Name [3] 307563 0
Australian Government, Medical Research Future Fund
Country [3] 307563 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Unit / Level Level 3 JD Story Building, Saint Lucia QLD Australia 4067
Country
Australia
Secondary sponsor category [1] 308249 0
None
Name [1] 308249 0
Address [1] 308249 0
Country [1] 308249 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307622 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 307622 0
Ethics committee country [1] 307622 0
Australia
Date submitted for ethics approval [1] 307622 0
18/11/2020
Approval date [1] 307622 0
21/12/2020
Ethics approval number [1] 307622 0
HREC/2020/QCHQ/69922

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

Contacts
Principal investigator
Name 107894 0
Dr Sainath Raman
Address 107894 0
Level 6, Centre for Children's Health Research (CCHR) 62 Graham Street South Brisbane QLD 4101, Australia
Country 107894 0
Australia
Phone 107894 0
+61 432956149
Fax 107894 0
Email 107894 0
[email protected]
Contact person for public queries
Name 107895 0
Sainath Raman
Address 107895 0
Level 6, Centre for Children's Health Research (CCHR) 62 Graham Street South Brisbane QLD 4101, Australia
Country 107895 0
Australia
Phone 107895 0
+61 432956149
Fax 107895 0
Email 107895 0
[email protected]
Contact person for scientific queries
Name 107896 0
Sainath Raman
Address 107896 0
Level 6, Centre for Children's Health Research (CCHR) 62 Graham Street South Brisbane QLD 4101, Australia
Country 107896 0
Australia
Phone 107896 0
+61 432956149
Fax 107896 0
Email 107896 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Any data request will require approval by the Children’s Health Queensland, Human Research Ethics Committee. sharing requests will be checked individually. Data sharing requests will be assessed on an individual basis.

Conditions for requesting access:
• -

What individual participant data might be shared?
• All of the individual participant data collected during the trial.

What types of analyses could be done with individual participant data?
• Post-hoc exploratory analyses

When can requests for individual participant data be made (start and end dates)?
From:
From 1 year after the end of the trial for 3 further years.

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• By emailing the principal investigator at [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol2025https://doi.org/10.1097/pcc.0000000000003674  By emailing the principal investigator at sainath.... [More Details]
Ethical approval    By emailing the principal investigator at sainath.... [More Details]


Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe authors reply.2024https://dx.doi.org/10.1097/PCC.0000000000003578
N.B. These documents automatically identified may not have been verified by the study sponsor.