High-dose Intravenous Vitamin C in Patients With Septic Shock (HIGH-VIS)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Sepsis, Severe
• Intervention / Treatment: Drug: Sodium Ascorbate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mark P Plummer, PhD; Phone Number: +61 419708399; Email: mark.plummer@mh.org.au
• Study Contact Backup: Name: Adam M Deane, PhD; Phone Number: +61 431967560; Email: adam.deane@mh.org.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Intensive Care Unit Royal Melbourne Hospital
      • Contact: Mark P Plummer, PhD; Phone Number: +61(0)419708399; Email: mark.plummer@mh.org.au
      • Contact: Adam M Deane, PhD; Email: adam.deane@mh.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermediate dose; 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; As previously described
Experimental: High dose; 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; As previously described
No Intervention: Usual care; Usual care for septic shock. No vitamin C will be given

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients that die during their hospital admission	Hospital mortality	Through to study completion: 12 months
Hospital length of stay	Hospital length of stay	Through to study completion: 12 months

Collaborators and Investigators

• Sponsor: Melbourne Health
• Collaborators: University of Melbourne; Monash Medical Centre; The Florey Institute of Neuroscience and Mental Health
• Investigators: Principal Investigator: Mark P Plummer, PhD, Melbourne Health

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2021
• Primary Completion (Anticipated): September 22, 2023
• Study Completion (Anticipated): December 22, 2023

Study Registration Dates

• First Submitted: January 19, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 2021.026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual participant data will not be made available to a third-party.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No