Clinical trial NCT03756220: Ascorbic Acid and Thiamine Effect in Septic Shock
Official title: Combination Therapy of Vitamin C and Thiamine for Septic Shock: Multi-center, Double-blinded, Randomized, Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Septic Shock
Sepsis
Keywords: Septic shock
Sepsis
Vitamin C
Thiamine
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
Collaborators: name: National Research Foundation of Korea
First posted: 2018-11-28
Enrollment: 116
Sex: ALL
Minimum age (years): 19
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, Double-blinded, Randomized, Controlled Study
Primary purpose: TREATMENT

Brief summary: The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

Detailed description: Sepsis is a complex disease involving life-threatening organ dysfunction caused by a dysregulated host response to infection and is still associated with unacceptably high mortality. Sepsis management should be undertaken as a medical emergency and focused on timely intervention, including early identification and treatment of infection through appropriate antimicrobial therapy and source control when applicable as well as reversing hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite these supportive therapies, morbidity and mortality have remained high, suggesting the need for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis; however, no agents have been proven to definitely improve survival.

Vitamin C plays a role in mediating inflammation through antioxidant activities and is also important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol, and vasopressin. Recently, several clinical trials have reported the positive effects of vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier. Early intravenous supplementation is therefore needed to limit loss of microcirculation and oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic adjunct for patients with sepsis and was added to reduce the risk of renal oxalate crystallization. These findings led to a recent before-and-after study showing that treatment of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ dysfunction and reduced the mortality rate.

The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

Eligibility criteria: Inclusion Criteria:

1. Adult patients (\> 18 years)
2. Septic shock: sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure ≥65 mm Hg and a serum lactate level \>2 mmol/L despite adequate volume resuscitation. Sepsis is defined as clinically suspected or confirmed infection with acute organ failure identified as an acute change in total SOFA score with 2 points or more.

Exclusion Criteria:

1. Transferred patients from other hospitals after application of vasopressors or mechanical ventilation
2. Patients who signed a "Do not attempt resuscitation" order or who had set limitations on invasive care
3. Patients who have a terminal, unresponsive illness and survival discharge is not expected (metastatic terminal cancer, etc.)
4. Patients who experienced cardiac arrest before enrollment or when death is anticipated within 24 hours despite maximal treatment
5. Patients who take more than 1g of Vitamin C per day before enrollment or who take supplemental thiamine
6. Pregnant woman
7. Known Glucose-6-phosphate dehydrogenase deficiency
8. Patients with a history of hypersensitivity to vitamin C or thiamine
9. Known Mediterranean anemia
10. Known hyperoxaluria
11. Known cystinuria
12. Acute gout attack
13. Known oxalate renal stone
14. Patients who meet the inclusion criteria 24 hours after emergency department arrival or when enrollment is delayed more than 24 hours after diagnosis of septic shock
15. Inability or refusal of a subject or legal surrogate to give informed consent

Primary outcomes:
measure: Delta Sequential Organ Failure Assessment (SOFA) score
timeFrame: Enrollment to 72 hours
Secondary outcomes:
measure: 28-day mortality
timeFrame: Day 28
measure: 7-day mortality (early death)
timeFrame: Day 7
measure: 90-day mortality
timeFrame: Day 90
measure: Time to death
timeFrame: Enrollment to Day 28
measure: In-hospital death
timeFrame: Up to 12 weeks
measure: Intensive care unit death (ICU) death
timeFrame: Up to 12 weeks
measure: Time to Shock reversal
timeFrame: Enrollment to Day 14
measure: Vasopressor free days
timeFrame: Enrollment to Day 14
measure: Ventilator free days
timeFrame: Enrollment to Day 14
measure: Ventilator duration
timeFrame: Up to 12 weeks
measure: Renal replacement therapy (RRT) free days
timeFrame: Enrollment to Day 14
measure: New use of renal replacement therapy (RRT)
timeFrame: Up to 12 weeks
measure: New onset or aggravation of acute kidney injury (AKI)
timeFrame: Enrollment to Day 14
measure: Length of ICU stay
timeFrame: Up to 12 weeks
measure: ICU free day
timeFrame: Enrollment to Day 14
measure: Length of hospital stay
timeFrame: Up to 12 weeks
Other outcomes:
measure: CRP (C-reactive protein) change during initial 72 hours
timeFrame: Enrollment to 72 hours
measure: Procalcitonin change during initial 72 hours
timeFrame: Enrollment to 72 hours
measure: Dose of vasopressor at 24-hour
timeFrame: Enrollment to 24 hours
measure: Dose of vasopressor at 48-hour
timeFrame: Enrollment to 48 hours
measure: Dose of vasopressor at 72-hour
timeFrame: Enrollment to 72 hours
measure: Maximum dose of vasopressor during initial 72 hours
timeFrame: Enrollment to 72 hours
Locations:
city: Seongnam
country: Korea, Republic of
facility: Department of Emergency Medicine, Seoul National University Bundang Hospital,
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine
city: Seoul
country: Korea, Republic of
facility: Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,
city: Seoul
country: Korea, Republic of
facility: Department of Emergency Medicine, Seoul National University College of Medicine,
city: Seoul
country: Korea, Republic of
facility: Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center,
city: Seoul
country: Korea, Republic of
facility: Department of Emergency Medicine, Yonsei University College of Medicine
Study officials:
affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine
name: Tae Gun Shin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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