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
• Last Update Posted: December 23, 2020
• 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

Tracking Information

• First Submitted Date: April 17, 2020
• First Posted Date: April 22, 2020
• Last Update Posted Date: December 23, 2020
• Actual Study Start Date: April 16, 2020
• Actual Primary Completion Date: October 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 20, 2020)

• Incidence of adverse events [ Time Frame: Days 1-4 ]
  Occurrence of adverse events during study drug infusion
• Incidence of serious adverse reactions [ Time Frame: Days 1-4 ]
  Occurrence of serious adverse events during study drug infusion
• Incidence of adverse reactions [ Time Frame: Days 1-4 ]
  Occurrence of adverse reactions during study drug infusion

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 27, 2020)

• Ventilator-free days [ Time Frame: Days 1-28 ]
  Documented days free off mechanical ventilation the first 28 days post enrollment
• ICU-free days [ Time Frame: Days 1-28 ]
  Documented days free of ICU admission the first 28 days post enrollment
• Hospital-free days [ Time Frame: Days 1-28 ]
  Documented days free of hospital admission the first 28 days post enrollment
• All-cause mortality [ Time Frame: Days 1-28 ]
  Incidence of mortality at 28 days by all causes
• Change in S/F ratio during HDIVC infusion [ Time Frame: Days 1-4 ]
  SpO2 (% peripheral oxygenation saturation) 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
• C-reactive protein (CRP) [ Time Frame: Days 1-4 ]
  The difference in serum CRP during HDIVC infusion reported in mg/dL
• Lactate dehydrogenase (LDH) [ Time Frame: Days 1-4 ]
  The difference in LDH during HDIVC infusion will be reported in IU/L
• D-dimer [ Time Frame: Days 1-4 ]
  The difference in D-dimer during HDIVC infusion will be reported in ug/mL
• Lymphocyte count [ Time Frame: Days 1-4 ]
  The difference in lymphocyte count during HDIVC infusion will be reported in 10e3/uL
• 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) and ratio compared with Day 1 versus Day 4
• 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

Original Secondary Outcome Measures (submitted: April 20, 2020)

• Ventilator-free days [ Time Frame: Days 1-28 ]
  Documented days free off mechanical ventilation the first 28 days post enrollment
• ICU-free days [ Time Frame: Days 1-28 ]
  Documented days free of ICU admission the first 28 days post enrollment
• Hospital-free days [ Time Frame: Days 1-28 ]
  Documented days free of hospital admission the first 28 days post enrollment
• All-cause mortality [ Time Frame: Days 1-28 ]
  Incidence of mortality at 28 days by all causes
• Change in S/F ratio during HDIVC infusion [ Time Frame: Days 1-4 ]
  SpO2 (% peripheral oxygenation saturation) 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
• C-reactive protein (CRP) [ Time Frame: Days 1-7 ]
  The difference in serum CRP from start of HDIVC infusion to day 7 will be reported in mg/dL
• Lactate dehydrogenase (LDH) [ Time Frame: Days 1-7 ]
  The difference in LDH from start of HDIVC infusion to day 7 will be reported in IU/L
• D-dimer [ Time Frame: Days 1-7 ]
  The difference in D-dimer from start of HDIVC infusion to day 7 will be reported in ug/mL
• Lymphocyte count [ Time Frame: Days 1-7 ]
  The difference in lymphocyte count from start of HDIVC infusion to day 7 will be reported in 10e3/uL
• Neutrophil to Lymphocyte ratio (NLR) [ Time Frame: Days 1-7 ]
  The NLR will be calculated by dividing the absolute neutrophil count (10e3/uL) over the absolute lymphocyte count (10e3/uL) and ratio compared with Day 1 versus Day 7
• Serum Ferritin [ Time Frame: Days 1-7 ]
  The difference in serum ferritin will be calculated from the start of HDIVC infusion to day 7 and reported as ng/mL

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased Oxygenation
• 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

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.

• 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, CRP, 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
• Study Phase: Phase 1; Phase 2

Study Design

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

Condition

• COVID-19
• Hypoxia

Intervention

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

Study Arms

• Active Comparator: Mild hypoxemia
  S/F ratio >250 prior to Vitamin C infusion
  Intervention: Drug: L-ascorbic acid
• Active Comparator: Severe Hypoxemia
  S/F ratio ≤250 prior to Vitamin C infusion
  Intervention: Drug: L-ascorbic acid

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.
• 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). pii: E292. doi: 10.3390/nu12020292. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 20, 2020): 20
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: October 13, 2020
• Actual Primary Completion Date: October 13, 2020 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04357782
• Other Study ID Numbers: Davis 001
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Brian C. Davis, MD, Hunter Holmes Mcguire Veteran Affairs Medical Center
• Study Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Collaborators: McGuire Research Institute

Investigators

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

• PRS Account: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Verification Date: December 2020