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

• ClinicalTrials.gov Identifier: NCT04357782
• Recruitment Status: Completed
• First Posted: April 22, 2020
• Results First Posted: February 24, 2022
• Last Update Posted: February 25, 2022
• Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Collaborator: McGuire Research Institute
• Information provided by (Responsible Party): Brian C. Davis, MD, Hunter Holmes Mcguire Veteran Affairs Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19; Hypoxia	Drug: L-ascorbic acid	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Administration of Intravenous Vitamin C in Novel Coronavirus Infection and Decreased Oxygenation (AVoCaDO): A Phase I/II Safety, Tolerability, and Efficacy Clinical Trial
• Actual Study Start Date: April 16, 2020
• Actual Primary Completion Date: October 13, 2020
• Actual Study Completion Date: October 13, 2020

Arms and Interventions

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 Name: 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 Name: Vitamin C, Ascor

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC) [ Time Frame: Days 1-4 ]
   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
2. Number of Participants With Serious Adverse Reactions [ Time Frame: Days 1-4 ]
   Number of participants with serious adverse events during study drug infusion
3. Number of Participants With Adverse Reactions [ Time Frame: Days 1-4 ]
   Number of participants with adverse reactions during study drug infusion

Secondary Outcome Measures :

1. Ventilator-free Days [ Time Frame: Days 1-28 ]
   Documented days free off mechanical ventilation the first 28 days post enrollment
2. Intensive Care Unit (ICU)-Free Days [ Time Frame: Days 1-28 ]
   Documented days free of ICU admission the first 28 days post enrollment
3. Hospital-free Days [ Time Frame: Days 1-28 ]
   Documented days free of hospital admission the first 28 days post enrollment
4. All-cause Mortality [ Time Frame: Days 1-28 ]
   Incidence of mortality at 28 days by all causes
5. Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC) [ Time Frame: Days 1-4 ]
   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
6. C-reactive Protein (CRP) [ Time Frame: Days 1-4 ]

   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.

7. Lactate Dehydrogenase (LDH) [ Time Frame: Days 1-4 ]

   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.

8. D-dimer [ Time Frame: Days 1-4 ]

   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.

9. Lymphocyte Count [ Time Frame: Days 1-4 ]

   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.

10. Neutrophil to Lymphocyte Ratio (NLR) [ Time Frame: Days 1-4 ]

    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.

11. Serum Ferritin [ Time Frame: Days 1-4 ]

    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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Virginia

Hunter Holmes Mcguire Veteran Affairs Medical Center

Richmond, Virginia, United States, 23249

Sponsors and Collaborators

Hunter Holmes Mcguire Veteran Affairs Medical Center

McGuire Research Institute

Investigators

• Principal Investigator: Brian C Davis, MD; Staff Physician, GI Division

  Study Documents (Full-Text)

Documents provided by Brian C. Davis, MD, Hunter Holmes Mcguire Veteran Affairs Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] July 7, 2020

More Information

Publications:

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.

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.

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.

• Responsible Party: Brian C. Davis, MD, Staff Physician, Hunter Holmes Mcguire Veteran Affairs Medical Center
• ClinicalTrials.gov Identifier: NCT04357782
• Other Study ID Numbers: Davis 001
• First Posted: April 22, 2020
• Results First Posted: February 24, 2022
• Last Update Posted: February 25, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Brian C. Davis, MD, Hunter Holmes Mcguire Veteran Affairs Medical Center:

Vitamin C; Ascorbic Acid; Hypoxia; Sepsis; Acute Lung Injury; Acute Respiratory Distress Syndrome; Severe acute respiratory syndrome (SARS)- Coronavirus (CoV)-2

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Hypoxia; Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Ascorbic Acid; Vitamins; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents