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

Primary Purpose

Sepsis, Severe, Septic Shock

Status
Recruiting
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
Sodium Ascorbate
Sponsored by
Melbourne Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis, Severe

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Intensive Care Unit Royal Melbourne HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

No Intervention

Arm Label

Intermediate dose

High dose

Usual care

Arm Description

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

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

Usual care for septic shock. No vitamin C will be given

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Plasma C-reactive protein
Change in plasma C-reactive protein from baseline
Plasma procalcitonin
Change in procalcitonin from baseline
Plasma thrombomodulin
Change in thrombodulin from baseline
Inflammatory markers
Change in IL-6, IL-10 and TNF-alpha from baseline
Body temperature
Change in body temperature from baseline
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
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.
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.
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.
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.
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.
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.
Maximum plasma concentration of vitamin C (cMax)
Maximum plasma concentration CMax within 72 hours
Area under the vitamin C plasma concentration versus time curve
Area under the vitamin C plasma concentration versus time curve
Vitamin C plasma elimination half-life
Vitamin C plasma elimination half-life
Urinary markers of renal injury
Change in urinary KIM-1 and NGAL from baseline
Plasma cystatin C
Change in plasma cystatin C from baseline
Plasma proteomics
Change in proteomics from baseline
Number of patients screened
Number of patients screened
Randomised to screened patient ratio
Ratio of patients randomized to the study compared to the number of patients screened
Percentage of randomized patients compliant with study protocol
Compliance with vitamin C drug regimens

Full Information

First Posted
January 19, 2021
Last Updated
November 2, 2022
Sponsor
Melbourne Health
Collaborators
Monash Medical Centre, The Florey Institute of Neuroscience and Mental Health, University of Melbourne
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1. Study Identification

Unique Protocol Identification Number
NCT04796636
Brief Title
High-dose Intravenous Vitamin C in Patients With Septic Shock
Acronym
HIGH-VIS
Official Title
HIGH-dose Intravenous VItamin C in Patients With Septic Shock: HIGH-VIS Trial
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 27, 2021 (Actual)
Primary Completion Date
September 22, 2023 (Anticipated)
Study Completion Date
December 22, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Melbourne Health
Collaborators
Monash Medical Centre, The Florey Institute of Neuroscience and Mental Health, University of Melbourne

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Severe, Septic Shock

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Open label phase 1 randomized controlled trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intermediate dose
Arm Type
Experimental
Arm Description
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
Arm Title
High dose
Arm Type
Experimental
Arm Description
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
Arm Title
Usual care
Arm Type
No Intervention
Arm Description
Usual care for septic shock. No vitamin C will be given
Intervention Type
Drug
Intervention Name(s)
Sodium Ascorbate
Intervention Description
As previously described
Primary Outcome Measure Information:
Title
Time to cessation of vasopressor support
Description
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.
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Plasma C-reactive protein
Description
Change in plasma C-reactive protein from baseline
Time Frame
24, 48 and 72 hours
Title
Plasma procalcitonin
Description
Change in procalcitonin from baseline
Time Frame
24, 48 and 72 hours
Title
Plasma thrombomodulin
Description
Change in thrombodulin from baseline
Time Frame
24, 48 and 72 hours
Title
Inflammatory markers
Description
Change in IL-6, IL-10 and TNF-alpha from baseline
Time Frame
24, 48 and 72 hours
Title
Body temperature
Description
Change in body temperature from baseline
Time Frame
24, 48 and 72 hours
Title
Sequential Organ Failure Assessment score
Description
Change in daily Sequential Organ Failure Assessment (SOFA) score: minimum score 0 and maximum score 24 with higher scores meaning worse outcomes
Time Frame
7 days
Title
Cardiovascular Sequential organ failure assessment score
Description
Change in cardiovascular component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Neurological Sequential organ failure assessment score
Description
Change in neurological component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Haematological Sequential organ failure assessment score
Description
Change in haematological component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Liver Sequential organ failure assessment score
Description
Change in liver component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Renal Sequential organ failure assessment score
Description
Change in renal component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Respiratory Sequential organ failure assessment score
Description
Change in respiratory component of sequential organ failure assessment score. Scored from 0 to 4 with 4 indicated a worse outcome.
Time Frame
7 days
Title
Maximum plasma concentration of vitamin C (cMax)
Description
Maximum plasma concentration CMax within 72 hours
Time Frame
72 hours
Title
Area under the vitamin C plasma concentration versus time curve
Description
Area under the vitamin C plasma concentration versus time curve
Time Frame
72 hours
Title
Vitamin C plasma elimination half-life
Description
Vitamin C plasma elimination half-life
Time Frame
72 hours
Title
Urinary markers of renal injury
Description
Change in urinary KIM-1 and NGAL from baseline
Time Frame
72 hours
Title
Plasma cystatin C
Description
Change in plasma cystatin C from baseline
Time Frame
72 hours
Title
Plasma proteomics
Description
Change in proteomics from baseline
Time Frame
72 hours
Title
Number of patients screened
Description
Number of patients screened
Time Frame
Duration of study: 12 months
Title
Randomised to screened patient ratio
Description
Ratio of patients randomized to the study compared to the number of patients screened
Time Frame
Duration of study: 12 months
Title
Percentage of randomized patients compliant with study protocol
Description
Compliance with vitamin C drug regimens
Time Frame
Duration of study: 12 months
Other Pre-specified Outcome Measures:
Title
Number of patients that die during their hospital admission
Description
Hospital mortality
Time Frame
Through to study completion: 12 months
Title
Hospital length of stay
Description
Hospital length of stay
Time Frame
Through to study completion: 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mark P Plummer, PhD
Phone
+61 419708399
Email
mark.plummer@mh.org.au
First Name & Middle Initial & Last Name or Official Title & Degree
Adam M Deane, PhD
Phone
+61 431967560
Email
adam.deane@mh.org.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark P Plummer, PhD
Organizational Affiliation
Melbourne Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Intensive Care Unit Royal Melbourne Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark P Plummer, PhD
Phone
+61(0)419708399
Email
mark.plummer@mh.org.au
First Name & Middle Initial & Last Name & Degree
Adam M Deane, PhD
Email
adam.deane@mh.org.au

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Individual participant data will not be made available to a third-party.

Learn more about this trial

High-dose Intravenous Vitamin C in Patients With Septic Shock

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