Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased Oxygenation (AVoCaDO)

Administration of Intravenous Vitamin C in Novel Coronavirus Infection and Decreased Oxygenation (AVoCaDO): A Phase I/II Safety, Tolerability, and Efficacy Clinical Trial

Previous research has shown that high dose intravenous vitamin C (HDIVC) may benefit patients with sepsis, acute lung injury (ALI), and the acute respiratory distress syndrome (ARDS). However, it is not known if early administration of HDIVC could prevent progression to ARDS.

We hypothesize that HDIVC is safe and tolerable in Coronavirus disease 2019 (COVID-19) subjects given early or late in the disease course and may reduce the risk of respiratory failure requiring mechanical ventilation and development of ARDS along with reductions in supplemental oxygen demand and inflammatory markers.

Study Overview

• Status: Completed
• Conditions: COVID-19; Hypoxia
• Intervention / Treatment: Drug: L-ascorbic acid

Detailed Description

The purpose of this study is to assess the safety, tolerability, potential efficacy of high dose intravenous vitamin C (HDIVC) therapy for patients with COVID-19 and decreased oxygenation. COVID-19 is a rapidly evolving pandemic with numerous prediction models suggesting potential shortages in ventilators, ICU beds, and high rates of hospital mortality. Case-series suggest sepsis and the acute respiratory distress syndrome (ARDS) are driving hospitalizations, morbidity (ICU beds, ventilator use, organ failures), and mortality. A therapy is urgently needed to be given early in the disease course in order to attenuate the infectious and inflammatory process, reduce risk of intubation, and reduce progression of organ failure and ARDS. By administering HDIVC at the first objective sign of worsening oxygenation, documented by change in peripheral capillary oxygen saturation (SpO2) to fraction of inspired oxygen (FIO2) ratio (S/F) or decreased SpO2 at baseline (mild hypoxia group), HDIVC may reduce the inflammatory process and development of respiratory failure requiring intubation. We will also enroll patients already in respiratory failure on ventilators (severe hypoxia group) and document safety and tolerability in both cohorts. By calculating ventilator and ICU-free days, we can potentially signal clinically relevant endpoints that could be used in larger trials needed to answer a crucial therapeutic question-can early administration of HDIVC in COVID-19 lead to faster recovery or improve outcomes? Moreover, we will document change in inflammatory markers that are elevated in COVID-19 (d-dimer, C reactive protein (CRP), lactate dehydrogenase (LDH), liver enzymes, and ferritin) to develop a mechanistic understanding and risk stratification of response to HDIVC infusion. Ultimately, if HDIVC is deemed safe and tolerable in hospitalized COVID-19 subjects, a larger clinical trial will be indicated. AVoCaDO will produce safety and tolerability data to test HDIVC in a multi-center, rapid, randomized, placebo-controlled trial of subjects with COVID-19.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes Mcguire Veteran Affairs Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hospitalized with diagnosis of COVID-19 based on positive reverse transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 of nasal, oropharyngeal, or bronchoalveolar (BAL) specimen
• Mild deoxygenation defined as S/F ratio decreased by 25% from baseline on admission, or SpO2 <95% breathing ambient air on admission
• Non-childbearing potential or childbearing potential with a negative pregnancy test at screening, and using a reliable method of contraception (i.e., abstinence, hormonal contraception, intrauterine device (IUD), or vasectomized partner)

Exclusion Criteria:

• Known allergy to Vitamin C
• Inability to obtain consent from patient or next of kin
• Chronic kidney disease, stage IV or above (eGFR <30)
• Presence of diabetic ketoacidosis, use of insulin infusion, or frequent need for point-of-care glucose monitoring (>6 times/24 hour period) as determined by treating physician
• History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Active or history of kidney stone within past 12 months
• Pregnancy
• Enrolled in another COVID-19 clinical trial that does not allow concomitant study drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mild hypoxemia; S/F ratio >250 prior to Vitamin C infusion	Drug: L-ascorbic acid; 50 mg/kg L-ascorbic acid infusion given every 6 hours for 4 days (16 total doses); Other Names: Vitamin C, Ascor
Active Comparator: Severe Hypoxemia; S/F ratio ≤250 prior to Vitamin C infusion	Drug: L-ascorbic acid; 50 mg/kg L-ascorbic acid infusion given every 6 hours for 4 days (16 total doses); Other Names: Vitamin C, Ascor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC)	Occurrence of adverse events during study drug infusion as defined in the Ascor package insert ie acute kidney injury (increase in serum creatinine 3x baseline prior to initial HDIVC dose, hemolysis, iatrogenic hypoglycemia, pain at swelling site of infusion, crystalluria on urinalysis (UA) after last HDIVC dose	Days 1-4
Number of Participants With Serious Adverse Reactions	Number of participants with serious adverse events during study drug infusion	Days 1-4
Number of Participants With Adverse Reactions	Number of participants with adverse reactions during study drug infusion	Days 1-4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free Days	Documented days free off mechanical ventilation the first 28 days post enrollment	Days 1-28
Intensive Care Unit (ICU)-Free Days	Documented days free of ICU admission the first 28 days post enrollment	Days 1-28
Hospital-free Days	Documented days free of hospital admission the first 28 days post enrollment	Days 1-28
All-cause Mortality	Incidence of mortality at 28 days by all causes	Days 1-28
Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC)	oxygen saturation by pulse oximetry (SpO2) will be divided by fraction of inspired oxygen (FiO2) at start of study infusion and compared with S/F ratio at end of study infusion	Days 1-4
C-reactive Protein (CRP)	The difference in serum CRP during HDIVC infusion reported in mg/dL Local lab with upper measurement limit of 19 mg/dL The change was determined from two time points ie Day 4value minus Day 1 value.	Days 1-4
Lactate Dehydrogenase (LDH)	The difference in LDH during HDIVC infusion will be reported in IU/L The change was determined from two time points ie Day 4 value minus Day 1 value.	Days 1-4
D-dimer	The difference in D-dimer during HDIVC infusion will be reported in ug/mL The change was determined from two time points ie Day 4 value minus Day 1 value.	Days 1-4
Lymphocyte Count	The difference in lymphocyte count during HDIVC infusion will be reported in 10^3 cells/uL The change was determined from two time points ie Day 4 value minus Day 1 value.	Days 1-4
Neutrophil to Lymphocyte Ratio (NLR)	The NLR will be calculated by dividing the absolute neutrophil count (10e3/uL) over the absolute lymphocyte count (10e3/uL) The change was determined from two time points ie Day 4 value minus Day 1 value.	Days 1-4
Serum Ferritin	The difference in serum ferritin will be calculated from the start of HDIVC infusion to day 4 and reported as ng/mL The change was determined from two time points ie Day 4 value minus Day 1 value.	Days 1-4

Collaborators and Investigators

• Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Collaborators: McGuire Research Institute
• Investigators: Principal Investigator: Brian C Davis, MD, Staff Physician, GI Division

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• Sindel A, Taylor T, Chesney A, Clark W, Fowler AA 3rd, Toor AA. Hematopoietic stem cell mobilization following PD-1 blockade: Cytokine release syndrome after transplantation managed with ascorbic acid. Eur J Haematol. 2019 Aug;103(2):134-136. doi: 10.1111/ejh.13248. Epub 2019 Jun 7.
• 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.
• Fowler Iii AA, Kim C, Lepler L, Malhotra R, Debesa O, Natarajan R, Fisher BJ, Syed A, DeWilde C, Priday A, Kasirajan V. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. 2017 Feb 4;6(1):85-90. doi: 10.5492/wjccm.v6.i1.85. eCollection 2017 Feb 4.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2020
• Primary Completion (Actual): October 13, 2020
• Study Completion (Actual): October 13, 2020

Study Registration Dates

• First Submitted: April 17, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): February 25, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Hypoxia; Ascorbic Acid; Sepsis; Acute Respiratory Distress Syndrome; Vitamin C; Acute Lung Injury; Severe acute respiratory syndrome (SARS)- Coronavirus (CoV)-2
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Signs and Symptoms, Respiratory; COVID-19; Coronavirus Infections; Hypoxia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: Davis 001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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