A Phase 2 interventional study of Vitamin C and Thiamine in Shock, Septic, Critically Ill and Vasoplegic Syndrome, sponsored by Australian and New Zealand Intensive Care Research Centre. Completed at 8 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-10-10.
Sponsored by Australian and New Zealand Intensive Care Research Centre · Phase 2, Interventional, and Treatment
Sepsis has been characterised as a dysregulated host response to infection. Adjunctive therapies targeting the inflammatory cascade are being increasingly explored, although to date, have failed to demonstrate consistent benefit, and sepsis continues to manifest poor outcomes. Hospital mortality in patients with septic shock remains as high as 22% in Australia and New Zealand. From a global perspective, 31 million sepsis and 19 million severe sepsis cases are expected to be treated in hospitals all over the world per year.
To date, experimental data have reported that both high dose intravenous vitamin C and corticosteroids attenuate the acceleration of the inflammatory cascade and possibly reduce the endothelial injury characteristic of sepsis, enhance the release of endogenous catecholamines and improve vasopressor responsiveness.
Therefore, the investigators plan to conduct a feasibility pilot prospective, multi-centre, randomised, open-label, trial in ICU patients with septic shock to test whether the intravenous administration of high dose Vitamin C (6g/d), Thiamine (400mg/d) and Hydrocortisone (200mg/d) leads to a more rapid resolution shock and vasopressor dependence.
The investigators plan to conduct a feasibility pilot prospective, multi-centre, randomised, open-label, trial in ICU patients with septic shock to test whether the intravenous administration of high dose Vitamin C (6g/d), Thiamine (400mg/d) and Hydrocortisone (200mg/d) for a maximum of ten days leads to a more rapid resolution shock and vasopressor dependence.
Hypothesis:
Treatment with a combination of intravenous Vitamin C, Thiamine and Hydrocortisone reduces duration of vasopressor (measured by hours alive and vasopressor free) use censored at 7 days compared to standard care with Hydrocortisone alone.
This is a prospective, feasibility, pilot, multi-centre, randomised, open-label controlled trial. This study will be performed in seven Victorian ICUs in Australia. Patients admitted to an ICU of the participating hospitals with the primary diagnosis of septic shock will be screened for inclusion into this study.
Rationale:
Experimental data have demonstrated that both corticosteroids and intravenous vitamin C attenuate the release of pro-inflammatory mediators, reduce the endothelial injury characteristic of sepsis (thereby reducing endothelial permeability and improving microcirculatory flow), augment the release of endogenous catecholamines and enhance vasopressor responsiveness. In animal models, these effects have resulted in reduced organ injury and increased survival. However, their effect in critically ill humans is unknown.
Previous research suggests that vitamin C and glucocorticoids may act synergistically and improve vasopressor responsiveness in patients with sepsis and septic shock.
Randomisation:
ICU patients will be enrolled as soon as possible but no later than 24 hours after fulfilling the criteria for septic shock. Patients will be allocated in a 1:1 ratio to either the treatment group, receiving intravenous Vitamin C (1.5g every 6 hours), Thiamine (200mg every 12 hours) and Hydrocortisone (50mg every 6 hours), or to the control group, receiving Hydrocortisone (50mg every 6 hours) alone.
Treatment allocation will occur using a computerized system and concealed allocation. The clinical staff involved in patient care will administer the additional drugs to those allocated to the treatment arm of the trial as soon as possible after the identification of septic shock and randomization.
Patients readmitted to ICU during the same hospital stay will not receive any further doses of study drugs.
Study Treatment will continue until:
Study Drugs
This study will be an open label study:
Intervention group:
In both groups (treatment and control), patients will be treated with hydrocortisone 50mg IV q 6 hourly for the duration of study treatment. After shock resolution and/or a maximum fo 7 days Hydrocortisone will be tapered off or stopped.
Statistical analysis:
Originally, the investigators assumed a mean (SD) duration of vasopressor dependency of 50 (28) hours and estimated a required sample size of 120 patients (60 per group) to identify a clinically relevant decrease of vasopressor dependency and an increase in days alive and vasopressor free at 7 days of 25% (20 hours) (i.e. increase from 41 to 55 hours of days alive and vasopressor free at day 7) with a power of 90% at an alpha level of 0.05.
The investigators have recalculated the sample size based on the pooled standard deviation of hours alive and vasopressor free of the first 59 participants. The pooled standard deviation of hours alive and vasopressor free at 7 days for the 59 patients is 51.6 hours.
To have a 90% power (2 sided p-value of 0.05) to detect a 25-hour difference based on a standard deviation of 51.6, the trial will require 180 patients (90 per group). Allowing for a 20% inflation for non-normality and dropout/withdrawal, the required total sample size is 216 (108 per group). The robustness of the sample size estimate will be further assessed after recruitment of 108 patients (50% of the sample size).
Consent: The major ethical issues associated with this study relate involve the recruitment of participants who are dependent on medical care and in need of immediate intervention for the management of life-threatening haemodynamic instability.
Once subjects are recovered and are able to consider the information sheet, they will be offered the opportunity to withdraw from study follow-up. If a participant dies due to the nature of their critical illness before consent was able to be obtained from the person responsible/medical treatment decision maker, then consent will not be sought and data collected will be used. This is in line with the process followed by other similar intensive care studies conducted previously and approved by the relevant HRECs all where consent to continue has been utilised.
1,078 studies on the registry are indexed under Shock, Septic; 232 are open to participants now.
This study's enrollment of 216 is above the median of 79 across 636 interventional studies indexed under Shock, Septic.
Browse Shock, Septic studies →Australian and New Zealand Intensive Care Research Centre is the lead sponsor of 49 studies on the registry; 16 are open to participants now.
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Patient in the intensive care unit (ICU) with septic shock:
Exclusion Criteria:
Patients with known or suspected
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
intravenous: Ascorbic acid (Vitamin C: 1.5g every 6 hours) Thiamine (Vitamin B1: 200mg every 12 hours) Hydrocortisone (50mg every 6 hours)
Drug: Vitamin C · Drug: Thiamine · Drug: Hydrocortisone,
Hydrocortisone (50mg every 6 hours)
Drug: Hydrocortisone,
Ascorbic acid 1.5g every 6 hours i.v. while in ICU, until shock resolution for a maximum of ten days
Also known as: Ascorbic acid
Thiamine 200mg every 12 hours i.v. while in ICU, until shock resolution for a maximum of ten days
Also known as: Vitamin B1
Hydrocortisone 50mg every 6 hours i.v while in ICU, until shock resolution or for a maximum of 7 days, then tapered or stopped.
Also known as: Solu Cortef
Time alive and free of vasopressors at day 7 (168 hours) after randomization.
This is defined by the patient being alive at discontinuation of all vasopressors for at least 4 hours in the presence of a MAP\>65 mmHg for the same 4 hour period as recorded in the ICU charts and censored at 7 days. If a patient dies while on vasopressor therapy, in such a patient, the time alive and vasopressor free time will be 0 - This approach will correct for the competing effect of mortality on duration of vasopressor therapy.
Time frame: 7 days (168 hours)
ICU mortality
Patient died during the ICU admission
Time frame: 90 days after randomization
Alive and ICU-free days at day 28 calculated as the number of days alive and out of the ICU to day 28
Alive and ICU-free days calculated as the number of days alive and out of the ICU to day 28
Time frame: 28 days after randomization
Hospital mortality
Patient died during the hospital admission
Time frame: 90 days after randomization
28-day mortality
Patient died within 28 days after randomization
Time frame: 28 days after randomization
90-day mortality
Patient died within 90 days after randomization
Time frame: 90 days after randomization
Delta of Sequential Organ Failure Assessment (SOFA) score at 72 hours
defined as the initial total SOFA\* score minus the day three (72 hours) SOFA score \*total SOFA = Sequential Organ Failure Assessment = sum of each organ system point score. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The organ scores are ranging from 0-4, with the best score being 0 and the worst being 4 points. The maximal (and worst) total SOFA score is 24 points.
Time frame: 72 hours after randomization
Hospital length of stay
Duration the patient stayed in the hospital
Time frame: 90 days after randomization
28 day cumulative vasopressor free hours
Cumulative vasopressor free hours from shock resolution to day28 post randomisation
Time frame: 28 days after randomization
28 day cumulative invasive mechanical ventilation free hours
Cumulative invasive mechanical ventilation-free hours during the 28 day period post randomisation
Time frame: 28 days after randomization
RRT duration
Length of renal replacement therapy dependency during the 28 day period post randomisation
Time frame: 28 days after randomization
Plan to share: Yes — Data Sharing Policy is available from the website.
Data sharing details ↗ · www.monash.edu
This study is completed, as verified in Oct 2019. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Ascorbic Acid · Thiamine
Australian and New Zealand Intensive Care Research Centre