A Randomized, Double Blind, Placebo-Controlled Study to Investigate the Effects of Vitamin C, Hydrocortisone and Thiamine on the Outcome of Patients With Severe Sepsis and Septic Shock
Phase: PHASE4
Conditions: Sepsis, Septic Shock, Critical Illness, Fluid Overload
Sponsor: University Medical Centre Ljubljana

 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
Title: 
Double-Blinded 
Randomized 
Prospective Study On the Effects of Vitamin C, 
Hydrocortisone and Thiamine in Severe Sepsis 
and Septic Shock Patients. 
 
 
 
October 25th 2017 
 
 

Double-Blinded Randomized Prospective Study On the Effects of Vitamin C, Hydrocortisone and Thiamine in 
Severe Sepsis and Septic Shock Patients. October 25th 2017 
AIM OF OUR STUDY: 
The goal is to determine the effects on clinical course and outcome of patients with 
severe sepsis and septic shock treated with vitamin C, hydrocortisone and thiamine.  
 
BACKGROUND: 
This study will be conducted in the intensive care unit of Department of 
Gastroenterology, UMC Ljubljana. All of the patients with severe sepsis and septic 
shock admitted to the ICU in the past 12 hours will be screened for possible inclusion 
in the study. The diagnosis of severe sepsis and septic shock will be based on the 
1992 American College of Chest Physicians/Society of Critical Care Medicine 
Consensus Conference definitions.  
 
PLAN OF THE STUDY: 
After determining the eligibility for inclusion in our study, we will acquire the written 
consent from the patient or relatives. We will randomize the patient either in the 
treatment or placebo group. The randomization will be done before-hand with the 
online tool Research Randomizer (online: https://www.randomizer.org). After 
acquiring the randomized numbers, they will be placed in sealed envelopes. These 
envelopes will be available to the on-call doctor. The envelopes will then be sent to 
our outpatient clinic, where the studied substances will be mixed by a nurse, that will 
have no contact with the patients or the ICU staff. The substances will be marked 
with Vitamin C, Thiamine and Hydrocortisone, regardless if normal saline or the 
actual substances are inside the vials. Only this nurse will have the data regarding 
the contents of the vials.  
 
Vitamin C:  Vitamin C will be mixed as 1500 mg vitamin C in 50ml container, which 
will then be infused over 30 minutes to 1 hour. The bag will be labeled by the 
pharmacy as Vitamin C. The dosing schedule is 1500mg every 6 hours for 4 days or 
until discharge from the ICU.  
 
Vitamin C placebo will consist of an identical container of 50cc normal saline (but 
with no vitamin C) and will be labelled vitamin C. Placebo will be infused over 30-60 
minutes as per the infusion instructions of the active vitamin.   
 
Hydrocortisone:  Hydrocortisone will be mixed as 50 mg of Hydrocortisone in 50 ml 
of 0.9 % Nalco. Patients will be treated with hydrocortisone 50mg IV q 6 hourly for 4 
days or until ICU discharge.   
 
Hydrocortisone placebo will be provided in an identical 50 ml bag of 0.9 % NaCl.  Off 
label treatment with hydrocortisone or another corticosteroid will not be allowed.  
 
Thiamine: Intravenous thiamine will be given in a dose of 200mg q 12 hourly for 4 
days or until ICU discharge. Placebo patients will receive a matching vial of Normal 
Saline.  
 
Based on literature we expect that survival and clinical course in sepsis and septic 
shock is correlated with fluid resuscitation and vasopressor use. Because of this, all 
of the included patients will be monitored with invasive hemodynamic monitoring (in 
our ICU we will be using the Edwards EV 1000 monitors).  
 

Double-Blinded Randomized Prospective Study On the Effects of Vitamin C, Hydrocortisone and Thiamine in 
Severe Sepsis and Septic Shock Patients. October 25th 2017 
All of the patients will be treated the same as per internationally recognized 
guidelines for treatment of septic shock. While the use of corticosteroids in severe 
sepsis is off-label, the patients will be informed of possible side-effects. This fact will 
also be written in the consent.  
 
Neither the patients or the relatives will receive no financial compensation for study 
inclusion. During the hospitalization, the patients will receive three different 
substances in dosages, that are non toxic. During the study we will conduct 
intermittent statistical analysis, and if we would discover increased mortality or 
severe side effects, the study will be terminated. The confidentiality of personal data 
will be protected accordingly with the rules and laws of patient's privacy. The identity 
of patients will not be disclosed. The data acquired during the study will be available 
to the study participant. The anticipated costs will be covered by the Department of 
Gastroenterology, UMC Ljubljana. No financial compensation will be given to 
researchers.   
 
INCLUSION CRITERIA:  
I. Diagnosis of severe sepsis or septic shock within 12 hours of admission in our 
ICU.  
II. Informed consent.  
 
EXCLUSION CRITERIA:  
I. Age < 18 years 
II. Pregnancy 
III. DNR/DNI with limitations of care 
IV. Patients with fatal underlying disease who are unlikely to survive to hospital 
discharge (e.g.: disseminated malignant disease) 
V. Patients primarily admitted for acute coronary syndromes, acute cerebrovascular 
incidents or active GI bleeds 
VI. Patients that need immediate surgical treatment  
VII. Patients with HIV and a CD4 < 50 mm2, 
VIII Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.   
IX. Patients with severe sepsis/septic shock transferred from another hospital 
X. Patients with features of sepsis/septic shock > 24 hours 
XI. Patients who require treatment with corticosteroids for an indication other than 
sepsis (chronic corticosteroid use, known Addison’s Disease, Ulcerative colitis, 
Crohn's disease...) 
 
 
 

Double-Blinded Randomized Prospective Study On the Effects of Vitamin C, Hydrocortisone and Thiamine in 
Severe Sepsis and Septic Shock Patients. October 25th 2017 
During the study we will be acquiring the following data from patients:  
 
1. Age, 
2. Sex, 
3. Body weight, 
4. Admitting diagnosis and source of infection, 
5. Isolated pathogens, 
6. Comorbidities, 
7. The need for mechanical ventilation, 
8. The use of vasopressors (all doses will be converted to Norepinephrine 
equivalents), 
9. The duration of vasoactive therapy, 
10. Daily urine output, 
11. Fluid balance after 24 and 72 hours, 
12. The presence of acute kidney failure  
13. Duration of ICU stay and hospital stay, 
14. Survival in ICU, hospital, after 28 and 60 days 
15. Routine blood test for the first 4 days,  
 
a. creatinine 
 
b. WBC 
 
c. Platelets 
 
d. Bilirubin 
 
e. PaO2/FiO2 ration 
 
e. procalcitonin (PCT) and procalcitonin clearens 
 
f.  lactate 
 
g. blood samples will be stored for possible additional analysis   
 
The patients’ admission APACHE II and APACHE IV scores will be recorded. The 
APACHE IV score allows calculation of the predicted hospital mortality and predicted 
ICU length of stay (LOS).  The daily SOFA (Sepsis-related Organ Failure 
Assessment) score will be recorded for the first 4 treatment days. 
 
STUDY END-POINTS: 
 
PRIMARY END-POINT 
i. Hospital Mortality 
 
SECONDARY END-POINTS 
i. 60-day mortality 
ii. 28-day mortality 
iii. Time to vasopressor independence. Defined as the time from starting the active 
treatment/placebo to discontinuation of all pressors 
iv. PCT clearance (PCT-c) calculated using the following formula: initial PCT minus 
PCT at 96 hours, divided by the initial PCT multiplied by 100. 
v. Delta SOFA score, defined as the initial SOFA score minus the day 4 SOFA score 
vi. ICU mortality 
vii. 
ICU length of stay (LOS) and ICU free days. ICU free days is calculated as 
the number of days alive and out of the ICU to day 28 
viii. 
Hospital LOS 
 

Double-Blinded Randomized Prospective Study On the Effects of Vitamin C, Hydrocortisone and Thiamine in 
Severe Sepsis and Septic Shock Patients. October 25th 2017 
 
DATA ANALYSIS 
Summary statistics will be used to describe the clinical data and presented as mean 
± SD, median with interquartile range (IQR) or percentages as appropriate.  Chi 
squared analysis with Fisher’s exact test (when appropriate) and Student’s t test 
(Mann Whiney U test for non-normal distributions) were used to compare data 
between the active treatment group and the placebo group with statistical 
significance declared for probability values of 0.05 or less.  
 
 
EXPECTED RESULTS: 
We expect a faster recovery, shorter hospitalization, shorter use of vasoactive drugs 
and better survival in treatment group vs. control group.  
 
 
Sebastian Stefanovic, MD 
Department of Gastroenterology,  
UMC Ljubljana 
 
 
 

Double-Blinded Randomized Prospective Study On the Effects of Vitamin C, Hydrocortisone and Thiamine in 
Severe Sepsis and Septic Shock Patients. October 25th 2017 
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