Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001191684p
Ethics application status
Submitted, not yet approved
Date submitted
26/09/2023
Date registered
17/11/2023
Date last updated
26/02/2024
Date data sharing statement initially provided
17/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Mega-dose Ascorbate for Sepsis (MEGA-SCORES) - a pilot phase 1 double blind randomised controlled trial
Scientific title
Mega-dose Ascorbate for Sepsis (MEGA-SCORES) in critically ill adults - a pilot feasibility phase 1 double blind randomised controlled trial
Secondary ID [1] 310493 0
nil known
Universal Trial Number (UTN)
Trial acronym
MEGA-SCORES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Septic shock 331283 0
Condition category
Condition code
Infection 328040 328040 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sodium ascorbate is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 mL presented in a plain glass vial as a clear, colourless solution. Clinical Trials Pharmacy at each participating site will aseptically prepare the study medication with a diluent to yield a solution in 1000 mL.

Study treatment medication will be administered via a dedicated lumen of a peripheral or central venous catheter as a continuous infusion with a bolus dose of 0.5 g/kg ideal body weight (IBW) administered over 2 hours followed by 2.5 g/kg (IBW) administered over 22 hours. The maximum ideal body weight for the infusion rate will be 100 kg (maximum total dose 300 grams, maximum total volume 2000 mL over 24 hours). Adherence to intervention will be closely monitored via the electronic medical records.
Intervention code [1] 326881 0
Treatment: Drugs
Comparator / control treatment
Patients randomised to the control group will receive an equivalent volume of placebo which will be prepared as 1000 mL bags of 0.9% sodium chloride.
Control group
Placebo

Outcomes
Primary outcome [1] 335915 0
Feasibility as determined by:
- Number of patients screened as determined by study screening log
- Recruitment rate as determined by study screening log
- Randomised to screened patient ratio as determined by study screening log
- Reasons for exclusions as determined by study screening log
- Compliance with drug administration protocol determined from the electronic medical record
- Time from meeting eligibility criteria to first dose of sodium ascorbate as determined by study enrolment log
- Adverse events and serious adverse events determined from the electronic medical record

This will be assessed as a composite outcome.

Examples of known/possible adverse events:
- Hypernatremia: study medication will be permanently held for a plasma sodium >160 mmol/L
- Haemolysis – will be determined from the electronic medical record after reviewing full blood counts, blood film relevant haemolysis screen on biochemistry
- Tissue necrosis on extravasation: determined by physical examination
- Falsely elevated glucometer readings: determined from the electronic medical record
- Falsely elevated ketone readings: determined from the electronic medical record.
Timepoint [1] 335915 0
At study completion
Secondary outcome [1] 426125 0
Time to cessation of vasopressor support.
Hourly vasopressor requirement will be documented on the electronic medical record by the bedside nurse.
Timepoint [1] 426125 0
Upto to day 7 (168hrs) after randomisation
Secondary outcome [2] 426126 0
Change in plasma C-reactive protein (CRP)
Timepoint [2] 426126 0
at 24, 48, and 72 hrs from start of study medication
Secondary outcome [3] 426127 0
Change in plasma thrombomodulin
Timepoint [3] 426127 0
at 24, 48, and 72 hrs from start of study medication
Secondary outcome [4] 426128 0
Time course plasma inflammatory markers (multiplex) including but not limited to plasma IL-2, IL-10, FGF-2, TNF-a, TNF-ß
Timepoint [4] 426128 0
at 24, 48, and 72 hrs from start of study medication
Secondary outcome [5] 426129 0
Time course of daily body temperature which will be measured using a digital thermometer
Timepoint [5] 426129 0
4 hourly from the T=0 hours to T=72 hours from start of study medication
Secondary outcome [6] 426132 0
Change in organ failure as assessed by the sequential organ failure assessment (SOFA) score
Timepoint [6] 426132 0
Baseline to day 7 from start of study medication
Secondary outcome [7] 426133 0
Change in SOFA component scores: cardiovascular, haematologic, liver, neurologic, kidney, and respiratory from baseline to Day 7 from start of study medication. This will be measured as a composite outcome.
Timepoint [7] 426133 0
Baseline to day 7 from start of study medication
Secondary outcome [8] 426134 0
Plasma ascorbate concentration
Timepoint [8] 426134 0
at 0, 2, 24, 48, and 72 hrs from start of study medication
Secondary outcome [9] 426135 0
Plasma sodium concentration
Timepoint [9] 426135 0
at 24, 48, and 72 hrs from start of study medication
Secondary outcome [10] 426144 0
Peak plasma creatinine
Timepoint [10] 426144 0
from baseline to day 7 from start of study medication. Individual sample time points will be as per routine clinical sampling done once a day.
Secondary outcome [11] 426145 0
Plasma creatinine AUC
Timepoint [11] 426145 0
from baseline to day 7 from start of study medication. Individual sample time points will be as per routine clinical sampling done once a day.
Secondary outcome [12] 426146 0
Total urine output determined from the electronic medical records
Timepoint [12] 426146 0
at 24, 48, and 72 hrs from start of study medication
Secondary outcome [13] 426147 0
Plasma proteomics
Timepoint [13] 426147 0
At study completion
Secondary outcome [14] 426148 0
Immunoprofiling assessed by flow cytometry
Timepoint [14] 426148 0
At study completion
Secondary outcome [15] 426149 0
Alive and ICU-free days calculated as the number of days alive and out of the ICU to day 28. If alive, ICU-free days will be calculated as 28 minus the number of days in ICU (as per electronic medical records). Patients who die within 28 days, will be assigned a score of 0.
Timepoint [15] 426149 0
Day 28 following commencement of drug administration
Secondary outcome [16] 426150 0
Hospital mortality
Timepoint [16] 426150 0
Data to be collected at hospital discharge
Secondary outcome [17] 426151 0
Hospital length of stay. This will be calculated by subtracting hospital admission date from the hospital discharge date. Both these dates will be collected from the electronic medical records.
Timepoint [17] 426151 0
Data to be collected from electronic medical records at hospital discharge
Secondary outcome [18] 428214 0
Plasma metabolomics
Timepoint [18] 428214 0
At study completion

Eligibility
Key inclusion criteria
INCLUSION CRITERIA
- Aged 18-80 years
- Diagnosis of septic shock defined as:
> Suspected or proven infection; AND
> An arterial lactate >2 mmol/L at any time in the preceding 24 hrs; AND
> Need for vasopressor therapy at a noradrenaline equivalent dose greater than or equal to 5 µg/min to keep MAP >65 mmHg for >2 hrs despite fluid resuscitation therapy.
- Vasopressor running as a continuous infusion for <48 hrs at the time of randomisation
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
EXCLUSION CRITERIA
- Aged <18 or >80 years
- Pregnancy confirmed on either urine or blood sample
- Creatinine > 150 mmol/L
- Type 1 diabetes mellitus
- History of ketoacidosis
- Congestive heart failure
- Use of SGLT2 Inhibitors
- Renal replacement therapy
- DNI (do not intubate) orders
- Patients with a known history of glucose-6 phosphate dehydrogenase (G-6PD) deficiency
- Patients with a history of renal stones or oxaluria
- Patients with known or suspected scurvy
- Patients previously enrolled in this study
- Plasma sodium <130 or >150 mmol/L
- Haemoglobin < 80 g/L
- People for whom preservation of red blood cells is of high clinical priority
- Receiving isoprenaline
- Anticipated to require intravenous sodium bicarbonate during the intervention period
- Persons who have shown hypersensitivity to any of the components of sodium ascorbate

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)
Allocation of ascorbate versus control to treatments 'A' and 'B' will be determined by and known only to Clinical Trials Pharmacies until study completion.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated, variable size blocks, stratified by baseline noradrenaline requirement
greater than or equal to 20 µg/min, targeting 15 participants per group in a 1:1 ratio. The randomisation sequence will be generated by the trial statistician as treatments 'A' and 'B' and uploaded to a secure web-based platform (REDCap) form where study participants will be allocated.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
There is insufficient data for mega-dose sodium ascorbate in human sepsis to perform accurate power calculations for a time-to-event analysis. As this is a feasibility study, a convenience samples of 15 patients per group has been chosen based on Whitehead et al with the aim of generating data for a power calculation for a phase II trial that will have 90% power, as alpha of 0.05 and a large anticipated standardised effect size (Whitehead et al. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res 2016 Jun; 25(3):1057-1073).

Qualitative and quantitative analyses will be performed to asses the primary outcome of feasibility. Analysis of vasopressor cessation will be undertaken as time-to-event (cessation of vasopressor) using a competing risks regression framework, with death as a competing event. If no deaths are observed, then analysis will revert to Cox proportional hazards regression. The group estimates will be presented as the respective sub-hazard (or hazard) ratios with associated 95% confidence intervals (95%CI), and presented as the respective cumulative incidence rates as per Fine & Gray (Citation: A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association 1999, 94(446):496-509). The vasopressor support analysis will be unadjusted, and a secondary analysis performed adjusting for noradrenaline requirement greater than or equal to 20 µg/min. Secondary analysis will be conducted as days alive and vasopressor free at day 28, with deaths assigned zero days. Length of ICU stay will be analysed similarly as days alive and ICU-free at day 28, with deaths assigned zero. Baseline covariates will be presented as number (%), median [interquartile range, IQR], or mean (standard deviation, SD); between group differences will be analysed by chi-squared, Kruskal-Wallis test or linear regression.
Plasma concentration-time curves for ascorbate, and other biomarkers, will be presented as mean profiles with corresponding 95%CI.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/04/2024
Actual
Date of last participant enrolment
Anticipated
30/04/2025
Actual
Date of last data collection
Anticipated
31/05/2025
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 25485 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 25487 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 25488 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 25489 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 41297 0
3084 - Heidelberg
Recruitment postcode(s) [2] 41299 0
3168 - Clayton
Recruitment postcode(s) [3] 41300 0
5000 - Adelaide
Recruitment postcode(s) [4] 41301 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 314694 0
Charities/Societies/Foundations
Name [1] 314694 0
The Hospital Research Foundation Group
Country [1] 314694 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network
Address
Level 3, Roma Mitchell Building, 136 North Terrace, Adelaide, South Australia, SA 5000
Country
Australia
Secondary sponsor category [1] 316664 0
None
Name [1] 316664 0
Address [1] 316664 0
Country [1] 316664 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 313893 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 313893 0
Ethics committee country [1] 313893 0
Australia
Date submitted for ethics approval [1] 313893 0
06/10/2023
Approval date [1] 313893 0
Ethics approval number [1] 313893 0

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

Contacts
Principal investigator
Name 129098 0
A/Prof Mark Plummer
Address 129098 0
4G751 ICU Research department, Royal Adelaide Hospital, Port road, Adelaide, SA 5000
Country 129098 0
Australia
Phone 129098 0
+61 08 7074 1800
Fax 129098 0
Email 129098 0
[email protected]
Contact person for public queries
Name 129099 0
Mark Plummer
Address 129099 0
4G751 ICU Research department, Royal Adelaide Hospital, Port road, Adelaide, SA 5000
Country 129099 0
Australia
Phone 129099 0
+61 08 7074 1800
Fax 129099 0
Email 129099 0
[email protected]
Contact person for scientific queries
Name 129100 0
Mark Plummer
Address 129100 0
4G751 ICU Research department, Royal Adelaide Hospital, Port road, Adelaide, SA 5000
Country 129100 0
Australia
Phone 129100 0
+61 08 7074 1800
Fax 129100 0
Email 129100 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?
De-identified data will be made available upon direct request to the primary investigator and reviewed case-by-case by the management committee.
When will data be available (start and end dates)?
Data will be made available from the time of publication up until 15 years post study commencement in-keeping with data management outlined in the ethics application.
Available to whom?
Anyone will be eligible to apply.
Available for what types of analyses?
Scientific analyses
How or where can data be obtained?
Data will not be placed in a public repository but will be directly sent to approved individuals or institutions after consideration of their application to PI Associate Professor Mark Plummer ([email protected]).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.