Sepsis, SeverePhase 1HIGH-VISNCT04796636
High-dose Intravenous Vitamin C in Patients With Septic Shock
A Phase 1 study testing Sodium Ascorbate in people with Sepsis, Severe and Septic Shock, run by Melbourne Health at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Sepsis, Severe, Septic Shock
- What is being tested?
- Sodium Ascorbate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteAustralia
- Study dates
- 27 Sep 2021to 22 Dec 2023
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Australia1 site, 1 recruiting
- Recruiting
Intensive Care Unit Royal Melbourne Hospital
Melbourne, Victoria, 3050
Mark P Plummer, PhD, +61(0)419708399, mark.plummer@mh.org.au
Adam M Deane, PhD, adam.deane@mh.org.au
About this study
Official title: 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.
Read the 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.
- Conditions
- Sepsis, Severe, Septic Shock
- Being tested
- Sodium Ascorbate
- Medical subject headings
- Sepsis, Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium AscorbateDrug
As previously described
| Study group | Role | What they receive |
|---|---|---|
| Intermediate dose | Experimental | 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 Receives: Drug: Sodium Ascorbate |
| High dose | Experimental | 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 Receives: Drug: Sodium Ascorbate |
| Usual care | No intervention | Usual care for septic shock. No vitamin C will be given |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 7 days
Secondary outcomes (21)
Plasma C-reactive protein
Change in plasma C-reactive protein from baseline
Measured: 24, 48 and 72 hours
Plasma procalcitonin
Change in procalcitonin from baseline
Measured: 24, 48 and 72 hours
Plasma thrombomodulin
Change in thrombodulin from baseline
Measured: 24, 48 and 72 hours
Inflammatory markers
Change in IL-6, IL-10 and TNF-alpha from baseline
Measured: 24, 48 and 72 hours
Body temperature
Change in body temperature from baseline
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 7 days
Maximum plasma concentration of vitamin C (cMax)
Maximum plasma concentration CMax within 72 hours
Measured: 72 hours
Area under the vitamin C plasma concentration versus time curve
Area under the vitamin C plasma concentration versus time curve
Measured: 72 hours
Vitamin C plasma elimination half-life
Vitamin C plasma elimination half-life
Measured: 72 hours
Urinary markers of renal injury
Change in urinary KIM-1 and NGAL from baseline
Measured: 72 hours
Plasma cystatin C
Change in plasma cystatin C from baseline
Measured: 72 hours
Plasma proteomics
Change in proteomics from baseline
Measured: 72 hours
Number of patients screened
Number of patients screened
Measured: Duration of study: 12 months
Randomised to screened patient ratio
Ratio of patients randomized to the study compared to the number of patients screened
Measured: Duration of study: 12 months
Percentage of randomized patients compliant with study protocol
Compliance with vitamin C drug regimens
Measured: Duration of study: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Mar 2021
- Study start27 Sep 2021
- Primary completion22 Sep 2023 (estimated)
- Study completion22 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Sepsis, SevereStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Open label phase 1 randomized controlled trial
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Melbourne Health
- Sponsor type
- University, hospital or other
- Collaborators
- Monash Medical Centre, The Florey Institute of Neuroscience and Mental Health, University of Melbourne
- Responsible party
- Sponsor
- Investigators
- Mark P Plummer, PhD, Principal investigator, Melbourne Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04796636
- Sponsor's protocol ID
- 2021.026
- Acronym
- HIGH-VIS
- Status last verified
- Nov 2022
- First submitted
- 19 Jan 2021
- Last updated
- 4 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Individual participant data will not be made available to a third-party.
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- HIGH-dose Intravenous VItamin C in Patients With Septic Shock: HIGH-VIS Trial
- ClinicalTrials.gov ID
- NCT04796636
- Acronym / sponsor ID
- HIGH-VIS / 2021.026
- Conditions
- Sepsis, Severe, Septic Shock
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Melbourne HealthUniversity, hospital or other
- Collaborators
- Monash Medical Centre, The Florey Institute of Neuroscience and Mental Health, University of Melbourne
- Study start
- 27 Sep 2021 (actual)
- Primary completion
- 22 Sep 2023 (estimated)
- Study completion
- 22 Dec 2023 (estimated)
- First posted
- 15 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Open label phase 1 randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Intermediate dose | Experimental | Drug: Sodium AscorbateSodium 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 |
| High dose | Experimental | Drug: Sodium AscorbateSodium 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 | No intervention | –Usual care for septic shock. No vitamin C will be given |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sodium AscorbateAs previously described | Drug | High dose, Intermediate dose |
Primary outcome
Time to cessation of vasopressor support
Time frame: 7 days
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.
21 secondary outcomes
Plasma C-reactive protein
Time frame: 24, 48 and 72 hours
Plasma procalcitonin
Time frame: 24, 48 and 72 hours
Plasma thrombomodulin
Time frame: 24, 48 and 72 hours
Inflammatory markers
Time frame: 24, 48 and 72 hours
Body temperature
Time frame: 24, 48 and 72 hours
Sequential Organ Failure Assessment score
Time frame: 7 days
Cardiovascular Sequential organ failure assessment score
Time frame: 7 days
Neurological Sequential organ failure assessment score
Time frame: 7 days
Haematological Sequential organ failure assessment score
Time frame: 7 days
Liver Sequential organ failure assessment score
Time frame: 7 days
Renal Sequential organ failure assessment score
Time frame: 7 days
Respiratory Sequential organ failure assessment score
Time frame: 7 days
Maximum plasma concentration of vitamin C (cMax)
Time frame: 72 hours
Area under the vitamin C plasma concentration versus time curve
Time frame: 72 hours
Vitamin C plasma elimination half-life
Time frame: 72 hours
Urinary markers of renal injury
Time frame: 72 hours
Plasma cystatin C
Time frame: 72 hours
Plasma proteomics
Time frame: 72 hours
Number of patients screened
Time frame: Duration of study: 12 months
Randomised to screened patient ratio
Time frame: Duration of study: 12 months
Percentage of randomized patients compliant with study protocol
Time frame: Duration of study: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2022.
- Individual participant dataSharing planned: No. Individual participant data will not be made available to a third-party.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark P Plummer, PhD principal investigator
Melbourne Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sodium Ascorbate in people with Sepsis, Severe and Septic Shock, run by Melbourne Health at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Mark P Plummer, PhD (+61 419708399, mark.plummer@mh.org.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to cessation of vasopressor support (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2022.