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The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03335124
Recruitment Status : Terminated (Due to insufficient recruitment)
First Posted : November 7, 2017
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
Sebastian Stefanovic, MD, University Medical Centre Ljubljana

Tracking Information
First Submitted Date  ICMJE October 25, 2017
First Posted Date  ICMJE November 7, 2017
Last Update Posted Date February 19, 2019
Actual Study Start Date  ICMJE September 26, 2017
Actual Primary Completion Date December 1, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2017)
Hospital mortality [ Time Frame: From date of randomization till time of discharge, assessed up to 12 months ]
We will compare mortality between the treatment and placebo groups during the hospitalization
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2017)
  • 60 day mortality [ Time Frame: 60 days from inclusion in the study ]
    We will compare mortality between the treatment and placebo groups after 60 days after inclusion in the study
  • 28 day mortality [ Time Frame: 28 days from inclusion in the study ]
    We will compare mortality between the treatment and placebo groups after 28 days after inclusion in the study
  • Time to vasopressor independence [ Time Frame: Defined as the time from starting the active treatment/placebo to discontinuation of all pressors, till discharged from ICU, assessed in the first month ]
    Defined as the time from starting the active treatment/placebo to discontinuation of all pressors
  • PCT clearance [ Time Frame: The first 4 days in Intensive Care Unit ]
    Clearance of calculated procalcitonin using the following formula: initial PCT minus PCT at 96 hours, divided by the initial PCT multiplied by 100.
  • Delta SOFA score [ Time Frame: The first 4 days in Intensive Care Unit ]
    Delta Systemic Organ Failure Assesment score, defined as the initial SOFA score minus the day 4 SOFA score. The Sequential Organ Failure Assessment (SOFA) is a morbidity severity score and mortality estimation tool developed from a large sample of ICU patients throughout the world. The higher the value, the higher the mortality. The maximum score is 24, the lowest 0.
  • ICU length of stay (LOS) and ICU free days. [ Time Frame: ICU free days is calculated as the number of days alive and out of the ICU to day 28 ]
    ICU free days is calculated as the number of days alive and out of the ICU to day 28
  • Hospital Length of Stay [ Time Frame: Hospital Length of Stay through the study completion, assessed up to 12 months ]
    The length of stay in the hospital
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock
Official Title  ICMJE 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
Brief Summary The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. New therapeutic approaches to sepsis are desperately required; considering the global burden of sepsis these interventions should be effective, cheap, safe and readily available. The aim is to study the synergistic effect of vitamin C, hydrocortisone and thiamine on survival in patients with severe sepsis and septic shock.
Detailed Description

AIM OF THE 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, University Medical Center (UMC) Ljubljana. All of the patients with severe sepsis and septic shock admitted to the Intensive Care Unit (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, the investigators will acquire the written consent from the patient or relatives. The investigators (doctor on call) will randomize the patient either in the treatment or placebo group. The randomization will be done before-hand with the online tool Research Randomizer. 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.

Based on literature the investigators 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 (All of the patients will be monitored with the Edwards EV 1000 monitors).

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, there will be intermittent statistical analysis, and if increased mortality or severe side effects will be found then 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.

During the study the following data will be acquired from the 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. White Blood Cells (WBC) c. Platelets d. Bilirubin e. Partial Pressure of Oxygen in Arterial Blood/Fraction of Inspired Oxygen (PaO2/FiO2) ratio e. procalcitonin (PCT) and procalcitonin clearance f. lactate g. blood samples will be stored for possible additional analysis

The patients' admission Acute Physiology and Chronic Health Evaluation (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 Sepsis-related Organ Failure Assessment (SOFA) score will be recorded for the first 4 treatment days.

Data analysis:

Summary statistics will be used to describe the clinical data and presented as mean ± standard deviation (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 Whitney 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.

Data Safety & storage:

The main risk to subjects is the accidental release of Protected Health Information (PHI). Careful record management methods will be in place to ensure this type of privacy breach does not occur. The data set will be kept in a password-protected file and stored separately from the subject identification (ID) key in the locked office of the principal investigator. Only the research team will have access to this information, and will not disclose this information to any other person or entity. Three years after the completion of the study, all collected data will be destroyed by permanently deleting electronic copies.

EXPECTED RESULTS:

The investigators expect a faster recovery, shorter hospitalization, shorter use of vasoactive drugs and better survival in treatment group versus (vs.) control group.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE
  • Sepsis
  • Septic Shock
  • Critical Illness
  • Fluid Overload
Intervention  ICMJE
  • Drug: Vitamin C
    Vitamin C: Vitamin C will be applied as per instructions described in arm/group descriptions.
    Other Name: Ascorbic Acid
  • Drug: Hydrocortisone
    Hydrocortisone: Hydrocortisone will be applied as per instructions described in arm/group descriptions.
    Other Name: Corticosteroids
  • Drug: Thiamine
    Intravenous thiamine will be applied as per instructions described in arm/group descriptions.
    Other Name: B1 Vitamin
  • Drug: 0.9% Sodium Chloride Injection
    0.9 % Sodium Chloride will be applied as placebo as per instructions described in arm/group descriptions.
    Other Name: Normal Saline
Study Arms  ICMJE
  • Experimental: Active substances

    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.

    Hydrocortisone: Hydrocortisone will be mixed as 50 mg of Hydrocortisone in 50 ml of 0.9 % Sodium Chloride. Patients will be treated with hydrocortisone 50mg IV q 6 hourly for 4 days or until ICU discharge.

    Thiamine: Intravenous thiamine will be given in a dose of 200mg q 12 hourly for 4 days or until ICU discharge.

    Interventions:
    • Drug: Vitamin C
    • Drug: Hydrocortisone
    • Drug: Thiamine
  • Placebo Comparator: Control
    Vitamin C placebo will consist of an identical container of 50cc normal saline (0.9% Sodium Chloride Injection) (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 placebo will be provided in an identical 50 ml bag of 0.9% Sodium Chloride Injection. Placebo patients will receive a matching vial of 0.9% Sodium Chloride Injection.
    Intervention: Drug: 0.9% Sodium Chloride Injection
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 17, 2019)
5
Original Estimated Enrollment  ICMJE
 (submitted: November 6, 2017)
30
Actual Study Completion Date  ICMJE December 1, 2018
Actual Primary Completion Date December 1, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of severe sepsis or septic shock within 12 hours of admission in our Intensive Care Unit (ICU).
  • Informed consent.

Exclusion Criteria:

  • Age < 18 years
  • Pregnancy
  • Do Not Resuscitate (DNR/DNI) with limitations of care
  • Patients with fatal underlying disease who are unlikely to survive to hospital discharge (e.g.: disseminated malignant disease)
  • Patients primarily admitted for acute coronary syndromes, acute cerebrovascular incidents or active gastrointestinal (GI) bleeds
  • Patients that need immediate surgical treatment
  • Patients with HIV and a cell count of cluster of differentiation 4 (CD4) cells < 50 mm2,
  • Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.
  • Patients with severe sepsis/septic shock transferred from another hospital
  • Patients with features of sepsis/septic shock > 24 hours
  • Patients who require treatment with corticosteroids for an indication other than sepsis (chronic corticosteroid use, known Addison's Disease, Ulcerative colitis, Crohn's disease...)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Slovenia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03335124
Other Study ID Numbers  ICMJE CSEPSIS
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All collected IPD
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: For a year after the completion of the study
Access Criteria: Contributing authors that will sign the declaration of patient data confidentiality.
Responsible Party Sebastian Stefanovic, MD, University Medical Centre Ljubljana
Study Sponsor  ICMJE University Medical Centre Ljubljana
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sebastian Stefanovic, MD University Medical Center Ljubljana, Department of Gastroenterology
PRS Account University Medical Centre Ljubljana
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP