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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hypoxia, COVID-19

Intervention / Treatment
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* Drug: L-ascorbic acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin C, Ascorbic Acid, Hypoxia, Sepsis, Acute Lung Injury, Acute Respiratory Distress Syndrome, Severe acute respiratory syndrome (SARS)- Coronavirus (CoV)-2