Clinical trial NCT04796636: High-dose Intravenous Vitamin C in Patients With Septic Shock
Official title: HIGH-dose Intravenous VItamin C in Patients With Septic Shock: HIGH-VIS Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Sepsis, Severe
Septic Shock
Lead sponsor: Melbourne Health
Sponsor class: OTHER
Collaborators: name: Monash Medical Centre
name: The Florey Institute of Neuroscience and Mental Health
name: University of Melbourne
First posted: 2021-03-15
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label phase 1 randomized controlled trial
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to cessation of vasopressor support
timeFrame: 7 days
Secondary outcomes:
measure: Plasma C-reactive protein
timeFrame: 24, 48 and 72 hours
measure: Plasma procalcitonin
timeFrame: 24, 48 and 72 hours
measure: Plasma thrombomodulin
timeFrame: 24, 48 and 72 hours
measure: Inflammatory markers
timeFrame: 24, 48 and 72 hours
measure: Body temperature
timeFrame: 24, 48 and 72 hours
measure: Sequential Organ Failure Assessment score
timeFrame: 7 days
measure: Cardiovascular Sequential organ failure assessment score
timeFrame: 7 days
measure: Neurological Sequential organ failure assessment score
timeFrame: 7 days
measure: Haematological Sequential organ failure assessment score
timeFrame: 7 days
measure: Liver Sequential organ failure assessment score
timeFrame: 7 days
measure: Renal Sequential organ failure assessment score
timeFrame: 7 days
measure: Respiratory Sequential organ failure assessment score
timeFrame: 7 days
measure: Maximum plasma concentration of vitamin C (cMax)
timeFrame: 72 hours
measure: Area under the vitamin C plasma concentration versus time curve
timeFrame: 72 hours
measure: Vitamin C plasma elimination half-life
timeFrame: 72 hours
measure: Urinary markers of renal injury
timeFrame: 72 hours
measure: Plasma cystatin C
timeFrame: 72 hours
measure: Plasma proteomics
timeFrame: 72 hours
measure: Number of patients screened
timeFrame: Duration of study: 12 months
measure: Randomised to screened patient ratio
timeFrame: Duration of study: 12 months
measure: Percentage of randomized patients compliant with study protocol
timeFrame: Duration of study: 12 months
Other outcomes:
measure: Number of patients that die during their hospital admission
timeFrame: Through to study completion: 12 months
measure: Hospital length of stay
timeFrame: Through to study completion: 12 months
Locations:
city: Melbourne
country: Australia
facility: Intensive Care Unit Royal Melbourne Hospital
state: Victoria
Study officials:
affiliation: Melbourne Health
name: Mark P Plummer, PhD
role: PRINCIPAL_INVESTIGATOR
References: