Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS)
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| ClinicalTrials.gov Identifier: NCT03756220 |
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Recruitment Status :
Completed
First Posted : November 28, 2018
Last Update Posted : October 28, 2020
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Septic Shock Sepsis | Drug: Combination therapy of vitamin C and thiamine Drug: Normal saline solution | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 116 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | Multi-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 : | December 1, 2018 |
| Actual Primary Completion Date : | January 13, 2020 |
| Actual Study Completion Date : | April 14, 2020 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment
Combination therapy of vitamin C and thiamine for 2 days.
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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:
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Placebo Comparator: Control
Normal Saline Solution
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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 Name: 0.9% NaCl |
- Delta Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 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)
- 28-day mortality [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Enrollment to Day 28 ]Days until death
- In-hospital death [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Enrollment to Day 14 ]Days not receiving any vasopressor
- Ventilator free days [ Time Frame: Enrollment to Day 14 ]Days not receiving mechanical ventilation
- Ventilator duration [ Time Frame: Up to 12 weeks ]Days receiving mechanical ventilation during hospital stay
- Renal replacement therapy (RRT) free days [ Time Frame: Enrollment to Day 14 ]Days not receiving Renal replacement therapy
- New use of renal replacement therapy (RRT) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Up to 12 weeks ]Number of days in the ICU during hospital admission
- ICU free day [ Time Frame: Enrollment to Day 14 ]Days not being in the ICU
- Length of hospital stay [ Time Frame: Up to 12 weeks ]Number of days in the hospital during hospital admission
- CRP (C-reactive protein) change during initial 72 hours [ Time Frame: Enrollment to 72 hours ]72-hour change in CRP (%)
- Procalcitonin change during initial 72 hours [ Time Frame: Enrollment to 72 hours ]72-hour change in procalcitonin (%)
- Dose of vasopressor at 24-hour [ Time Frame: Enrollment to 24 hours ]Norepinephrine equivalent dose at 24 hours from enrollment
- Dose of vasopressor at 48-hour [ Time Frame: Enrollment to 48 hours ]Norepinephrine equivalent dose at 48 hours from enrollment
- Dose of vasopressor at 72-hour [ Time Frame: Enrollment to 72 hours ]Norepinephrine equivalent dose at 72 hours from enrollment
- Maximum dose of vasopressor during initial 72 hours [ Time Frame: Enrollment to 72 hours ]Maximum norepinephrine equivalent dose during initial 72 hours
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| Ages Eligible for Study: | 19 Years to 89 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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): NCT03756220
| Korea, Republic of | |
| Department of Emergency Medicine, Seoul National University Bundang Hospital, | |
| Seongnam, Gyeonggi-do, Korea, Republic of | |
| Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine | |
| Seoul, Korea, Republic of | |
| Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, | |
| Seoul, Korea, Republic of | |
| Department of Emergency Medicine, Seoul National University College of Medicine, | |
| Seoul, Korea, Republic of | |
| Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center, | |
| Seoul, Korea, Republic of | |
| Department of Emergency Medicine, Yonsei University College of Medicine | |
| Seoul, Korea, Republic of | |
| Principal Investigator: | Tae Gun Shin, MD, PhD | Samsung Medical Center, Sungkyunkwan University School of Medicine |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Tae Gun Shin, Associate professor, Samsung Medical Center |
| ClinicalTrials.gov Identifier: | NCT03756220 |
| Other Study ID Numbers: |
2018R1C1B6006821 |
| First Posted: | November 28, 2018 Key Record Dates |
| Last Update Posted: | October 28, 2020 |
| Last Verified: | October 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| 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 |
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Septic shock Sepsis Vitamin C Thiamine |
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Shock, Septic Shock Sepsis Infections Systemic Inflammatory Response Syndrome Inflammation Pathologic Processes Ascorbic Acid |
Thiamine Vitamins Micronutrients Physiological Effects of Drugs Antioxidants Molecular Mechanisms of Pharmacological Action Protective Agents Vitamin B Complex |