Clinical trial NCT04357782: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: COVID-19
Hypoxia
Keywords: Vitamin C
Ascorbic Acid
Hypoxia
Sepsis
Acute Lung Injury
Acute Respiratory Distress Syndrome
Severe acute respiratory syndrome (SARS)- Coronavirus (CoV)-2
Lead sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
Sponsor class: FED
Collaborators: name: McGuire Research Institute
First posted: 2020-04-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Primary purpose: TREATMENT

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, 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.

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

Primary outcomes:
measure: Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC)
timeFrame: Days 1-4
measure: Number of Participants With Serious Adverse Reactions
timeFrame: Days 1-4
measure: Number of Participants With Adverse Reactions
timeFrame: Days 1-4
Secondary outcomes:
measure: Ventilator-free Days
timeFrame: Days 1-28
measure: Intensive Care Unit (ICU)-Free Days
timeFrame: Days 1-28
measure: Hospital-free Days
timeFrame: Days 1-28
measure: All-cause Mortality
timeFrame: Days 1-28
measure: Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC)
timeFrame: Days 1-4
measure: C-reactive Protein (CRP)
timeFrame: Days 1-4
measure: Lactate Dehydrogenase (LDH)
timeFrame: Days 1-4
measure: D-dimer
timeFrame: Days 1-4
measure: Lymphocyte Count
timeFrame: Days 1-4
measure: Neutrophil to Lymphocyte Ratio (NLR)
timeFrame: Days 1-4
measure: Serum Ferritin
timeFrame: Days 1-4
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Hunter Holmes Mcguire Veteran Affairs Medical Center
state: Virginia
Study officials:
affiliation: Staff Physician, GI Division
name: Brian C Davis, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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. No abstract available.
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.
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.
citation: 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.
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.
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):292. doi: 10.3390/nu12020292.