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
4/02/2022
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 prospectively performed at randomization, at 28 days post randomization and 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 prospectively performed at randomization, at 28 days post randomization and 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. Assessed by an audit of hospital financial records.
Secondary outcome [9] 390412 0
Safety outcomes: Proportion with major adverse events defined as death, amputations, hyperglycemia, hospital-acquired microbiologically confirmed infection, oxalate nephropathy, hypernatremia and hemolysis.
Assessed by manual data collection from patient clinical records.
Timepoint [9] 390412 0
Censored at 28 days.
Secondary outcome [10] 405911 0
Neurodevelopmental vulnerability post sepsis.
Assessed formal follow-up survey and questionnaire.
Timepoint [10] 405911 0
6 months from date of index admission
Secondary outcome [11] 405912 0
New onset of AKI.
Assessed by manual data collection from patient clinical records.
Timepoint [11] 405912 0
Censored at 28 days
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.

Eligibility
Key inclusion criteria
Criterion 1: Child aged >=7 days and <18 years and admitted to PICU.
Criterion 2: Decision by treating physician to treat as sepsis (including parenteral antibiotics and inotropes)
Criterion 3: Treatment of septic shock with vasopressor/inotrope therapy for >1 hour, or at a Vasopressor-Inotrope-Score of at least 10.

Inotrope requirement will be calculated by means of the Vasoactive-Inotrope Score (VIS)63: VIS = dopamine dose (micgrogram/kg/min) + dobutamine dose (microgram/kg/min) + 100 x adrenaline dose (microgram/kg/min) + 100 x noradrenaline dose (microgram/kg/min) + 10 x milrinone dose (microgram/kg/min) + 10,000 x argipressin(vasopressin) dose (unit/kg/min). Note: vasopressin doses are often recorded as mU/kg/hour, which needs conversion to U/kg/min for the VIS score.
Minimum age
7 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 <7 days
- Known chronic renal failure (defined as requiring continuous RRT prior to the onset of sepsis)
- 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
- Patients with sepsis/septic shock who have been treated with inotropes for 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
- 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 utilised to report on the baseline characteristics of the total study cohort and each subgroup, as well as by site. The primary outcome measure will be analysed using competing-risks regression. Stratification variables (administration of steroids prior to enrolment, and site) will be accounted for as fixed effects in the model. Analysis of secondary outcomes will be undertaken using a similar approach using appropriate regression models for the outcome under investigation. 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
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
3
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] 18404 0
Monash Children’s Hospital - Clayton
Recruitment hospital [5] 18406 0
Perth Children's Hospital - Nedlands
Recruitment hospital [6] 18407 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [7] 18408 0
Sydney Children's Hospital - Randwick
Recruitment hospital [8] 18409 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [9] 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] 32498 0
3168 - Clayton
Recruitment postcode(s) [5] 32500 0
6009 - Nedlands
Recruitment postcode(s) [6] 32501 0
5006 - North Adelaide
Recruitment postcode(s) [7] 32502 0
2031 - Randwick
Recruitment postcode(s) [8] 32503 0
2145 - Westmead
Recruitment postcode(s) [9] 32504 0
3052 - Parkville
Recruitment outside Australia
Country [1] 23372 0
New Zealand
State/province [1] 23372 0
Auckland
Country [2] 23373 0
Switzerland
State/province [2] 23373 0
Zurich
Country [3] 23374 0
Korea, Republic Of
State/province [3] 23374 0
Chonnan
Country [4] 24540 0
Brazil
State/province [4] 24540 0
São Paulo
Country [5] 24541 0
Brazil
State/province [5] 24541 0
Botucatu

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

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 individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial.
When will data be available (start and end dates)?
From 1 year after the end of the trial for 3 further years.
Available to whom?
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.
Available for what types of analyses?
Post-hoc exploratory analyses
How or where can data be obtained?
By emailing the principal investigator at [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10235Study protocol    By emailing the principal investigator at sainath.... [More Details]
10236Ethical approval    By emailing the principal investigator at sainath.... [More Details]



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
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