High-dose Intravenous Vitamin C in Patients With Septic Shock

Study Overview
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Brief Summary
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Despite promising observational and phase 1 data, the therapeutic potential of vitamin C for the management of septic shock has not borne out in recent large multi-centre randomized controlled trials. There is biological plausibility for benefit with intravenous vitamin C, and the investigators hypothesize that the doses used in these trials were insufficient to demonstrate an effect. High-dose vitamin C has been trialed in patients with cancer and burns and proven to be safe. The investigators have recently demonstrated a dramatic benefit of high-dose intravenous vitamin C in reversing organ dysfunction in a large mammalian model of sepsis. The proposed prospective interventional study will be the first to administer high-dose intravenous vitamin C in critically ill patients with sepsis. The objectives of this study will be to determine whether high-dose intravenous vitamin C (i) reduces vasopressor requirement in critically ill patients with septic shock (ii) reverses organ dysfunction and (iii) is well tolerated.

Detailed Description
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The investigators plan to conduct a phase 1, feasibility, prospective, two-centre, randomised, open-label, trial in 30 ICU patients with septic shock to test whether the intravenous administration of two stepped doses of high-dose intravenous vitamin C for 48 hours leads to a reduction in duration of vasopressor requirement and an improvement in organ failure scores and blood biomarkers of sepsis compared to standard care. Patients will be randomized 1:1:1 to receive either 30 g of vitamin C twice daily for 48 hours (+ 30 g load) (n=10), 60 g of vitamin C twice daily for 48 hours (+ 30 g load) (n=10) or usual care (no vitamin C) (n=10). Vitamin C is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml. At study commencement (T = 0) patients randomized to either vitamin C arm will receive a loading dose of 30 grams of vitamin C infused through central venous access via a dedicated line over 2 hours (50 ml/hr =15 g/hr). In patients randomized to 60 g/day, this will be immediately followed by an infusion of 30 grams of vitamin C (100 ml) over 6 hours which will then be repeated at 14, 26 and 38 hours (i.e., 2 days of treatment). In patients randomized to the higher dose, two vials (200 ml = 60 grams) will be infused through a central venous catheter over 6 hours immediately following the 30 gram loading dose. This dose will be repeated at 14, 26 and 38 hours (i.e., 2 days of treatment). Patients in the control arm will receive usual care. The investigators also plan to describe the pharmacokinetic parameters of high-dose intravenous vitamin C in critically ill patients with septic shock. These results will inform a subsequent multi-centre, blinded, parallel group randomized controlled trial to determine the efficacy of high-dose intravenous vitamin C for the reversal of septic shock and potentially improved survival.

Official Title
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HIGH-dose Intravenous VItamin C in Patients With Septic Shock: HIGH-VIS Trial

Conditions
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Sepsis, Severe, Septic Shock

Intervention / Treatment
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* Drug: Sodium Ascorbate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of septic shock within 24 hours of admission to the ICU Age 18 - 80 years Presence of a central venous catheter for vasopressor infusion Presence of an arterial line to monitor blood pressure Definition of sepsis Suspected or documented infection and an increase of ≥ 2 SOFA points consequent to the infection. Definition of septic shock Sepsis AND an arterial lactate >2 mmol/L AND need for vasopressor therapy to keep MAP >65 mmHg for > 2 hours despite fluid resuscitation therapy. Exclusion Criteria: Age <18 or > 80 years Pregnant DNI (do not intubate) orders i.e., Goals of Care other than A Patients with a primary admission diagnosis of a traumatic brain injury Patients with features of septic shock admitted in the ICU > 24 hours Patients with a known history of glucose-6 phosphate dehydrogenase (G-6PD) deficiency Patients with a history of renal stones Patients with known or suspected scurvy Patients previously enrolled in this study Plasma sodium >150 mmol/L Plasma sodium < 130 mmol/L Haemoglobin < 90 g/L Jehova's witness Receiving isoprenaline

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label phase 1 randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermediate dose<br>Sodium ascorbate (vitamin C) is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml. 30 gram load over 2 hours (T = 0 - 2 hours) 30 gram infusion over 6 hours (T = 2-8 hours) which will be repeated at 14, 26 and 38 hours | Drug: Sodium Ascorbate<br>* As previously described<br>|
| Experimental: High dose<br>Sodium ascorbate (vitamin C) is provided by the manufacturer (Orthomolecular Medisearch Laboratory P/L, Braeside, Victoria, Australia) as 30 grams in 100 ml. 30 gram load over 2 hours (T = 0 - 2 hours) 60 gram infusion over 6 hours (T = 2-8 hours) which will be repeated at 14, 26 and 38 hours | Drug: Sodium Ascorbate<br>* As previously described<br>|
| No Intervention: Usual care<br>Usual care for septic shock. No vitamin C will be given | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to cessation of vasopressor support | Time to cessation of vasopressor support (up to day 14). This will be defined as per the VITAMINS trial, as the patient being alive at discontinuation of all vasopressors for at least 4 hours in the presence of MAP >65 mmHg for the same 4 hour period as reported in the ICU charts. Use of vasopressor will be defined as any use of noradrenaline, adrenaline, vasopressin, metaraminol, dopamine or phenylephrine. Data on doses will be obtained hourly and the doses summed for each study day. Vasopressor dose will be calculated as the sum of norepinephrine and 'norepinephrine equivalent' doses. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma C-reactive protein | Change in plasma C-reactive protein from baseline | 24, 48 and 72 hours | 
| Plasma procalcitonin | Change in procalcitonin from baseline | 24, 48 and 72 hours | 
| Plasma thrombomodulin | Change in thrombodulin from baseline | 24, 48 and 72 hours | 
| Inflammatory markers | Change in IL-6, IL-10 and TNF-alpha from baseline | 24, 48 and 72 hours | 
| Body temperature | Change in body temperature from baseline | 24, 48 and 72 hours | 
| Sequential Organ Failure Assessment score | Change in daily Sequential Organ Failure Assessment (SOFA) score: minimum score 0 and maximum score 24 with higher scores meaning worse outcomes | 7 days | 
| Cardiovascular Sequential organ failure assessment score | Change in cardiovascular component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Neurological Sequential organ failure assessment score | Change in neurological component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Haematological Sequential organ failure assessment score | Change in haematological component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Liver Sequential organ failure assessment score | Change in liver component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Renal Sequential organ failure assessment score | Change in renal component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Respiratory Sequential organ failure assessment score | Change in respiratory component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome. | 7 days | 
| Maximum plasma concentration of vitamin C (cMax) | Maximum plasma concentration CMax within 72 hours | 72 hours | 
| Area under the vitamin C plasma concentration versus time curve | Area under the vitamin C plasma concentration versus time curve | 72 hours | 
| Vitamin C plasma elimination half-life | Vitamin C plasma elimination half-life | 72 hours | 
| Urinary markers of renal injury | Change in urinary KIM-1 and NGAL from baseline | 72 hours | 
| Plasma cystatin C | Change in plasma cystatin C from baseline | 72 hours | 
| Plasma proteomics | Change in proteomics from baseline | 72 hours | 
| Number of patients screened | Number of patients screened | Duration of study: 12 months | 
| Randomised to screened patient ratio | Ratio of patients randomized to the study compared to the number of patients screened | Duration of study: 12 months | 
| Percentage of randomized patients compliant with study protocol | Compliance with vitamin C drug regimens | Duration of study: 12 months |