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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Infusion | Active Comparator | L-Ascorbic Acid (Vitamin C), intravenous infusion |
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| Placebo | Placebo Comparator | Dextrose 5% Water |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| L-ascorbic acid | Drug | 50 mg/kg intravenous vitamin C infusion every 6 hours for up to 96 hours |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in COVID Disease Status | COVID disease status was measured for improvement using the World Health Organization (WHO) ordinal scale for clinical improvement of COVID-19 over ICU admission within 27 days. The WHO scale is a 9-point ordinal scale ranging from uninfected (0), ambulatory (1-2), hospitalized with severe disease (5), hospitalized with intubation and organ support (6-7) and death (score of 8). | Over 27 days from baseline, day 60 and day 90 day |
| Measure | Description | Time Frame |
|---|---|---|
| Renal Safety Biomarkers - Serum Oxalate | Change in serum oxalate levels | On days 5,7 and 14 |
| Renal Safety Biomarkers - Urine Oxalate Stones | Microscopic analysis of urine for presence of oxalate stones |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alpha (Berry) A Fowler, III, MD | Virginia Commonwealth University | Principal Investigator |
| Brian Davis, MD | Hunter Holmes McGuire VA Medical Center - Richmond, VA | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Virginia Commonwealth University | Richmond | Virginia | 23298 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32087114 | Background | 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. | |
| 31573637 | Background | 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. |
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There is no default plan to share individual participant data. May be considered upon reaching the VCU IRB
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| ID | Title | Description |
|---|---|---|
| FG000 | Infusion | L-Ascorbic Acid (Vitamin C), intravenous infusion L-ascorbic acid: 50 mg/kg intravenous vitamin C infusion every 6 hours for up to 96 hours |
| FG001 | Placebo | Dextrose 5% Water Placebo: Dextrose 5% Water |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Infusion | L-Ascorbic Acid (Vitamin C), intravenous infusion L-ascorbic acid: 50 mg/kg intravenous vitamin C infusion every 6 hours for up to 96 hours |
| BG001 | Placebo | Dextrose 5% Water Placebo: Dextrose 5% Water |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in COVID Disease Status | COVID disease status was measured for improvement using the World Health Organization (WHO) ordinal scale for clinical improvement of COVID-19 over ICU admission within 27 days. The WHO scale is a 9-point ordinal scale ranging from uninfected (0), ambulatory (1-2), hospitalized with severe disease (5), hospitalized with intubation and organ support (6-7) and death (score of 8). | All data points were not available for all subjects at follow-up, Day 27, 60, 90, due to participants not actively being admitted within the ICU and available for assessments. | Posted | Mean | Standard Deviation | score on a scale | Over 27 days from baseline, day 60 and day 90 day |
|
Adverse events were monitored/assessed from baseline to the end of study procedures, or until participants withdrew from the study, up to day 90 for each enrolled participant
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Infusion | L-Ascorbic Acid (Vitamin C), intravenous infusion L-ascorbic acid: 50 mg/kg intravenous vitamin C infusion every 6 hours for up to 96 hours |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| While on study, a subject experienced arrythmia possible ventricular tachycardia (VT) and cardiac ar | Cardiac disorders | Non-systematic Assessment | While on study, a subject experienced arrythmia possible ventricular tachycardia (VT) and cardiac arrest that resulted in death of the subject on 11NOV2021 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vtach episode during study drug infusion | Cardiac disorders | Non-systematic Assessment | Patient experienced Vtach episode during study drug infusion. Infusion paused, ekg done, study infusion restarted by bedside attending. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Alpha Fowler | Virginia Commonwealth University | (804) 519-4369 | alpha.fowler@vcuhealth.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 10, 2021 | Mar 6, 2024 | Prot_SAP_002.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D055371 | Acute Lung Injury |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D001205 | Ascorbic Acid |
| ID | Term |
|---|---|
| D013400 | Sugar Acids |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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| Placebo | Other | Dextrose 5% Water |
|
| On days 5,7 and 14 |
| Renal Safety Biomarkers - 24-hour Urine Oxalate Levels | Renal safety will be Measured via renal safety biomarkers - 24- hour urine oxalate level | On days 5,7 and 14 |
| Acute Kidney Injury-free Days | Renal-failure free days, with AKI defined by the KDIGO criteria | Over 27 days from baseline |
| Number of Deaths | Mortality by all cause was comprehensively collected using hospital encounter information over 27 days from baseline, in addition to public record review at day 60 and day 90. Results for this outcome represents the number of deaths that have occurred between each time point. | Over 27 days from baseline, day 60 and day 90 day |
| Change in Plasma Ferritin Levels | Difference in plasma ferritin levels in ng/mL, compared to baseline levels | Day 0 (baseline), day 1, day 7 |
| Change in Plasma D-dimer Levels | Difference in D-dimer levels in mcg/mL, compared to baseline levels | Day 0 (baseline), days 1, 2, 3, 4, 5, 6, and 7 |
| Change in Serum Lactate Dehydrogenase (LDH) Levels | Difference in lactate dehydrogenase (LDH) levels in units/L, compared to baseline levels | Day 0 (baseline), days 1, 2, 3, 4, 5, 6 and 7 |
| Change in Plasma IL-6 Levels | Difference in plasma IL-6 levels in pg/mL, compared to baseline levels | Day 0 (baseline), days 1, 2, 3, 4, 5, 6 and 7 |
| Number 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 | At 28-days |
| Number of Patients Alive and Free of Invasive Mechanical Ventilation | Number of patients alive and not requiring invasive mechanical ventilation. The results represent the number of patients who were ventilator free. | At 28-days |
| 32096845 | Background | 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. |
| 31978969 | Background | 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. |
| 24484547 | Background | 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. |
| 21358394 | Background | 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. |
| 22523283 | Background | 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. |
| 23917525 | Background | 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. |
| 28825709 | Background | 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. |
| 32091533 | Background | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex/Gender, Customized | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Weight at Admission (kg) | Mean | Standard Deviation | Kilograms |
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| OG001 | Placebo | Dextrose 5% Water Placebo: Dextrose 5% Water |
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| Secondary | Renal Safety Biomarkers - Serum Oxalate | Change in serum oxalate levels | Due to staffing/operational challenges in conjunction with only following participants during the ICU admission not all subjects participated in day 5, 7, & 14 oxalate collection. During COVID, methods to limit access to potential exposure & limited PPE restricted collection timepoints. Also, an internal facility error in collection process was noted by outside lab during processing samples. Facility process updated to include new methods, however multiple samples were unable to be processed. | Posted | Mean | Standard Deviation | umol per liter | On days 5,7 and 14 |
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| Secondary | Renal Safety Biomarkers - Urine Oxalate Stones | Microscopic analysis of urine for presence of oxalate stones | Due to staffing/operational challenges in conjunction with only following participants during the ICU admission not all subjects participated in day 5, 7, & 14 oxalate collection. During COVID, methods to limit access to potential exposure & limited PPE restricted collection timepoints. Also, an internal facility error in collection process was noted by outside lab during processing samples. Facility process updated to include new methods, however multiple samples were unable to be processed. | Posted | Count of Participants | Participants | On days 5,7 and 14 |
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| Secondary | Renal Safety Biomarkers - 24-hour Urine Oxalate Levels | Renal safety will be Measured via renal safety biomarkers - 24- hour urine oxalate level | Due to staffing/operational challenges in conjunction with only following participants during the ICU admission not all subjects participated in day 5, 7, & 14 oxalate collection. During COVID, methods to limit access to potential exposure & limited PPE restricted collection timepoints. Also, an internal facility error in collection process was noted by outside lab during processing samples. Facility process updated to include new methods, however multiple samples were unable to be processed. | Posted | Mean | Standard Deviation | umol/day | On days 5,7 and 14 |
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| Secondary | Acute Kidney Injury-free Days | Renal-failure free days, with AKI defined by the KDIGO criteria | Posted | Mean | Standard Deviation | Days | Over 27 days from baseline |
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| Secondary | Number of Deaths | Mortality by all cause was comprehensively collected using hospital encounter information over 27 days from baseline, in addition to public record review at day 60 and day 90. Results for this outcome represents the number of deaths that have occurred between each time point. | Posted | Count of Participants | Participants | Over 27 days from baseline, day 60 and day 90 day |
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| Secondary | Change in Plasma Ferritin Levels | Difference in plasma ferritin levels in ng/mL, compared to baseline levels | The data is not available for all subjects for all days as reflected in the numbers analyzed. | Posted | Mean | Standard Deviation | ng/mL | Day 0 (baseline), day 1, day 7 |
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| Secondary | Change in Plasma D-dimer Levels | Difference in D-dimer levels in mcg/mL, compared to baseline levels | Data was not available for all of the subjects for all of the days and therefore was not analyzed as reflected in the numbers. | Posted | Mean | Standard Deviation | mg/L FEU | Day 0 (baseline), days 1, 2, 3, 4, 5, 6, and 7 |
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| Secondary | Change in Serum Lactate Dehydrogenase (LDH) Levels | Difference in lactate dehydrogenase (LDH) levels in units/L, compared to baseline levels | Not all of the data was available for all of the subjects as listed below for analysis. | Posted | Mean | Standard Deviation | mmol/L | Day 0 (baseline), days 1, 2, 3, 4, 5, 6 and 7 |
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| Secondary | Change in Plasma IL-6 Levels | Difference in plasma IL-6 levels in pg/mL, compared to baseline levels | Not all data available for all subjects as indicated below for analysis. | Posted | Mean | Standard Deviation | pg/mL | Day 0 (baseline), days 1, 2, 3, 4, 5, 6 and 7 |
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| Secondary | Number 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 | The analyzed population did not reflect all participants still in the study at this time point due to only collecting data for participants remaining in the ICU. | Posted | Count of Participants | Participants | At 28-days |
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| Secondary | Number of Patients Alive and Free of Invasive Mechanical Ventilation | Number of patients alive and not requiring invasive mechanical ventilation. The results represent the number of patients who were ventilator free. | The analyzed population did not reflect all participants still in the study at this time point due to only collecting data for participants remaining in the ICU. | Posted | Count of Participants | Participants | At 28-days |
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| 5 |
| 22 |
| 0 |
| 22 |
| 0 |
| 22 |
| EG001 | Placebo | Dextrose 5% Water Placebo: Dextrose 5% Water | 7 | 25 | 1 | 25 | 3 | 25 |
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| Infiltrated IV | General disorders | Non-systematic Assessment | Swelling at the IV site, removed and reinserted. |
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D055370 | Lung Injury |
| D006880 |
| Hydroxy Acids |
| D002241 | Carbohydrates |
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