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SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)

Primary Purpose

COVID-19, Lung Injury, Acute, Kidney Injury

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
L-ascorbic acid
Placebo
Sponsored by
Virginia Commonwealth University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adults of 18 years or older
  • Patients hospitalized with a diagnosis of COVID-19 based on central laboratory-confirmed COVID-19 Novel Coronavirus Disease-2019, based on a positive SARS-CoV-2 RT-PCR confirmed within 72 hours prior to enrollment of nasal, oropharyngeal, or BAL specimen with hypoxemia, (i.e., decrease in oxygenation, as outlined below)
  • Pulse oximetry saturation (SpO2) < 93% on room air in WHO COVID-19 ordinal scale 3 patients, regardless the need for assisted ventilation, or oxygenation.
  • Any new requirement of supplemental oxygen, with any oxygen device (WHO COVID-19 ordinal scale 4-7, regardless of pulse oximetry reading)
  • In patients with supplemental oxygen at home, any increase in the requirement of supplemental oxygen.

Exclusion Criteria:

  • Age less than 18 years
  • Known allergy to Vitamin C
  • Inability to obtain consent from patient or next of kin
  • Presence of diabetic ketoacidosis
  • ANY history of oxalate stones at any time
  • Patients with Kidney Disease Improving Global Outcomes (KDIGO), CKD stage 4 (eGFR < 30 ml/min, CKD stage 5 and end-stage renal disease on dialysis patients are excluded.
  • Patients with Acute Kidney Injury, stage 3 (see page 28).
  • Pregnant, or lactating
  • Known diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Patients who received the following medications within 7 days prior to enrollment, or plan to receive during enrollment, or 7 days after enrollment: aluminum hydroxide, bortezomib, copper, deferoxamine, amphetamines including derivatives such as fluphenazine.
  • Patients with active sickle cell crisis
  • Prisoners

Sites / Locations

  • Hunter Holmes McGuire VA Medical Center
  • Virginia Commonwealth University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Infusion

Placebo

Arm Description

L-Ascorbic Acid (Vitamin C), intravenous infusion

Dextrose 5% Water

Outcomes

Primary Outcome Measures

Change in COVID disease status
COVID disease status will be measured by the 9-point (from 0 to 8) World Health Organization (WHO) ordinal scale for disease improvement at 28 days.

Secondary Outcome Measures

Renal safety biomarkers - serum oxalate
Change in serum oxalate levels
Renal safety biomarkers - urine oxalate stones
Microscopic analysis of urine for presence of oxalate stones
Renal safety biomarkers - 24-hour urine oxalate levels
24-hour urine oxalate levels
Acute Kidney Injury-free days
Renal-failure free days, with AKI defined by the KDIGO criteria
Number of deaths
Mortality by all causes
Change in plasma ferritin levels
Difference in plasma ferritin levels in ng/mL, compared to baseline levels
Change in plasma D-dimer levels
Difference in D-dimer levels in mcg/mL, compared to baseline levels
Change in serum lactate dehydrogenase (LDH) levels
Difference in lactate dehydrogenase (LDH) levels in units/L, compared to baseline levels
Change in plasma IL-6 levels
Difference in plasma IL-6 levels in pg/mL, compared to baseline levels
Proportion of patients alive and free of respiratory failure
Respiratory failure defined as resource utilization requiring at least 1 of the following: Endotracheal intubation and mechanical ventilation, Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, extracorporeal membrane oxygenation
Proportion of patients alive and free of invasive mechanical ventilation
Percentage of patients alive and not requiring invasive mechanical ventilation

Full Information

First Posted
April 9, 2020
Last Updated
June 23, 2023
Sponsor
Virginia Commonwealth University
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1. Study Identification

Unique Protocol Identification Number
NCT04344184
Brief Title
SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)
Official Title
SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
December 18, 2020 (Actual)
Primary Completion Date
June 10, 2022 (Actual)
Study Completion Date
June 10, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Virginia Commonwealth University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will evaluate the safety of a 96-hour intravenous vitamin C infusion protocol (50 mg/kg every 6 hours) in patients with hypoxemia and suspected COVID-19.
Detailed Description
The intravenous vitamin C treatment protocol will be comprised of four intravenous infusions a day, that is 50 mg/kg every 6 hours in patients with laboratory-confirmed SARS-CoV-2 infection manifesting COVID-19 (Novel Coronavirus Disease 2019) with hypoxemia. Treatment protocol will continue for 4 days (96 hours), and, if needed, the last study-specific bloodwork with being collected on day 7. All subjects will be followed to day 28 (phase I) and day 90 (phase II) for collection of clinical outcomes data through electronic health records (EHR) even though the treatment protocol will be completed by 96 hours from randomization at the latest. Secondary outcome data will also be collected either during in-person (clinic) visit or via telephone at the 60 and 90-day follow-up.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, Lung Injury, Acute, Kidney Injury

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Infusion
Arm Type
Active Comparator
Arm Description
L-Ascorbic Acid (Vitamin C), intravenous infusion
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Dextrose 5% Water
Intervention Type
Drug
Intervention Name(s)
L-ascorbic acid
Other Intervention Name(s)
Vitamin C, Intravenous
Intervention Description
50 mg/kg intravenous vitamin C infusion every 6 hours for up to 96 hours
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Dextrose 5% Water
Primary Outcome Measure Information:
Title
Change in COVID disease status
Description
COVID disease status will be measured by the 9-point (from 0 to 8) World Health Organization (WHO) ordinal scale for disease improvement at 28 days.
Time Frame
Baseline to 28, 60 and 90 days
Secondary Outcome Measure Information:
Title
Renal safety biomarkers - serum oxalate
Description
Change in serum oxalate levels
Time Frame
On days 5,7 and 14
Title
Renal safety biomarkers - urine oxalate stones
Description
Microscopic analysis of urine for presence of oxalate stones
Time Frame
On days 5,7 and 14
Title
Renal safety biomarkers - 24-hour urine oxalate levels
Description
24-hour urine oxalate levels
Time Frame
On days 5,7 and 14
Title
Acute Kidney Injury-free days
Description
Renal-failure free days, with AKI defined by the KDIGO criteria
Time Frame
On day 28, 90
Title
Number of deaths
Description
Mortality by all causes
Time Frame
On day 28, 60 and 90 days
Title
Change in plasma ferritin levels
Description
Difference in plasma ferritin levels in ng/mL, compared to baseline levels
Time Frame
Days 1-7 compared with baseline
Title
Change in plasma D-dimer levels
Description
Difference in D-dimer levels in mcg/mL, compared to baseline levels
Time Frame
Days 1-7 compared with baseline
Title
Change in serum lactate dehydrogenase (LDH) levels
Description
Difference in lactate dehydrogenase (LDH) levels in units/L, compared to baseline levels
Time Frame
Days 1-7 compared with baseline
Title
Change in plasma IL-6 levels
Description
Difference in plasma IL-6 levels in pg/mL, compared to baseline levels
Time Frame
Days 1-7 compared with baseline
Title
Proportion of patients alive and free of respiratory failure
Description
Respiratory failure defined as resource utilization requiring at least 1 of the following: Endotracheal intubation and mechanical ventilation, Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, extracorporeal membrane oxygenation
Time Frame
At 28-days
Title
Proportion of patients alive and free of invasive mechanical ventilation
Description
Percentage of patients alive and not requiring invasive mechanical ventilation
Time Frame
At 28-days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adults of 18 years or older Patients hospitalized with a diagnosis of COVID-19 based on central laboratory-confirmed COVID-19 Novel Coronavirus Disease-2019, based on a positive SARS-CoV-2 RT-PCR confirmed within 72 hours prior to enrollment of nasal, oropharyngeal, or BAL specimen with hypoxemia, (i.e., decrease in oxygenation, as outlined below) Pulse oximetry saturation (SpO2) < 93% on room air in WHO COVID-19 ordinal scale 3 patients, regardless the need for assisted ventilation, or oxygenation. Any new requirement of supplemental oxygen, with any oxygen device (WHO COVID-19 ordinal scale 4-7, regardless of pulse oximetry reading) In patients with supplemental oxygen at home, any increase in the requirement of supplemental oxygen. Exclusion Criteria: Age less than 18 years Known allergy to Vitamin C Inability to obtain consent from patient or next of kin Presence of diabetic ketoacidosis ANY history of oxalate stones at any time Patients with Kidney Disease Improving Global Outcomes (KDIGO), CKD stage 4 (eGFR < 30 ml/min, CKD stage 5 and end-stage renal disease on dialysis patients are excluded. Patients with Acute Kidney Injury, stage 3 (see page 28). Pregnant, or lactating Known diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency Patients who received the following medications within 7 days prior to enrollment, or plan to receive during enrollment, or 7 days after enrollment: aluminum hydroxide, bortezomib, copper, deferoxamine, amphetamines including derivatives such as fluphenazine. Patients with active sickle cell crisis Prisoners
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alpha (Berry) A Fowler, III, MD
Organizational Affiliation
Virginia Commonwealth University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Brian Davis, MD
Organizational Affiliation
Hunter Holmes McGuire VA Medical Center - Richmond, VA
Official's Role
Study Director
Facility Information:
Facility Name
Hunter Holmes McGuire VA Medical Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no default plan to share individual participant data. May be considered upon reaching the VCU IRB
Citations:
PubMed Identifier
32087114
Citation
Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. doi: 10.1016/S1473-3099(20)30120-1. Epub 2020 Feb 19. No abstract available. Erratum In: Lancet Infect Dis. 2020 Sep;20(9):e215.
Results Reference
background
PubMed Identifier
31573637
Citation
Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, Damm T, Cassity E, Wieliczko A, Halquist M. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825. Erratum In: JAMA. 2020 Jan 28;323(4):379.
Results Reference
background
PubMed Identifier
32096845
Citation
Fowler AA 3rd, Fisher BJ, Kashiouris MG. Vitamin C for Sepsis and Acute Respiratory Failure-Reply. JAMA. 2020 Feb 25;323(8):792-793. doi: 10.1001/jama.2019.21987. No abstract available.
Results Reference
background
PubMed Identifier
31978969
Citation
Kashiouris MG, L'Heureux M, Cable CA, Fisher BJ, Leichtle SW, Fowler AA. The Emerging Role of Vitamin C as a Treatment for Sepsis. Nutrients. 2020 Jan 22;12(2):292. doi: 10.3390/nu12020292.
Results Reference
background
PubMed Identifier
24484547
Citation
Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
Results Reference
background
PubMed Identifier
21358394
Citation
Fisher BJ, Seropian IM, Kraskauskas D, Thakkar JN, Voelkel NF, Fowler AA 3rd, Natarajan R. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med. 2011 Jun;39(6):1454-60. doi: 10.1097/CCM.0b013e3182120cb8. Erratum In: Crit Care Med. 2011 Aug;39(8):2022.
Results Reference
background
PubMed Identifier
22523283
Citation
Fisher BJ, Kraskauskas D, Martin EJ, Farkas D, Wegelin JA, Brophy D, Ward KR, Voelkel NF, Fowler AA 3rd, Natarajan R. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012 Jul 1;303(1):L20-32. doi: 10.1152/ajplung.00300.2011. Epub 2012 Apr 20.
Results Reference
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PubMed Identifier
23917525
Citation
Fisher BJ, Kraskauskas D, Martin EJ, Farkas D, Puri P, Massey HD, Idowu MO, Brophy DF, Voelkel NF, Fowler AA 3rd, Natarajan R. Attenuation of sepsis-induced organ injury in mice by vitamin C. JPEN J Parenter Enteral Nutr. 2014 Sep;38(7):825-39. doi: 10.1177/0148607113497760. Epub 2013 Aug 5.
Results Reference
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PubMed Identifier
28825709
Citation
Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM, Cowin BL, Bruner E, Murphy MM, Chen W, Spangrude GJ, Hu Z, DeBerardinis RJ, Morrison SJ. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017 Sep 28;549(7673):476-481. doi: 10.1038/nature23876. Epub 2017 Aug 21.
Results Reference
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PubMed Identifier
32091533
Citation
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
Results Reference
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SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)

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