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Trial registered on ANZCTR


Registration number
ACTRN12617001184369
Ethics application status
Approved
Date submitted
8/08/2017
Date registered
11/08/2017
Date last updated
7/09/2020
Date data sharing statement initially provided
19/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Vitamin C administration in severe sepsis
Scientific title
Vitamin C administration in severe sepsis: a pilot randomised controlled trial of vasopressor requirements
Secondary ID [1] 292607 0
None
Universal Trial Number (UTN)
UTN: U1111-1186-1269
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 304285 0
Condition category
Condition code
Infection 303632 303632 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Vitamin C (ASCOR L500)
Dose: 25 mg/kg/6h (total: 100 mg/kg/d)
Duration: 4 days
Mode: intravenous infusion
Intervention code [1] 298818 0
Treatment: Drugs
Comparator / control treatment
Placebo (D5W) infusion
Control group
Placebo

Outcomes
Primary outcome [1] 302989 0
Norepinephrine dose requirement
Timepoint [1] 302989 0
Daily for 4 days
Primary outcome [2] 303028 0
Duration of norepinephrine administration
Timepoint [2] 303028 0
Up to 4 days
Secondary outcome [1] 337638 0
Plasma vitamin C concentrations
Timepoint [1] 337638 0
Daily for 4 days
Secondary outcome [2] 337639 0
Vasopressin requirements
Timepoint [2] 337639 0
Daily for 4 days
Secondary outcome [3] 337640 0
Inflammatory biomarker concentrations (plasma CRP)
Timepoint [3] 337640 0
Daily for 4 days
Secondary outcome [4] 337641 0
Illness severity (SOFA scores)
Timepoint [4] 337641 0
Daily for 4 days
Secondary outcome [5] 337642 0
Mortality (hospital)
Timepoint [5] 337642 0
Up to 90 days
Secondary outcome [6] 337643 0
Length of stay (hospital)
Timepoint [6] 337643 0
censored at day 28
Secondary outcome [7] 337719 0
Urinary vitamin C concentrations
Timepoint [7] 337719 0
Daily for 4 days

Eligibility
Key inclusion criteria
1. Receiving IV antimicrobial therapy specifically for infection
2. Receiving >/=5 µg/min (>/=0.06 µg/kg/min) noradrenaline/adrenaline
3. Evidence of organ dysfunction - SOFA >/= 2 for at least ONE of:
respiratory system (PaO2/FiO2 < 300)
liver (bilirubin >33)
coagulation (platelets <100)
renal system (creatinine >171)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age < 18 years
2. Consent cannot be obtained
3. Patient not expected to survive 24 hours
4. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
5. Known or suspected pregnancy or breastfeeding

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)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size calculations based on the vitamin C-dependent decreases in norepinephrine dose and duration from Zabet et al (J Res Pharm Pract, 2016) indicate that a total of 36 participants (18 per group) will have a power of 95% to detect a difference of 22 hours norepinephrine duration or a difference of 6 µg/min norepinephrine dose with 5% type 1 error. Therefore, a total of 40 participants will be enrolled to account for an anticipated 10% loss due to withdrawal of consent to continue.
The primary analysis will be as intention-to-treat principle followed by a per-protocol analysis of patients fully complying with the trial protocol. For the primary endpoint, an unadjusted hazard ratio (HR) and 95% confidence interval (CI) using Cox proportional hazards regression based on a binary outcome of achieving or not achieving relevant clinical outcome will be calculated. As a sensitivity analysis, the primary analysis will be repeated on the per-protocol population. As a further sensitivity analysis, multivariable Cox proportional hazard models will be fitted with treatment group and potential confounders of patient age and APACHE scores included as independent variables. Subgroup analyses (e.g. patient age, initial CRP concentration) will be included as interaction terms in a multivariable Cox proportional hazards model. Multivariate analyses will include stratification of outcomes by vitamin C levels on admission to determine whether there is a benefit to all patients regardless of baseline vitamin C and severity of sepsis. Potential interactions will also be examined with age, severity and comorbidities. For all secondary endpoints, unadjusted and adjusted (for patient age and APACHE score) estimates of the effect size and corresponding 95% CIs using linear, logistic, or Cox proportional hazards regression (as appropriate) will be performed. For all time-to-event analyses of secondary endpoints, patients lost to follow-up will be censored at the time of lost contact. For all other analyses of secondary outcomes complete case analyses will be used. All reported CIs will be two-sided 95% intervals, and tests will be done at the two-sided 5% significance level. We use will use the R language for statistical computing for all analyses.

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 outside Australia
Country [1] 9135 0
New Zealand
State/province [1] 9135 0
Canterbury

Funding & Sponsors
Funding source category [1] 297193 0
Government body
Name [1] 297193 0
Health Research Council of New Zealand
Address [1] 297193 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 297193 0
New Zealand
Funding source category [2] 297206 0
Charities/Societies/Foundations
Name [2] 297206 0
Canterbury Medical Research Foundation
Address [2] 297206 0
Level 1/230 Antigua Street, Christchurch 8011
Country [2] 297206 0
New Zealand
Primary sponsor type
Individual
Name
Dr Anitra Carr
Address
Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 296214 0
None
Name [1] 296214 0
Address [1] 296214 0
Country [1] 296214 0
Other collaborator category [1] 279668 0
Individual
Name [1] 279668 0
Prof Geoff Shaw
Address [1] 279668 0
Department of Intensive Care, Christchurch Hospital, Private Bag 4710, Christchurch 8140
Country [1] 279668 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298350 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 298350 0
Ministry of Health, Health and Disability Ethics Committees, PO Box 5013, Wellington 6140
Ethics committee country [1] 298350 0
New Zealand
Date submitted for ethics approval [1] 298350 0
30/11/2016
Approval date [1] 298350 0
02/05/2017
Ethics approval number [1] 298350 0
16/NTA/238

Summary
Brief summary
Sepsis is a major health problem worldwide and in New Zealand. Despite a massive effort in recent years to develop therapies, none has as yet proven successful in reducing mortality in patients with sepsis, which currently remains the leading cause of death in most intensive care units. Studies indicate that critically ill patients, including those with sepsis, exhibit very low vitamin C levels compared to healthy people. Furthermore, recent preclinical trials and clinical studies indicate a potential role for vitamin C in decreasing inflammation, vasopressor requirements, and multiple organ failure, and improving outcomes in patients with severe sepsis and septic shock, including decreased mortality. Our study will be a double blind randomised placebo controlled trial to test the efficacy of intravenous (IV) vitamin C administration in patients with severe sepsis, with a specific focus on vasopressor requirements. Participants with severe sepsis will be recruited after being admitted to the Christchurch Hospital Intensive Care Unit (ICU). Forty participants will be randomised into two groups: IV vitamin C (100 mg/kg body weight/day) or IV placebo (1:1 ratio) for a duration of 4 days. Blood and urine samples will be collected daily from patients to measure vitamin C levels along with selected biomarkers of inflammation and organ function. The analyses of these biomarkers, which relate to the severity of sepsis, will determine whether levels are changed in patients who receive the intervention. Clinical outcomes will also be monitored; we hypothesise that the patients who receive vitamin C will have improved outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76802 0
Dr Anitra Carr
Address 76802 0
Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch 8140
Country 76802 0
New Zealand
Phone 76802 0
+643 364 0649
Fax 76802 0
Email 76802 0
anitra.carr@otago.ac.nz
Contact person for public queries
Name 76803 0
Dr Anitra Carr
Address 76803 0
Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch 8140
Country 76803 0
New Zealand
Phone 76803 0
+643 364 0649
Fax 76803 0
Email 76803 0
anitra.carr@otago.ac.nz
Contact person for scientific queries
Name 76804 0
Dr Anitra Carr
Address 76804 0
Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch 8140
Country 76804 0
New Zealand
Phone 76804 0
+643 364 0649
Fax 76804 0
Email 76804 0
anitra.carr@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results