COVID-19, Hypoxia
Conditions
Keywords
Vitamin C, Ascorbic Acid, Hypoxia, Sepsis, Acute Lung Injury, Acute Respiratory Distress Syndrome, Severe acute respiratory syndrome (SARS)- Coronavirus (CoV)-2
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.
Interventions
DRUGL-ascorbic acid
50 mg/kg L-ascorbic acid infusion given every 6 hours for 4 days (16 total doses)
Sponsors
McGuire Research Institute
Hunter Holmes Mcguire Veteran Affairs Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC) | 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 |
| Number of Participants With Serious Adverse Reactions | Days 1-4 | Number of participants with serious adverse events during study drug infusion |
| Number of Participants With Adverse Reactions | Days 1-4 | Number of participants with adverse reactions during study drug infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | Days 1-28 | Incidence of mortality at 28 days by all causes |
| Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC) | 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 |
| C-reactive Protein (CRP) | 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. |
| Lactate Dehydrogenase (LDH) | 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. |
| Ventilator-free Days | Days 1-28 | Documented days free off mechanical ventilation the first 28 days post enrollment |
| Lymphocyte Count | 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. |
| Neutrophil to Lymphocyte Ratio (NLR) | 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. |
| Serum Ferritin | 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. |
| D-dimer | 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. |
| Intensive Care Unit (ICU)-Free Days | Days 1-28 | Documented days free of ICU admission the first 28 days post enrollment |
| Hospital-free Days | Days 1-28 | Documented days free of hospital admission the first 28 days post enrollment |
Countries
United States
Participant flow
Recruitment details
38 screened upon admission to hospital with positive severe acute respiratory syndrome (SARS)-Coronavirus (CoV)-2 infection and hypoxemia. Seven declined consent, six had history of nephrolithiasis, four had chronic kidney disease stage IV or V, one had glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Participants by arm
| Arm | Count |
|---|---|
| Mild Hypoxemia S/F ratio \>250 prior to Vitamin C infusion
L-ascorbic acid: 50 mg/kg L-ascorbic acid infusion given every 6 hours for 4 days (16 total doses) | 10 |
| Severe Hypoxemia S/F ratio ≤250 prior to Vitamin C infusion
L-ascorbic acid: 50 mg/kg L-ascorbic acid infusion given every 6 hours for 4 days (16 total doses) | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Discharged from hospital | 1 | 0 |
Baseline characteristics
| Characteristic | Mild Hypoxemia | Total | Severe Hypoxemia |
|---|---|---|---|
| Admission to Intensive Care Unit (ICU) | 2 Participants | 8 Participants | 6 Participants |
| Age, Continuous | 63.5 years | 63.5 years | 65.0 years |
| Chronic Kidney Disease (CKD), any stage | 3 Participants | 5 Participants | 2 Participants |
| Chronic liver disease | 2 Participants | 4 Participants | 2 Participants |
| Chronic Obstructive Lung Disease (COPD) | 4 Participants | 6 Participants | 2 Participants |
| Congestive heart failure | 1 Participants | 3 Participants | 2 Participants |
| Diabetes | 2 Participants | 8 Participants | 6 Participants |
| Hyperlipidemia | 5 Participants | 12 Participants | 7 Participants |
| Hypertension | 6 Participants | 13 Participants | 7 Participants |
| Immunocompromised | 4 Participants | 5 Participants | 1 Participants |
| Obesity, any class | 8 Participants | 12 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 9 Participants | 18 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 3 / 10 |
| other Total, other adverse events | 5 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 10 | 3 / 10 |
Outcome results
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
Time frame: Days 1-4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypoxemia | Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC) | 0 Participants |
| Severe Hypoxemia | Number of Participants With Adverse Events Related to High Dose Intravenous Vitamin C (HDIVC) | 0 Participants |
Primary
Number of Participants With Adverse Reactions
Number of participants with adverse reactions during study drug infusion
Time frame: Days 1-4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypoxemia | Number of Participants With Adverse Reactions | 1 Participants |
| Severe Hypoxemia | Number of Participants With Adverse Reactions | 2 Participants |
Primary
Number of Participants With Serious Adverse Reactions
Number of participants with serious adverse events during study drug infusion
Time frame: Days 1-4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypoxemia | Number of Participants With Serious Adverse Reactions | 0 Participants |
| Severe Hypoxemia | Number of Participants With Serious Adverse Reactions | 2 Participants |
Secondary
All-cause Mortality
Incidence of mortality at 28 days by all causes
Time frame: Days 1-28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypoxemia | All-cause Mortality | 0 Participants |
| Severe Hypoxemia | All-cause Mortality | 3 Participants |
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
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC) | 108 ratio | Standard Deviation 121 |
| Severe Hypoxemia | Change in S/F Ratio During High Dose Intravenous Vitamin C (HDIVC) | 26 ratio | Standard Deviation 140 |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | C-reactive Protein (CRP) | -3.8 mg/dL | Standard Deviation 5.1 |
| Severe Hypoxemia | C-reactive Protein (CRP) | -2.0 mg/dL | Standard Deviation 6.7 |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | D-dimer | -0.21 ug/mL | Standard Deviation 0.72 |
| Severe Hypoxemia | D-dimer | 3.71 ug/mL | Standard Deviation 6.9 |
Secondary
Hospital-free Days
Documented days free of hospital admission the first 28 days post enrollment
Time frame: Days 1-28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypoxemia | Hospital-free Days | 21.5 days |
| Severe Hypoxemia | Hospital-free Days | 8.5 days |
Secondary
Intensive Care Unit (ICU)-Free Days
Documented days free of ICU admission the first 28 days post enrollment
Time frame: Days 1-28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypoxemia | Intensive Care Unit (ICU)-Free Days | 28 days |
| Severe Hypoxemia | Intensive Care Unit (ICU)-Free Days | 13.5 days |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | Lactate Dehydrogenase (LDH) | -42 IU/L | Standard Deviation 131 |
| Severe Hypoxemia | Lactate Dehydrogenase (LDH) | 118 IU/L | Standard Deviation 497 |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | Lymphocyte Count | 329 10^3 cells/uL | Standard Deviation 514 |
| Severe Hypoxemia | Lymphocyte Count | 276 10^3 cells/uL | Standard Deviation 581 |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | Neutrophil to Lymphocyte Ratio (NLR) | -0.89 ratio | Standard Deviation 4.8 |
| Severe Hypoxemia | Neutrophil to Lymphocyte Ratio (NLR) | -0.04 ratio | Standard Deviation 5 |
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.
Time frame: Days 1-4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hypoxemia | Serum Ferritin | -299 ng/mL | Standard Deviation 449 |
| Severe Hypoxemia | Serum Ferritin | -1170 ng/mL | Standard Deviation 2997 |
Secondary
Ventilator-free Days
Documented days free off mechanical ventilation the first 28 days post enrollment
Time frame: Days 1-28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypoxemia | Ventilator-free Days | 28 days |
| Severe Hypoxemia | Ventilator-free Days | 23.5 days |