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Metabolic Resuscitation in Sepsis: A Randomized Clinical Trial

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ClinicalTrials.gov Identifier: NCT03389555
Recruitment Status : Not yet recruiting
First Posted : January 3, 2018
Last Update Posted : January 3, 2018
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
In this study, we aim to determine whether the combination of vitamin C, vitamin B1 (thiamine), and cotricosteroids improves the trajectory of organ failure and reduces mortality in patients with severe sepsis and septic shock as compared to placebo.

Condition or disease Intervention/treatment Phase
Sepsis Septic Shock Metabolic Disturbance Drug: vitamin C, vitamin B1, hydrocortisone Drug: Normal saline Phase 2 Phase 3

Detailed Description:

Severe Sepsis and Septic Shock are common and highly morbid clinical conditions without any specific therapy aside from antibiotics. A recent quasi-experimental study (Marik et. al., PMID 27940189) demonstrated a remarkable benefit when the combination of vitamin C, corticosteroids, and thiamine were given to patients with sepsis. In particular, patients who received this combination of medications required a shorter amount of time on vasopressors, suffered less organ failure, and had improved mortality. Vitamin C has long been suggested for treatment of patients with severe infection as it exerts significant anti-oxidant effects and reduces endothelial permeability. Corticosteroids, a mainstay of therapy for refractory shock in sepsis, have also been shown to enhance the beneficial cellular effects of vitamin C. Finally, thiamine has been shown to be an effective mitochondrial resuscitator in sepsis, especially for the ~30% of septic shock patients who present with thiamine deficiency (Donnino et. al, PMID 26771781).

In this study, we aim to reproduce the findings of Marik et. al. using a more rigorous study design (i.e. a blinded, randomized clinical trial) and focus on the important clinical outcomes of organ failure and death.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Vitamin C, Steroids, and Thiamine in Severe Sepsis and Septic Shock
Anticipated Study Start Date : January 1, 2018
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : September 30, 2019


Arms and Interventions

Arm Intervention/treatment
Experimental: Vitamin C, Vitamin B1, Corticosteroids

The combination of vitamin C, vitamin B1, hydrocortisone :

  • Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days
  • Vitamin B1 (thiamine) 100mg every 6 hours x 4-days
  • Hydrocortisone 50mg every 6 hours x 4-days followed by a taper over 3-days (50mg every 12 hours x1 day, 50mg every 24 hours x 2 days)
Drug: vitamin C, vitamin B1, hydrocortisone
Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV over 45-60 minutes every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days followed by a taper over 3 days.
Placebo Comparator: Placebo
Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components
Drug: Normal saline
Normal saline (0.9% NaCl solution) volume to match all components


Outcome Measures

Primary Outcome Measures :
  1. Sequential Organ Failure Assessment (SOFA) Score Change [ Time Frame: Enrollment to 72-hours ]
    Change in degree of organ dysfunction as defined by the Sequential Organ Failure Assessment (SOFA) Score


Secondary Outcome Measures :
  1. Renal Failure [ Time Frame: Enrollment until 72-hours after enrollment ]
    Development of renal failure as defined by a Kidney Disease Improving Global Outcomes [KDIGO] grade 3 or higher

  2. 30-day mortality [ Time Frame: Enrollment until 30-days after enrollment ]
    Mortality rate


Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult patient (age ≥ 18 years)
  2. Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection
  3. Receiving vasopressor (norepinephrine, phenylephrine, epinephrine, dopamine, or vasopressin)

Exclusion Criteria:

  1. Member of a protected population (pregnant, prisoner)
  2. Known kidney stones within the past 1 year
  3. Chronic kidney disease (CKD stage ≥3b and above)
  4. Known Glucose-6-Phosphate Dehydrogenase deficiency
  5. Known Hemachromatosis
  6. Comfort Measures Only status
  7. Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling physician)
  8. Receiving supplemental thiamine in a dose greater than that contained in a multivitamin
  9. Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this drug
  10. Clinical indication for thiamine as determined by the clinical team providing this drug
  11. Known allergy to vitamin C, hydrocortisone, or thiamine
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03389555


Contacts
Contact: Michael W Donnino, MD 617-754-2450 mdonnino@bidmc.harvard.edu

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
Detroit Receiving Hospital Not yet recruiting
Detroit, Michigan, United States, 48201
Contact: Robert Sherwin, MD         
Henry Ford Hospital Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Joseph Miller, MD         
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
More Information

Publications:
Responsible Party: Michael Donnino, Associate Professor of Emergency Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT03389555     History of Changes
Other Study ID Numbers: 2009P000004
First Posted: January 3, 2018    Key Record Dates
Last Update Posted: January 3, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Michael Donnino, Beth Israel Deaconess Medical Center:
Sepsis
Metabolic Resuscitation

Additional relevant MeSH terms:
Sepsis
Toxemia
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Vitamins
Ascorbic Acid
Thiamine
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Cortisol succinate
Hydrocortisone
Vitamin B Complex
Micronutrients
Growth Substances
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents