Evaluation of Hydrocortisone, Vitamin C and Thiamine for the Treatment of Septic Shock

Critically ill patients have low plasma levels of vitamin C. Additionally, ascorbic acid levels were inversely correlated with multi-organ dysfunction. Several studies have shown the benefit of using Vitamin C for treatment of critically ill patients; these benefits included dose dependent decrease in the SOFA score, lower vasopressor doses and duration, and lower fluid resuscitation requirements. Additionally, Intravenous Vitamin C has been shown to be safe and tolerable.

A small study demonstrated that septic shock is associated with thiamine deficiency. Additionally, a randomized controlled trial has shown that intravenous thiamine has decreased lactate levels and mortality in a subgroup of patients with thiamine deficiency. However, this benefit was not observed in the entire population of the study.

A recent study examined the effect of early treatment of patients with severe sepsis and septic shock with a combination of hydrocortisone, vitamin C, and thiamine and demonstrated a significant reduction in mortality as well as preventing organ failure progression. In this study, It has been suggested that this combination of the three agents work synergistically. The use of hydrocortisone in combination with vitamin C will increase the transport of vitamin C into the cells; since the pro inflammatory cytokines have shown to decrease the expression of the sodium-vitamin C transporter-2 (SVCT2) while glucocorticoids increase the SVCT2 expression. In an in vitro study a combination of hydrocortisone and vitamin C preserved the endothelial integrity of the lung vascular endothelial cells which was exposed to endotoxins. On the other hand either agent alone was not effective in comparison to placebo.

The objective of the current study is to explore the clinical benefits of using a combination of hydrocortisone, vitamin C, and thiamine (triple therapy) for the management of septic shock. To achieve this objective, we will compare two alternative treatment strategies, either triple therapy or usual care in patients with septic shock.

First aim: To assess the effectiveness of the triple therapy for septic shock Second aim: To assess the safety of triple therapy

1. Study Sites The study will be conducted in two hospitals (4 intensive care units) throughout the State of Qatar. All of the participating sites are part of Hamad Medical Corporation; the sites will include the MICU and SICU at Hamad General Hospital and the MICU and SICU at Al Wakra Hospital.
2. Initial screening The initial assessment will take place in the ED, inpatient ward, medical or surgical intensive care unit after the patient has been assessed by the clinical team. If the primary diagnosis is septic shock, the clinical team will follow the hospital septic shock pathway. The diagnosis of septic shock as well as the type of the suspected infection will be left to the discretion of the patient's clinical team. Initial management according to the hospital septic shock pathway includes: giving IV fluids bolus, oxygen (if needed), and antibiotic based on the hospital antibiotic guidelines; and taking blood lactate, blood cultures, and other blood tests.

3. Recruitment and consent signing All patients who present to the study site's ED), inpatient ward, medical or surgical intensive care unit and diagnosed with septic shock will be approached for study participation. Each site will follow the Ministry of Public health in Qatar, MRC and the IRB guidelines regarding HIPAA authorization, informed consent and use of the Deferred Consent. Prior to obtaining consent or waiver, all potential subjects will undergo standard of care management procedures.

   The clinical team will obtain potential subject or legally authorized representative (LAR)/family agreement (verbally, but noted by ED, inpatient ward, MICU or SICU provider on screening form) to be approached by the study representative to participate. This will avoid "cold calling" coercion that could occur if direct contact by research team members was the initial method of assessing willingness to enroll. If that agreement is obtained, a trained study representative will approach the potential subject to gain written authorization and consent.

   In situations where the potential subject is unable to provide written authorization and consent, and their LAR/family is not available, it is permissible to use the Deferred Consent. Sites will seek this consent waiver according to the local standards and procedures.Detailed description of the recruitment and consent signing are available in the study protocol approved by the IRB

4. Randomization and initiation of study The investigators will assure that physicians (members of the study team) are available to prescribe the study interventions (triple therapy) in the ED, inpatient ward and the ICU, and will assure that required documentation of authorization and consent, or the Deferred Consent have been properly completed prior to enrollment in the study. Randomization will be 1:1 into each arm and will be done by computer via a web-based randomization system. If consent is refused, No data will be collected, as the IRB does not approve of any information collection for research from the patients if consent is not provided.

   The study investigator will inform the clinical team as soon as the treatment allocation is assigned. If the subject is assigned to the usual care, the clinical team will follow the hospital septic shock pathway. If the subject is assigned to the triple therapy arm, the clinical team will follow the hospital septic shock pathway plus the addition of the triple therapy as described previously in this protocol. The assigned clinical team will continue to provide all other aspects of care to the subject.

5. Study coordination and randomization details:

   Each study site will be led by a designated site coordinator. These individuals will attend the study training sessions at the Hamad General Hospital then they will in turn train physicians and nurses at their site to execute all relevant study procedures.

   The site coordinator will assure that study-trained physicians and nurses are available to perform the study interventions in the ED, inpatient ward and the ICU, and will be responsible to assure that study required documentation have been properly completed prior to enrollment in the study.

   Once the consent is obtained, inclusion criteria and other baseline data will be entered into a web-based enrollment application.

   Stratified block randomization will be used in the ratio of 1:1. Randomization will be stratified by study sites and will be done completely at random in order to conceal group allocation. Each enrolled subject will be assigned an identification number. If consent is refused, baseline characteristics will be collected to compare patients who did and did not enroll in the study to be used for analysis of potential selection bias and to determine the generalizability of the study results.

   Once a patient is allocated to triple therapy arm, the site coordinator will inform the clinical team and the intervention will begin in addition to other aspects of usual care

6. Study interventions

   1. Protocol delivery When a subject is assigned to the triple therapy, the study team receives a packet of the study materials. These will include an instruction sheet that outlines the protocol arm with accompanying data collection forms (flowsheet). A similar data collection form but without instructions or prompts, will be used by the site investigator for subjects in the 'usual care' arm to ensure equivalent data collection.

      If the subject is transferred from the ED or inpatient ward to the ICU and the protocol will continue as planned. At the end of the 7 days intervention, study medications will be discontinued to the extent possible.

   2. Data variables collected Study data in both arms will be collected by the unit study coordinator as per the study protocol, reviewed by the co-primary investigators, and will then become part of the subject's research record.
7. Adverse and disease-related events The research group will be responsible for notifying the DSMB regarding all reported AEs as per the definition and the procedures in the study protocol.
8. Data collection and statistical considerations Aim #1 and Aim #2: Mortality and Morbidity benefits:The primary hypotheses to be tested sequentially as part of Aim 1 are: Hypothesis 1, that triple therapy results in lower hospital mortality than usual care (arm A vs. arm B) and; Hypothesis 2, that that triple therapy results in lower hospital morbidity than usual care (arm A vs. arm B) The primary hypothesis to be tested as part of Aim 2 is that triple therapy results in no more adverse effects than placebo

9. Sample size We estimated that a total of 188 patients will give the study a power more than 80% to detect a relative risk reduction of approximately 50% in the primary outcome between the two arms assuming that the mortality in the control arm will be around 40% (based on institutional data and mortality rate in the control group of Marik study) using a two-sided test at significance level of 0.05.

   To be able to perform the interim analysis after recruitment of 50% of patients, the sample size is increased to 190 patients. We decided to enroll 212 patients (106 in each group) to account for 10% possible withdrawals.

10. Analysis plan The trial is designed to test the primary hypothesis (whether triple therapy is superior to usual care for treatment of septic shock).

    1. Descriptive analysis:

       Baseline characteristics and outcome data will be described as mean with standard deviation for continuous variables, median with interquartile range for ordinal variables and frequencies and percentages for categorical variables. The baseline characteristics will be compared between the two arms to observe balance and the success of randomization. These comparisons will not be subjected to statistical testing; as such tests are not recommended.

    2. Primary outcome: the number and percentage of hospital mortality after randomization will be reported for each treatment group. A multivariate logistic regression will be used with adjusted for APACHE II score at baseline. At the final analysis, the null hypothesis will be rejected when p\<0.048. Analysis will be performed according to intention to treat principle.
11. Interim analysis is planned after recruitment of 50% of the predefined sample size (50 patients in each group). Decision to terminate the study at the interim analysis will be based on the O'Brien-Fleming boundary and will be taken by the DSMB as per the protocol. Thus, the study will be terminated if the two-sided P value of statistic test at the interim analysis is less than 0.005 and a boundary P value of 0.048 will be used for the statistical testing at the final analysis. If the intervention shows clinical superiority (defined as relative risk reduction of 10% or more) compared to usual care at the interim analysis but doesn't meet the statistical criteria for early termination, sample size adjustment will be performed. In this case, the sample size will be recalculated based on the observed event rates in both groups.