ATESS: Ascorbic Acid and Thiamine Effect in Septic Shock

Sponsor

Tae Gun Shin (Other)

Overall Status

Completed

CT.gov ID

NCT03756220

Collaborator

National Research Foundation of Korea (Other)

116

Enrollment

Locations

Arms

16.4

Actual Duration (Months)

19.3

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Septic Shock Sepsis	Drug: Combination therapy of vitamin C and thiamine Drug: Normal saline solution	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

116 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multi-center, Double-blinded, Randomized, Controlled StudyMulti-center, Double-blinded, Randomized, Controlled Study

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Combination Therapy of Vitamin C and Thiamine for Septic Shock: Multi-center, Double-blinded, Randomized, Controlled Study

Actual Study Start Date :

Dec 1, 2018

Actual Primary Completion Date :

Jan 13, 2020

Actual Study Completion Date :

Apr 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Combination therapy of vitamin C and thiamine for 2 days.	Drug: Combination therapy of vitamin C and thiamine Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days Other Names: Ascorbic Acid Injection Thiamine Injection
Placebo Comparator: Control Normal Saline Solution	Drug: Normal saline solution Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days Other Names: 0.9% NaCl

Arm

Intervention/Treatment

Experimental: Treatment

Combination therapy of vitamin C and thiamine for 2 days.

Drug: Combination therapy of vitamin C and thiamine

Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days

Other Names:

Ascorbic Acid Injection

Thiamine Injection

Placebo Comparator: Control

Normal Saline Solution

Drug: Normal saline solution

Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days

Other Names:

0.9% NaCl

Outcome Measures

Primary Outcome Measures

Delta Sequential Organ Failure Assessment (SOFA) score [Enrollment to 72 hours]
72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours)

Secondary Outcome Measures

28-day mortality [Day 28]
The number of participants who did not survive until Day 28 will be compared between the treatment and the control group
7-day mortality (early death) [Day 7]
The number of participants who did not survive until Day 7 will be compared between the treatment and the control group
90-day mortality [Day 90]
The number of participants who did not survive until Day 90 will be compared between the treatment and the control group
Time to death [Enrollment to Day 28]
Days until death
In-hospital death [Up to 12 weeks]
The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group
Intensive care unit death (ICU) death [Up to 12 weeks]
The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group
Time to Shock reversal [Enrollment to Day 14]
Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours.
Vasopressor free days [Enrollment to Day 14]
Days not receiving any vasopressor
Ventilator free days [Enrollment to Day 14]
Days not receiving mechanical ventilation
Ventilator duration [Up to 12 weeks]
Days receiving mechanical ventilation during hospital stay
Renal replacement therapy (RRT) free days [Enrollment to Day 14]
Days not receiving Renal replacement therapy
New use of renal replacement therapy (RRT) [Up to 12 weeks]
The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group
New onset or aggravation of acute kidney injury (AKI) [Enrollment to Day 14]
The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group
Length of ICU stay [Up to 12 weeks]
Number of days in the ICU during hospital admission
ICU free day [Enrollment to Day 14]
Days not being in the ICU
Length of hospital stay [Up to 12 weeks]
Number of days in the hospital during hospital admission

Other Outcome Measures

CRP (C-reactive protein) change during initial 72 hours [Enrollment to 72 hours]
72-hour change in CRP (%)
Procalcitonin change during initial 72 hours [Enrollment to 72 hours]
72-hour change in procalcitonin (%)
Dose of vasopressor at 24-hour [Enrollment to 24 hours]
Norepinephrine equivalent dose at 24 hours from enrollment
Dose of vasopressor at 48-hour [Enrollment to 48 hours]
Norepinephrine equivalent dose at 48 hours from enrollment
Dose of vasopressor at 72-hour [Enrollment to 72 hours]
Norepinephrine equivalent dose at 72 hours from enrollment
Maximum dose of vasopressor during initial 72 hours [Enrollment to 72 hours]
Maximum norepinephrine equivalent dose during initial 72 hours

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 89 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients (> 18 years)
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:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	Department of Emergency Medicine, Seoul National University Bundang Hospital,	Seongnam	Gyeonggi-do	Korea, Republic of
2	Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine	Seoul		Korea, Republic of
3	Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,	Seoul		Korea, Republic of
4	Department of Emergency Medicine, Seoul National University College of Medicine,	Seoul		Korea, Republic of
5	Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center,	Seoul		Korea, Republic of
6	Department of Emergency Medicine, Yonsei University College of Medicine	Seoul		Korea, Republic of