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

COVID-19 Clinical Trial

— AVoCaDO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04357782
• Other study ID #: Davis 001
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 16, 2020
• Est. completion date: October 13, 2020

Study information

• Verified date: February 2022
• Source: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: October 13, 2020
• Est. primary completion date: October 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Coronavirus Infections
• 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)

Locations

Country	Name	City	State
United States	Hunter Holmes Mcguire Veteran Affairs Medical Center	Richmond	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Hunter Holmes Mcguire Veteran Affairs Medical Center	McGuire Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (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. — View 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. — View 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. — View 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. — View Citation

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. — View 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). pii: E292. doi: 10.3390/nu12020292. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Number of Participants With Serious Adverse Reactions	Number of participants with serious adverse events during study drug infusion	Days 1-4
Primary	Number of Participants With Adverse Reactions	Number of participants with adverse reactions during study drug infusion	Days 1-4
Secondary	Ventilator-free Days	Documented days free off mechanical ventilation the first 28 days post enrollment	Days 1-28
Secondary	Intensive Care Unit (ICU)-Free Days	Documented days free of ICU admission the first 28 days post enrollment	Days 1-28
Secondary	Hospital-free Days	Documented days free of hospital admission the first 28 days post enrollment	Days 1-28
Secondary	All-cause Mortality	Incidence of mortality at 28 days by all causes	Days 1-28
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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