SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)
Phase: PHASE2
Conditions: COVID-19, Lung Injury, Acute, Kidney Injury
Sponsor: Virginia Commonwealth University

CLINICAL STUDY PROTOCOL 
 
 
 
 
SAFEty Study of Early Infusion of Vitamin 
C for Treatment of Novel Coronavirus 
Acute Lung Injury  
(SAFE EVICT CORONA-ALI) 
 
Protocol Version: 1.83 
Protocol Version IRB approved:  08/10/2021 
 
 
 
 
 
VCU IRB Number: HM20018977  
ClinicalTrials.gov Identifier: NCT04344184 
IND: 149518 
 
 

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Study Personnel 
Principal Investigator(s) 
Markos G Kashiouris, MD 
Virginia Commonwealth University 
Department of Internal Medicine 
Pulmonary and Critical Care Medicine 
 
  
Alpha A Fowler, III, MD 
Virginia Commonwealth University 
Department of Internal Medicine 
Pulmonary and Critical Care Medicine 
 Co-Investigators 
 
  
Brian C. Davis, MD 
Central Virginia VA Health System 
Department of Internal Medicine 
Gastroenterology and Hepatology Division 
 
  
Roy T. Sabo, PhD 
Department of Biostatistics 
Virginia Commonwealth University,  
Massey Cancer Institute 
 
  
Stefan Leichtle, MD 
Virginia Commonwealth University 
Department of Surgery 
Division of Trauma Surgery 
 
 
 
 
 
 
 
 
 
 
 
Clinical Coordinators:  
 
 
 
 
 
Regulatory Contact: 
Michael L’Heureux, MD 
Virginia Commonwealth University 
Department of Surgery 
Division of Trauma Surgery 
 
 
 
 
 
 
Kyle Narron and Luiza Bretas 
Virginia Commonwealth University 
Department of Internal Medicine 
Pulmonary and Critical Care Medicine 
 
 
Bret Brooks 
Virginia Commonwealth University 
Department of Internal Medicine 
Pulmonary and Critical Care Medicine 
 
 

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Synopsis 
Study Description 
The purpose of this proof-of-concept, phase 2 safety study is to examine the safety profile, 
and possible therapeutic effects of high-dose, intravenous vitamin C (HDIVC) compared to 
placebo in hospitalized adult patients with novel Coronavirus COVID-19 and hypoxemia. 
Objectives 
To assess the safety profile of a 4-day (96-hour) intravenous vitamin C treatment protocol 
(comprised of four intravenous infusions a day, that is 50 mg/kg every 6 hours) in patients 
with laboratory-confirmed SARS-CoV-2 infection manifesting COVID-19 (Novel 
Coronavirus Disease 2019) with hypoxemia. While performing this phase 2 proof-of-
concept, safety study, we will explore the following hypotheses: 
Endpoint 
Primary Endpoint (Safety): HDIVC infusion does not worsen the patients’ outcomes, as 
measured by differences in the mean 9-point (from 0 to 8) World Health Organization 
(WHO) ordinal scale for disease improvement, between the two populations at 28, 60 and 
90 days: 
 
Table 1. 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virologic evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
  
Limitation of Activities 
2 
Hospitalized mild disease 
Hospitalized, no oxygen therapy 
3 
  
Oxygen by mask or nasal prongs 
4 
Hospitalized Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
  
Intubation and mechanical ventilation 
6 
  
Ventilation + additional organ support – vasopressors, renal 
replacement therapy, ECMO 
7 
Dead 
Death 
8 
Secondary Endpoint A (Safety): Daily renal safety biomarkers on the day of randomization 
(Day 0), then day 1-7. These include (1) daily serum oxalate levels, (2) daily urine 
microscopic analysis for the presence of oxalate stones (3) daily random urine oxalate and 
24-hour urine oxalate levels on days 5,7 and 14.  
 
Secondary Endpoint B (Safety): acute kidney injury-free days at day 28, 90 (stemming from 
daily AKI assessment while patient is in the hospital).  
 
Secondary Endpoint C (Safety): All-cause mortality to day 28, 60 90 (daily assessment).  
 
Secondary Endpoint D: (Exploratory): COVID-19 and sepsis-specific inflammatory marker 
levels on Day 0, then on day 7. These include (1) ferritin, (2) D-dimer, (3) lactate 
dehydrogenase (LDH), (4) interleukin-6, and (5) Trough ascorbate plasma concentrations at 
24 hours, 48 hours, 96 hours and final plasma concentration assessment at168 hours. 
 
Secondary Endpoint E: (Safety): Proportion of patients alive and free of respiratory failure 
through 28-days. (Respiratory failure defined as resource utilization requiring at least 1 of 
the following: Endotracheal intubation and mechanical ventilation, Oxygen delivered by 
high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula 

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at flow rates >20L/min with fraction of delivered oxygen ≥0.5), noninvasive positive 
pressure ventilation, extracorporeal membrane oxygenation).  
 
Secondary Endpoint F: (Safety): Proportion of patients alive and free of invasive 
mechanical ventilation at 28-days. 
 

CLINICAL STUDY PROTOCOL 
 
 
Study Population 
Adult hospitalized patients who have central laboratory-confirmed COVID-19 (Novel 
Coronavirus Disease-2019, based on a positive SARS-CoV-2 RT-PCR confirmed within 72 
hours before enrollment) and new-onset hypoxemia, defined as oxygen saturation (SpO2) < 
93% on pulse oximeter (WHO COVID-19 ordinal scale 3), or requiring any amount of 
supplemental oxygen (WHO COVID-19 ordinal scale 4-7) at (1) Virginia Commonwealth 
University Medical Center, and (2) Central Virginia Veterans Affairs (VA) Health System, 
Richmond, Virginia 
Accrual Ceiling 
The accrual ceiling for this safety trial is a total of 60 patients, between the two centers. 
Phase 
Phase 2, proof-of-concept safety trial. 
Description of Sites/Facilities Enrolling Participants 
The study will involve 2 enrollment sites: (1) Virginia Commonwealth University Medical 
Center, and the (2) Central Virginia Veterans Affairs (VA) Health System, Richmond, 
Virginia. 
Description of Study Intervention 
1. A two-center, prospective, randomized, double-blind, placebo-controlled proof-of-
concept safety study. 
2. A maximum of 60 patients (30 in the treatment, and 30 in the placebo arm) will be 
enrolled between the two centers. 
3. Participants will be randomized to receive either intravenous vitamin C infusion (mixed 
in 5% dextrose in water) or placebo infusion (5% dextrose in water) in a 1:1 manner. 
4. All study drug doses will be administered via an intravenous central or peripheral line 
infusion. Should no central or peripheral line be available at the scheduled time of infusion, 
a call should be placed to the pharmacy to determine if the study drug may be co-infused 
into the line that is infusing a different drug. If co-infusion of study drug is contraindicated, 
then a maximum of 8 hours may delay study drug infusion. If clinical drug administration 
schedule is such that study drug will not have an available administration time beyond this 
delay, a dedicated new intravenous line (peripheral) should be inserted if the patient is 
agreeable. 
5. The study drug will be double-blinded with an identical appearing placebo. 
6. Active treatment duration will continue for 96 hours, or until study withdrawal.  
Study Duration 
The study will be completed in two phases: Phase 1 will end on day 28, and phase 2 at 90 
day follow up.  
Participant Duration 
The participant duration will be 90 days. Participants will receive the 4-day treatment 
period (96-hour); if needed, the last study-specific blood work will be collected up to 7 days 
follow-up after enrollment. Data up to 28 days follow-up will be collected from medical 
records, standard of care procedures, and chart review. Follow up data and patient-reported 
outcome measures will be collected by phone visit at day 90.  

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Schema 
 
 

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Schedule of Activities (SoA) 
Assessments 
Day 
0-1 
Day 
1-2 
Day 
2-3 
Day 
3-4 
Day 
5-7** 
Day 
8-14** 
Day 
15-21** 
Day 
22-28** 
Day 
60& 
90 
WHO-COVID-19 SCALE 
R 
R 
R 
R 
R 
R* 
R* 
R* 
 
AKI, present and stage of AKI 
R 
R 
R 
R 
R 
R* 
R* 
R* 
 
Creatinine, serum (BMP also includes 
sodium, chloride, potassium, BUN, 
bicarbonate, glucose) 
R 
R 
R 
R 
R 
R* 
R* 
R* 
 
Fluid Balance and Urine Output 
R 
R 
R 
R 
R 
R* 
R* 
R* 
 
Microscopic urine analysis 
R 
R 
R 
R 
R 
R14AKI 
R21AKI 
R28AKI 
 
Serum oxalate 
R 
R 
R 
R 
R 
R14AKI 
R21AKI 
R28AKI 
 
Random urine oxalate 
R 
R 
R 
R 
R 
 
 
 
 
24-hour urine oxalate collection 
 
 
 
 
R5, 
R7 
R14 
R21AKI 
R28AKI 
 
Alive and Free of ANY Respiratory 
Failure (yes/no) 
R 
R 
R 
R 
R 
R 
R 
R 
 
Alive and Free from INVASIVE 
mechanical ventilation (yes/no) 
R 
R 
R 
R 
R 
R 
R 
R 
 
Oxygen Device 
Oxygen Flow  
Air Flow [HHFNC only] 
FiO2 [if not NC] 
Intubated last 24 hours? 
Date & time of last intubation 
Extubated last 24 hours or last week? 
Date & time of last Extubation 
ECMO 
S 
S 
S 
S 
S 
S 
S 
S 
 
Body Weight (kg) 
S 
S 
S 
S 
S 
S 
S 
S 
 

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Vital Signs, Mental Status, qSOFA 
S 
S 
S 
S 
S 
S 
S 
S 
 
Maximum norepinephrine rate today 
S 
S 
S 
S 
S 
S 
S 
S 
 
Maximum vasopressin rate today 
S 
S 
S 
S 
S 
S 
S 
S 
 
Maximum dobutamine rate today 
S 
S 
S 
S 
S 
S 
S 
S 
 
Had Cardiac Arrest today (or last 
week)? 
S 
S 
S 
S 
S 
S 
S 
S 
 
Demographics 
Comorbidities 
Active Diagnoses 
Admission APR-DRG 
On O2 at home Y/N 
O2 liters at home 
Baseline creatinine 
Baseline CKD stage 
S 
 
 
 
 
 
 
 
 
Received Dialysis last 24 hours or 
last week 
Received CRRT last 24 hours or 
last week  
S 
S 
S 
S 
S 
S 
S 
S 
 
Any episode of hypoglycemia last 
24hours and week 
[Glucose < 50] 
S 
S 
S 
S 
S 
S 
S 
S 
 
Any clinical symptoms of kidney 
stones? 
Back pain, Flank pain 
Hematuria 
Visible stone passed 
Imaging consistent with new 
kidney stone 
R 
R 
R 
R 
R 
R 
R 
R 
 
     ’  CBC,   ff         
R 
R 
R 
R 
R 
R 
R 
R 
 

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including lymphocyte ratio, 
including potassium, magnesium 
and phosphorus, LDH, D-Dimer, 
CRP, Ferritin, ABG, Urinalysis all 
if performed for patient care, 
pregnancy test (if applies and was 
not obtained)   
Bilirubin Total, AST, ALT, ALP, 
albumin 
R 
 
 
 
R7 
S 
S 
S 
 
Received Steroids last 24 hours or 
last week? 
Steroid type and daily cumulative 
dose [for daily assessment] 
S 
S 
S 
S 
S 
S 
S 
S 
 
COVID-19 specific treatments, 
anticoagulants, and dosage: 
Remdesivir 
Dexamethasone  
Anticoagulants 
Other COVID-19 treatments 
S 
S 
S 
S 
S 
S 
S 
S 
 
Any atrial arrhythmias over the 
last interval [afib, aflutter, SVT] 
S 
S 
S 
S 
S 
S 
S 
S 
 
12-Lead EKG 
R 
S 
S 
S 
S 
S 
S 
S 
S 
Any significant ventricular 
arrhythmias over the last interval 
[not PVCs] 
S 
S 
S 
S 
S 
S 
S 
S 
 
Chest X-Ray  
Chest Computer Tomography 
S 
S 
S 
S 
S 
S 
S 
S 
S 
24-hour urine oxalate on day 5 
(after completion of the last dose) 
S 
S 
S 
S 
R 
S 
S 
S 
S 
Lowest daily blood glucose 
Highest lactate dehydrogenase 
RS 
R 
R 
R 
RS 
 
 
 
 

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(LDH), serum  
Highest D-dimer, plasma 
Highest ferritin, plasma 
Highest C-reactive protein (CRP), 
plasma 
IL-6, plasma  
Baseline and Trough Ascorbic 
Acid (vitamin C levels) 
R 
R 
R 
R 
R7 
 
 
 
 
AKI free-days days 
Urinalysis evaluation for stones 
S 
S 
RS 
S 
S 
S 
S 
S 
S 
Is the patient still hospitalized? If 
not Discharge date time 
 
 
 
 
 
 
 
R 
 
Total Ventilator-Free Days 
 
 
 
 
 
 
 
R 
 
Was the patient paralyzed for 
ARDS at any point? 
 
 
 
 
 
 
 
R 
 
Was placed on iNO at any point? 
 
 
 
 
 
 
 
R 
 
Was placed in a prone position at 
any point? 
 
 
 
 
 
 
 
R 
 
Was placed on ECMO at any point 
during this hospitalization? [VA or 
VV] 
 
 
 
 
 
 
 
R 
 
Did the patient had a 
tracheostomy at any point in this 
hospitalization? 
 
 
 
 
 
 
 
R 
R 
Date and Time of Death if applies 
 
 
 
 
 
 
 
R 
R 
Cause of Death if applies 
 
 
 
 
 
 
 
R 
R 
DNR? If yes when was DNR first 
placed 
 
 
 
 
 
 
 
R 
R 
Phone clinic follow-up patient-
reported outcome measure 
 
 
 
 
 
 
 
 
R 

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PROMIS Dyspnea Assistive 
Devices and Resources score 
(version 1.0). 
Footnotes 
The study protocol does not include phlebotomy (new stick) just for study labs for days 1-4. If labs are obtained for any other reason, then 
study labs marked as “R” will be collected as “add-on” to the hospital lab. The protocol does include study labs that will be used specifically 
for Research marked as RS. 
S = standard of care (when feasible), R = research (optional), RS: research specific including phlebotomy; BMP = basic metabolic profile, 
DNR = do not resuscitate, ECMO = Extracorporeal membrane oxygenation, iNO = inhaled nitric oxide, AKI = acute kidney injury, CRRT = 
Continuous renal replacement therapy (continuous dialysis), HD = Hemodialysis, CKD = Chronic kidney disease, CRP = C Reactive Protein, 
ABG = Arterial blood gas, CAM-ICU = ICU Delirium scale, IL-6 = Interleukin 6, afib = atrial fibrillation, aflutter = atrial flutter, SVT = 
Supraventricular Tachycardia, AST = Aspartate aminotransferase, ALT = Alanine aminotransferase, ALP = Alkaline phosphatase. 
R* IF the patient is in the hospital 
R7 only on day 7 within that interval 
R14 only on day 14 within that interval 
R21 only on day 21 within that interval 
R28 only on day 28 within that interval 
R14AKI collect on day 14 if patient develops AKI and still in the hospital 
R21AKI collect on day 21 if patient develops AKI and still in the hospital 
R28AKI collect on day 28 if patient develops AKI and still in the hospital 
End of Study Definition 
Treatment protocol will continue for 4 days (96 hours), and, if needed, the last study-specific bloodwork with being collected on day 7. Study will end if patient is 
withdrawn from the study, or lost to follow-up. All subjects will be followed to day 28 for collection of clinical outcomes data through electronic health records (EHR) 
even though the treatment protocol will be completed by 96 hours from randomization at the latest. Secondary outcome data will be collected either during in-person 
(clinic) visit or via telephone at the 90-day follow-up. Only acceptable reasons for early study termination include consent withdrawal or loss to follow-up. 

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Abbreviations 
Abbreviation  
Explanation 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ARDS 
Acute Respiratory Distress Syndrome 
Case Report Form 
Case Report Form 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
D5W 
Dextrose 5% Water  
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
FIP 
Feces-Induced Peritonitis 
HDIVC 
High-Dose Intravenous Vitamin C 

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ICU 
Intensive Care Unit 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactic Dehydrogenase 
MCV 
Medical College of Virginia 
RICVA 
Central Virginia VA Health System in Richmond, 
Virginia 
SAE 
Serious Adverse Event  
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SNS 
Strategic National Stockpile 
SOA 
Schedule of Activities 
US 
United States 
VA 
Veterans Affairs 
VCU 
Virginia Commonwealth University 
 
 

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Table of Contents 
SYNOPSIS .............................................................................................................................................. 4 
ABBREVIATIONS ................................................................................................................................ 14 
1 - STATEMENT OF COMPLIANCE .................................................................................................... 17 
1.1 Statement of Compliance ............................................................................................................. 17 
2 - INTRODUCTION ............................................................................................................................. 18 
2.1 Study Rationale ............................................................................................................................. 18 
2.2 Background ................................................................................................................................... 18 
2.3 Risk/Benefit Assessment ............................................................................................................. 24 
2.3.1 Known Potential Risks ............................................................................................................. 24 
2.3.2 Known Potential Benefits ......................................................................................................... 26 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................ 26 
3 - OBJECTIVES AND ENDPOINTS ................................................................................................... 28 
3.1 Objectives and Endpoints ............................................................................................................ 28 
4 - STUDY DESIGN .............................................................................................................................. 32 
4.1 Overall Design ............................................................................................................................... 32 
4.2 Scientific Rationale for Study Design ......................................................................................... 32 
4.3 Justification for Dose ................................................................................................................... 32 
4.4 End of Study Definition ................................................................................................................ 33 
5 - STUDY POPULATION .................................................................................................................... 34 
5.1 Inclusion Criteria ........................................................................................................................... 34 
5.2 Exclusion Criteria .......................................................................................................................... 34 
5.3.1 Special Considerations: Minorities .......................................................................................... 34 
5.3.2 Special Considerations: Acute Kidney Injury patients .......................................................... 34 
5.4 Screen Failures ............................................................................................................................. 37 
5.5 Strategies for Recruitment and Retention .................................................................................. 37 
6 - STUDY INTERVENTION ................................................................................................................. 37 
6.1 Study Intervention Description .................................................................................................... 37 
6.1.1 Dosing and Administration ....................................................................................................... 37 
6.2 Preparation/Handling/Storage/Accountability ........................................................................... 38 
6.2.1 Acquisition and accountability .................................................................................................. 38 
6.2.2 Formulation, Appearance, Packaging, and Labeling ............................................................... 38 
6.2.3 Product Storage and Stability................................................................................................... 38 
6.2.4 Preparation ............................................................................................................................... 38 
6.3 Measures to Minimize Bias: Randomization and Blinding ....................................................... 39 
6.4 Study Intervention Compliance ................................................................................................... 40 
6.5 Concomitant Therapy ................................................................................................................... 40 
6.5.1 Rescue Medicine ...................................................................................................................... 40 
7 - STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................. 44 
7.1 Discontinuation of Study Intervention ........................................................................................ 44 
7.2 Participant Discontinuation/Withdrawal from the Study .......................................................... 44 
7.3 Lost to Follow-Up .......................................................................................................................... 44 
8 - STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 44 
8.1 Efficacy Assessments .................................................................................................................. 44 
8.2 Safety and Other Assessments ................................................................................................... 47 
8.3 Adverse Events and Serious Adverse Events ........................................................................... 48 
8.3.1 Definition of Adverse Events (AE) ............................................................................................ 48 
8.3.2 Definition of Serious Adverse Events (SAE) ............................................................................ 48 
8.3.3 Classification of an Adverse Event .......................................................................................... 48 
The SAFE EVICT CORONA-ALI trial will utilize the Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0, published: November 27, 2017, which grades 1 through 5 with unique 
descriptions of severity for each adverse event based on the following: .......................................... 48 
Severity of Event ............................................................................................................................... 48 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated ...................................................................................................................................... 48 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). ....................................................................................... 48 

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Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care or ADLs. ............................... 48 
Grade 4 Life-threatening consequences; urgent intervention indicated. .......................................... 48 
Grade 5 Death related to AE. ............................................................................................................ 48 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ........................................ 49 
8.3.5 Adverse Event Reporting ......................................................................................................... 49 
8.3.6 Adverse Events, Serious Adverse Events, and Unanticipated Problems ................................ 50 
9 - STATISTICAL CONSIDERATIONS ................................................................................................ 51 
10 - SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 54 
10.1 Regulatory, Ethical, and Study Oversight Considerations ..................................................... 54 
10.1.1 Informed Consent Process ..................................................................................................... 54 
10.1.2 Study Discontinuation and Closure ........................................................................................ 55 
10.1.3 Data Confidentiality and Participant Policy ............................................................................ 56 
10.1.4 Future Use of Stored Human Specimens and Data .............................................................. 56 
10.1.5 Safety Oversight ..................................................................................................................... 56 
10.1.6 Key Roles and Study Governance ......................................................................................... 56 
10.1.7 Clinical Monitoring .................................................................................................................. 57 
10.1.8 Quality Assurance and Quality Control .................................................................................. 57 
10.1.9 Data Handling and Record Keeping ...................................................................................... 57 
10.1.10 Protocol Deviations .............................................................................................................. 57 
10.1.11 Publication and Data Sharing Policy .................................................................................... 57 
10.1.12 Conflict of Interest Policy ...................................................................................................... 57 
10.3 Protocol Amendment History .................................................................................................... 59 
REFERENCES ...................................................................................................................................... 61 
 
 
1 - Statement of Compliance 
1.1 Statement of Compliance 
The trial will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), and applicable United States (U.S.) Code of Federal 
Regulations (CFR). The Principal Investigator will assure that no deviation from funding 
agency and documented approval from the Institutional Review Board (IRB) will occur 
except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection 
and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to 
the study. All changes to the consent form will be IRB approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 

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2 - Introduction 
2.1 Study Rationale 
The World Health Organization (WHO) has declared COVID-19, the syndrome caused by 
the Severe Acute Respiratory Syndrome novel Coronavirus 2 (SARS-Cov-2), a pandemic. (1) 
As of April 23, 2020, there are 2,658,062 cases of COVID-19, with 184,643 deaths. (2) An 
alarming report (3) suggested that an unmitigated epidemic will cause up to 240,000 deaths in 
the United States alone. So far, no reliable treatment has been found, and the most promising 
measures have been the non-pharmacologic measures of social distancing, handwashing, 
school closures, and case isolations, among others. (3)  
A significant area of concern, and a potential contributing factor to the number of deaths, has 
been the effect of the SARS-Cov-2 on Intensive Care Unit (ICU) bed availability. Worst-case 
scenario analyses suggest that in the United States, 1.9 million COVID-19 patients could be 
admitted to the ICU, and 50% of those (960,000) would require invasive mechanical 
ventilation. (5) The obvious problem is that the U.S. has approximately 200,000 mechanical 
ventilators available, including the Centers for Disease Control (CDC) Strategic National 
Stockpile (SNS), the addition of anesthesia machines and old, retired stockpiled ventilators. 
(4) Also, 48% of U.S. hospitals have no intensive care unit specialists. (6)  
The most common reason for ICU admission for COVID-19 patients is a respiratory failure 
caused by SARS-Cov-2 induced Sepsis and Acute Respiratory Distress Syndrome (ARDS). 
(4) While the need for a treatment for COVID-19 is urgent and the non-pharmacologic efforts 
to “flatten the curve” will play a significant role in reducing the burden on the US health care 
system, being able to slow or stop the incidents of SARS-Cov-2 induced ARDS would 
further reduce the pressure on health care systems. Furthermore, the success of efforts to lift 
the current extreme restrictions, before herd immunity is achieved or a vaccine is available, 
would be bolstered by having a safe, easy to implement, and effective intervention aimed at 
reducing the progression of conditions which lead to a high need for ICU beds and 
ventilators. This study proposes to use High Dose Intravenous Vitamin C (HDIVC) to stop 
the progression of early COVID-19 Acute Lung Injury (ALI) before it progresses to Sepsis, 
Acute Hypoxemic Respiratory Failure (AHRF) and ARDS. If successful, this would reduce 
the number of COVID-19 patients requiring endotracheal intubation, mechanical ventilation, 
ICU admission, and potentially offer public health benefits. 
2.2 Background 
In December 2019, a cluster of pneumonia cases was reported in Wuhan, China, and a novel 
coronavirus, SARS-Cov-2, was identified. (7) The World Health Organization (WHO) 
designated the respiratory disease as coronavirus disease (COVID-19) on February 12, 2020. 
Numerous reports have since characterized the COVID-19 clinical syndrome, ranging from 
asymptomatic/mild illness to severe disease leading to respiratory failure requiring 
mechanical ventilation (i.e., ARDS, multi-organ failure, sepsis, and death). (7 − 9) A safe, 
effective, and inexpensive therapy is urgently needed, one that can alter the natural course of 
the disease process and reduce strain on healthcare systems. High Dose Intravenous Vitamin 
C (HDIVC) is one such potential therapy.  
Preliminary studies suggest that HDIVC is a safe and possibly effective treatment for ARDS, 
including ARDS of viral origin. (10) Since 1986, there has been increasing evidence that 
HDIVC may be useful in preventing multi-organ failure and mortality in ARDS patients. It 
remains unknown if HDIVC given early can halt the progression to ARDS and if it is 
effective in avoiding COVID-19 ARDS.  

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Basic Science Data to Support the Use of HDIVC in ARDS 
Animal studies performed at VCU have shown that vitamin C in high doses prevents 
pulmonary neutrophil infiltration in murine feces-induced peritonitis (FIP) model of 
sepsis/ARDS (Figure 1). Vitamin C (AscA) high parenteral doses increased the clearance of 
bacteria from the circulation in a preclinical model of ARDS. In the same murine model of 
sepsis, blood was obtained using sterile technique at varying time points after induction of 
feces induced peritonitis with or without associated HDIVC administration. Ten µl of blood 
was plated on agar plates and colonies enumerated following overnight incubation. HDIVC 
treated mice had a highly significant decrease in colony counts compared to untreated mice 
(p< 0.01). Bronchoalveolar lavage in these mice also demonstrated increased alveolar protein 
content after induction of FIP with unchanged alveolar protein content in FIP animals treated 
with HDIVC (data not shown), indicating that HDIVC maintained lung barrier function 
between the blood and the airspace. (25) 
Human Trials for the use of HDIVC in Sepsis-induced ARDS 
Vitamin C supplementation has been given in numerous trials for respiratory disease with 
mixed results (22,23).  
The first study, published in 1986, compared 16 ARDS patients treated with intravenous 
vitamin C (1000 mg IV every 6 hours) plus antioxidants (N-acetylcysteine, selenium, and 
vitamin E) to 16 ARDS patients who received the standard care at that time (i.e., control 
group). There was a dramatic reduction in mortality in the vitamin C group versus the 
standard of care group: 37% versus 71% (p<0.01). (12) A phase I trial in 2014 showed that 
plasma vitamin C levels in patients with severe sepsis and ARDS were low, almost at 
scorbutic levels (13) and that HDIVC administration had a dose-dependent effect in the 
prevention of multi-organ failure, as measured by the Sequential Organ Failure Assessment 
(SOFA) scores. (14) Patients who received a total of 200 mg/kg/day of HDIVC for 4 days 
(administered in 50 mg/kg/dose, every 6 hours) had significantly lower organ failure scores 
than patients in the placebo group. In addition, the patients in the HDIVC group (200 
mg/kg/day) recovered from the scorbutic plasma levels of vitamin C, achieving plasma levels 
as high as 3,000 µM on day 4.   
In one study with marine recruits (n=674), a randomized, double-blind study of oral vitamin 
C at 2,000 mg/day reduced the reported pneumonia cases compared with placebo  
. High dose vitamin C has also been administered in a case of Enterovirus-induced ARDS in 
a patient who developed severe respiratory failure and required mechanical ventilation and 
extracorporeal membrane oxygenation (ECMO) support. Rapid improvement in oxygenation 
occurred early after HDIVC, which was administered for 7 days total. The patient 
experienced no adverse events from HDIVC or any long-term sequelae. (21) 
Figure 1. Lung pathology slides (40x magnification) of septic mice with fecal induced peritonitis (FIP) 
demonstrating Acute Lung Injury (ALI) a feature of ARDS. On the right, sections of lung (40x 
magnification) 16 hours after infusion of Ascorbic Acid (FIP-AscA), shows resolution of inflammation, and 
attenuated inflammatory cell sequestration.  

Protocol Version 1.83 
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A recent trial using the trio of vitamin C/thiamine/hydrocortisone (VITAMINS) did not show 
improvement in time alive or vasopressor free days in a multicenter, randomized, open-label 
trial. However, this trial gave a lower dose of HDIVC than we are proposing, was an open 
label, unblinded, and not in patients with ARDS. (15)  
The multicenter, randomized, 
double-blind CITRIS-ALI trial 
led by our lab enrolled 167 
patients with ARDS who were 
randomized to receive 50 mg/kg 
of HDIVC or a placebo every 6 
hours for 4 days. The treatment 
group showed a statistically 
significant difference in 28-day 
all-cause mortality compared to 
the placebo group (Figure 2), 
although this was a secondary 
outcome. (11) The 28-day 
mortality was 29.8% in the 
vitamin C group versus 46.3% 
in the placebo group. This can 
be translated as a Number 
Needed to Treat (NNT) of 6 
patients to save one life from 
ARDS. The statistical effect on mortality remained up to 60-days following trial completion. 
(11) 
In addition, the CITRIS-ALI 
trial (11) showed that ARDS 
patients who received 
HDIVC (at 200 mg/kg/day 
for 4 days, n=84) had higher 
ventilator-free days 
compared to placebo (n=83), 
at 13.1 days compared to 
10.6 days (mean difference, 
2.47: 95% CI -0.9-5.85, 
P=0.15). Patients treated with 
HDIVC also had a significant 
increase in ICU free days 
(10.7 in the vitamin C group 
vs. 7.7 in the placebo group 
(mean difference, 3.2; 95% 
CI, 0.3 to 5.9; P = .03).  
It is important to note that none of the participants in the study developed any significant side 
effects from the intravenous vitamin C. The CITRIS-ALI trial results show promise for the 
use of HDIVC for acute respiratory failure with few significant short- or long-term side 
effects.  
Data for the use of HDIVC in COVID-19 induced Sepsis and ARDS 
High-dose Intravenous Vitamin C (HDIVC), even at much higher doses than we are 
suggesting in the present protocol, has been used successfully to treat COVID-19 patients in 
China. (18) The doses varied between 10,000 and 20,000 mg per day. (18) The authors report 
Figure 2. CITRIS-ALI 28 day all-cause mortality 
Figure 3. Ventilator-free 
days 
(30)
(39)
(n=84)
(n=82)
p=0.11
Ventilator Free Days
(33)
(42)
(n=84)
(n=82)
p=0.03
ICU Free Days
Fowler et al. JAMA. 2019 PMID: 31573637  
DAY 28

Protocol Version 1.83 
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that the oxygenation index improved in all these cases in “real-time,” and all the patients 
were cured and discharged. Importantly, none of the patients experienced any significant side 
effects. (18) A randomized clinical trial is underway in Wuhan, China, to administer 12,000 
mg of intravenous vitamin C every 12 hours for 7 days (significantly higher than our 
suggested protocol) compared with placebo. (NCT04264533) Further trials are currently in 
the planning and enrolling phase for HDIVC in sepsis and ARDS. Consumer groups are 
petitioning and urging the FDA to approve high-dose intravenous vitamin C for the COVID-
19. (20) This petition has reached 17,700 signatures as of May 5th, 2020. 
A summary of possible mechanisms of HDIVC for SARS-CoV-2 infection based on existing 
knowledge is presented in figure 3 below. 
 
How does Vitamin C improve ARDS and Respiratory Failure in Humans?  
Figure 3: Known biological effects of Vitamin C and suggested effects on COVID-19. NET: 
Neutrophil Extracellular Traps, TET-2  (tet methylcytosine dioxygenase 2). The methylcytosine 
dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The 
encoded protein is involved in myelopoiesis, and defects in this gene have been associated with 
several myeloproliferative disorders. Vitamin C is a cofactor for TET2. This figure was created 
by the authors of the protocol for the purpose of the protocol (unpublished data), based 

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The endothelial glycocalyx (Figure 4) 
plays an essential vasculo-protective 
role, modulating permeability, blood 
cell/vessel wall interactions, and shear 
stress sensing. Current research 
indicates the glycocalyx modulates 
inflammation and maintains anti-
thrombogenic, anti-adhesive 
endothelial surfaces. Glycocalyx 
components such as syndecan-1 are 
shed by enzymatic digestion (e.g., 
metalloproteinases) and exposure to reactive oxygen intermediates as occurs with acute 
inflammation of sepsis. Enzymatic degradation and release of cell-free DNA from activated 
neutrophils leads to loss of glycocalyx components (e.g., syndecan-1), which in turn leads to 
the display of potent adhesion receptors. This results in the sequestration of activated 
neutrophils and platelets in microvascular spaces amplifying vascular injury. In lung, this 
process produces loss of pulmonary capillary barrier function and rapid onset of alveolar 
injury with subsequent flooding of the alveolar space.  
 
 
Figure 5 shows that neutrophils activated in vitro release cell-free DNA (Panel B). Cell-free 
DNA release from activated neutrophils treated with vitamin C is completely attenuated. (25) 
In a post-hoc analysis, we used plasma 
obtained from patients enrolled in the 
multicenter, double-blind, randomized, 
placebo-controlled CITRIS-ALI trial. 
(27)  Figure 6 shows that patients who 
received intravenous vitamin C exhibited 
significantly decreased 48-hour plasma cell-free DNA levels compared to placebo, and, 
importantly, vitamin C infusion was associated with an attenuated plasma syndecan-1 levels 
compared to placebo (unpublished observation). These data from CITRIS-ALI in a well-
characterized patient population with sepsis-induced acute respiratory distress syndrome 
(ARDS) shows that increased concentrations of plasma cell-free DNA is associated with 
increased plasma syndecan-1 levels.  
We further found that changes in both 48-hour cell-free DNA and 48-hour syndecan-1 levels 
predicted 28-day all-cause hospital mortality (Figure 7). In this analysis, increased syndecan-
1 measured at 48 hours 
highly correlated with 
worsened indices of 
oxygenation (data not 
shown). Degradation of 
syndecan-1 plays a vital 
role in early phase 
vascular injury, serving 
as a risk factor for 
plasma leakage. These 
findings have 
implications. Plasma 
syndecan-1 
measurement in septic virally infected patients may serve as a critical biomarker and possibly 
Figure 4. The endothelial glycocalyx 
Figure 7. Human mortality, cf-DNA and syndecan-1 
Figure 5. Effect of Vitamin C on Human PMN 

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convey important prognostic implications of organ dysfunction produced by COVID-19 
infection. Suwarto et al. found that systemic viral infection (i.e., dengue) is associated with 
substantial endothelial glycocalyx degradation, as evidenced by significant increases in 
plasma syndecan-1. (26)  
These results suggest that patients could benefit from therapies targeted at protecting or 
restoring the glycocalyx. The data presented here strongly suggest that vitamin C’s protection 
of the glycocalyx in septic ARDS patients led to the reduced extent of organ failure observed 
in CITRIS-ALI. (27) (Figure 8). The mechanisms that degrade the glycocalyx are still not 
fully clarified. Still, the results of our 
biomarker analysis reported here more 
visibly point to neutrophil extracellular 
trap formation (i.e., cell-free DNA) as an 
essential factor in glycocalyx 
degradation. Efforts to restore the 
glycocalyx likely will include the 
stabilization of endothelial cell surface 
syndecan-1 expression, a vital backbone 
of the glycocalyx. The results of our 
biomarker analysis in patients from the 
CITRIS-ALI trial lead us to reason that 
intravenous infusion of vitamin C may 
well occupy a future role in glycocalyx 
protection and restoration and may have a substantial role in COVID-19 infection. With the 
available evidence pointing to vitamin C as playing a role in glycocalyx protection, likely 
vitamin C’s capacity both as an antioxidant and an anti-inflammatory agent is critical.  
Figure 8. Vitamin C, cfDNA and syndecan-1 

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Adverse effects of High-Dose Intravenous Vitamin C 
An NIH expert panel concluded that “Studies have shown that vitamin C can be safely 
administered to healthy volunteers or cancer patients at doses up to 1,500 mg/kg”, as per 
High-dose vitamin C (PDQ®)–Health professional version. (19). No safety issues were 
reported in the CITRIS-ALI study. (11) Another VCU study examining the use of HDIVC in 
patients undergoing atrial fibrillation ablation also reported no safety issues. (17)  
While vitamin C infused in high concentrations does pose a potential area of concern related 
to oxalate formation and the possibility of oxalate crystal formation in the urine that may 
lead to renal system stone formation, no stone formation was observed during the CITRIS-
ALI trial where vitamin C at 200 mg/kg per day was administered for 4 days. (17) More 
specifically for COVID-19, in a recent study none of the patients with COVID-19, who 
received high-dose intravenous vitamin C experienced any significant side effects due to the 
vitamin C. However, the CITRIS-ALI study did not look specifically for oxalate 
nephropathy, or long-term kidney outcomes in terms of AKI free-days days  (18) In contrast, 
studies of other potential COVID-19 treatments have already been halted due to serious side 
effects. (16) There is a clear knowledge gap in the literature in terms of the renal 
outcomes of high-dose, intravenous vitamin C. The highest level of evidence in terms of 
oxalate nephropathy and high-dose intravenous vitamin C is limited to case reports (28-30).  
A recent systematic review of high-dose intravenous vitamin C, identified “identified 74 
relevant articles reporting adverse events of vitamin C, but most studies did not have control 
or placebo group.” (31) There were nine high-quality double-blind randomized control trials 
(RCTs) reviewed did not show any significant adverse effects comparing to the placebo 
group. (31) Therefore, there is no definitive evidence that side-effects attributed to vitamin C 
could be from other therapies. Specific side-effects attributed to high-doses of intravenous 
vitamin C were “ specific adverse events attributed to high-dose IV vitamin C therapy, 
included “five cases of oxalate nephropathy, five cases of hypernatremia, three cases of 
hemolysis in patients with G6PD deficiency, two cases of glucometer error, and one case of 
kidney stones.” (31) 
Given its success in improving outcomes for non-COVID-19 related ARDS, research 
suggests that HDIVC given early may also prevent the progression to ARDS in COVID-19. 
While treatment of COVID-19 would take priority and would not be withheld from patients 
with ARDS, HDIVC may provide an important therapy to reduce the burden on the US health 
care system. Therefore, a proof-of-concept, phase 2 safety trial is needed.  
2.3 Risk/Benefit Assessment 
2.3.1 Known Potential Risks 
Potential Physical Risks of Ascorbic Acid Infusion: dry mouth, nausea, vomiting, dizziness, 
headache, factitious hyperglycemia (if checked with a point of care (POC) glucose testing), 
oxalate nephropathy, crystalluria, kidney stones and hemolysis in people with G6PD. 
Potential Psychological, Social, and Legal Risks of Ascorbic Acid Infusion: No 
psychological, social or legal risks are identifiable from an extensive literature search. 
Risks of Blood Draws:  Most research data will be collected via standard of care blood draws; 
however, it may be necessary to do study specific blood draws when participants are enrolled 
and on study day 7. The risks involved in drawing blood from a vein may include, but are not 
limited to, momentary pain at the site of the blood draw, possible bruising, redness, and 
swelling around the site, bleeding at the site, feeling of lightheadedness, and very rarely, an 
infection at the site of the blood draw.  
Since this is an ICU study, blood draws are required only if the patient does not already have 
an arterial or central line. If patient has one of these lines, then blood draws can be obtained 
through these lines without sticks. All effort is done for all study labs to be done with AM 
labs and other labs that are being done for clinical care. Usually ICU patients get many 

Protocol Version 1.83 
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blood draws throughout the day for other reasons. The consent 1.83 includes that patients 
may need up to 20 blood draws additional which will replace the POCT glucose 
measurements, since POCT glucose is not reliable. Further this need to continue up to 
72 hours after the last infusion to ensure that glucose measurements are accurate and 
minimize the risk of iatrogenic hypoglycemia.  
Risks of Peripheral Intravenous (IV) Catheter insertion: The vast majority of inpatients 
already have at least one peripheral IV line. In the rare occasion that an IV is not present, the 
study intervention requires infusion through a peripheral IV. Risk of peripheral IV insertion 
are exactly the same as the risk of blood draws. Risks are generally rare, since this procedure 
is performed hundreds of times a day in our hospital on all patients. Risk include insertion 
site pain, phlebitis, hematoma formation, and infusate extravasation. There are also extremely 
rare, but significant complications have been reported, including bloodstream and local 
infections, air embolization, nerve damage, arterial puncture. It is worth noting that when 
used as part of standard of care, peripheral IVs are inserted by the bedside nurse with just 
verbal consent.  

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Glucose Monitoring Plan: 
Guidance for blood glucose monitoring in patients enrolled in the SAFE-EVICT-CORONA-
ALI Trial: 
Ascorbic acid is known to artifactually raise point of care (POC) blood glucose readings by 
all POC devices. Thus, extreme care must be taken to assure an accurate blood glucose level 
from a metabolic laboratory (single serum glucose, SSG) before initiating insulin therapy, 
including sliding scale or scheduled insulin. 
Critical Care and Inpatient Unit Nursing and Treating Physician must be informed of vitamin 
C's effect on POC blood glucose and arterial blood gas measured glucose values. The PI(s) 
will instruct the ordering providers how to monitor blood glucose and insulin management in 
the study. Study personnel will follow each study patient closely to monitor insulin use to 
ensure that POC glucose screening is suspended for the research subject during the 96-hour 
treatment period. The following guidance for blood glucose monitoring in patients enrolled in 
this study will be provided to the attending staff: 
• This patient is enrolled in a study with Vitamin C, which artefactually increases POC 
glucose testing. 
• Special Order set should be used with monitoring of blood glucose.  
• Use only central laboratory serum glucose quantification method via BMP utilizing 
the hexokinase method and calibrated and accredited hospital analyzers. 
• Do Not Initiate or Utilize Sliding Scale, Scheduled Insulin, or Continuous Insulin 
Infusion without Laboratory Confirmation of Blood Glucose through the central 
laboratory chemistry with BMP (hexokinase method). 
• Those receiving insulin infusion or sliding scale insulin as a part of the standard of 
care should have metabolic glucose screening on the schedule determined by the 
attending/ordering physician. 
• Blood glucose monitoring for insulin administration guidance should only be by a 
central laboratory metabolic blood glucose results, whether or not the study patient is 
receiving insulin. 
• Do not use any POC device for glucose monitoring. POC glucose testing may 
resume 36 hours after the last infusion of study drug. 
2.3.2 Known Potential Benefits 
The first study, published in 1986, compared 16 ARDS patients treated with intravenous 
vitamin C (1000 mg intravenous every 6 hours) plus antioxidants (N-acetylcysteine, 
selenium, and vitamin E) to 16 ARDS patients who received the standard care at that time 
(i.e., control group). There was a significant reduction in mortality in the vitamin C group: 
37% versus 71% in the standard care group (p<0.01). (12) A phase I trial in 2014 revealed 
that plasma vitamin C levels in patients with severe sepsis and ARDS were low, almost at 
scorbutic levels (13). HDIVC administration (200 mg/kg/day) raised plasma levels up to 
3,000 µM by day 4 and had a dose-dependent effect in the prevention of multi-organ failure, 
as measured by the Sequential Organ Failure Assessment (SOFA) scores. (14) As mentioned 
above, our Phase 2 double-blind, placebo-control multicenter randomized control trial 
(CITRIS-ALI, 11) also suggested that 200mg/kg/day of HDIVC (administered in 50 
mg/kg/dose, every 6 hours) reduces the extent of organ failure (figure) and reduces 28-day 
and 60-day mortality in ARDS. Finally, ongoing treatment in China suggests that HDIVC 
may be effective in preventing ARDS in patients with COVID-19. The results of CITRIS-
ALI suggested that the Number Needed to Treat (NNT) is approximately six to save on 
human life. 
2.3.3 Assessment of Potential Risks and Benefits 
The identifiable risks arising from exposure to the intravenous ascorbic acid infusion are low. 
Due to the severity of COVID-19, the study related risks associated with the study procedures 

Protocol Version 1.83 
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are not greater than the risks associated with hospitalization due to COVID-19. Given the low 
risk associated with the study and the potential high likelihood of benefit, we assess the 
risk/benefit ratio to be low (i.e., that benefit far outweighs risk). 
 

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3 - Objectives and Endpoints 
3.1 Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
WHO COVID-19 9-point 
Ordinal Scale Outcome  
 
MEAN SCORE ON 
DAY 28, 60 AND 90 
This ordinal scale 
captures a range of safety 
outcomes and is ideal for 
safety studies. If any other 
unanticipated clinical 
harms of high-dose 
intravenous vitamin C 
occur, will be captured on 
this outcome. 
Secondary 
 
Renal safety biomarkers 
Daily serum oxalate 
Daily urinalysis 
24-hour urine oxalate 
on day 5 
Measured biomarkers will 
provide a sensitive way to 
identify the mechanisms 
of oxalate nephropathy  
AKI-free days at day 28 
and 90  
Renal-failure free 
days, with AKI defined 
by the KDIGO criteria 
(see table below). 
This endpoint aims to 
identify long-term kidney 
outcomes among the two 
groups  
All-cause mortality at 28 
60 and 90 days 
Safety Endpoint 
If the therapy offers 
significant benefit, or 
harm, compared with 
placebo  
Exploratory biomarkers 
Ferritin, D-dimer, LDH, 
CRP, plasma IL-6 on 
day 7 
 
The biomarkers aim to 
help interpret the 
outcomes, and further 
explain clinical differences 
in the above-measured 
outcomes 
Ascorbate trough levels  
Plasma ascorbate at 
baseline (0 hours) 
levels at 24 hours, 48 
hours, 96 hours and 
168 hours 
The PK of ascorbate is 
still unknown in the target 
patient population 
Alive and free of 
significant respiratory 
failure through 28-days 
 
At 28-days is the 
patient alive and not in 
respiratory failure, the 
principal cause of 
death by COVID-19 
Respiratory failure defined 
as at least one of the 
following:  
• Endotracheal 
intubation and 
mechanical 
ventilation 
• • x               
by high-flow nasal 

Protocol Version 1.83 
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cannula (heated, 
humidified) 
• Oxygen delivered 
via reinforced nasal 
cannula at flow 
rates >20L/min with 
fraction of delivered 
 x     ≥ .   
• Noninvasive 
positive pressure 
ventilation (CPAP 
or BIPAP) 
• Extracorporeal 
membrane 
oxygenation 
(ECMO of any 
type) 
Alive and free of 
mechanical ventilation at 
28-days 
Proportion of patients 
alive and free of 
invasive mechanical 
ventilation at 28-days. 
Is the patient dependent 
on mechanical ventilation 
by 28-days, that is 
development of significant 
chronic respiratory failure 

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WHO COVID-19, 9-point Ordinal Outcome Scale 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virologic evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
  
Limitation of Activities 
2 
Hospitalized mild disease 
Hospitalized, no oxygen therapy 
3 
  
Oxygen by mask or nasal prongs 
4 
Hospitalized Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
  
Intubation and mechanical ventilation 
6 
  
Ventilation + additional organ support – vasopressors, renal 
replacement therapy, ECMO 
7 
Dead 
Death 
8 
 

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Acute Kidney Injury (AKI) Definitions per KDIGO guidelines  
Khwaja, A. (2012). KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical 
Practice,120(4), c179-c184. 
 
 
 
 
 

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4 - Study Design 
4.1 Overall Design 
1. A phase 2, two-center, prospective, randomized, double blind placebo-controlled safety 
clinical trial. 
2. A maximum of 60 patients will be enrolled. 
3. Participants will be randomized to receive either intravenous Vitamin C (mixed in 5% 
dextrose in water) or placebo (5% dextrose in water) in a 1:1 manner. 
4. Active treatment will continue for 96-hour period or consent withdrawal or loss to follow-
up. One-fourth of the 24-hour calculated dosage will be administered in 30-minute 
intravenous infusions of 50 mg/kg and occur every 6 hours for a total of sixteen 30-minute 
infusions. That is 200 mg/kg total per day for 4 days. The standard of care therapy will be 
followed. All COVID-19 known therapies will be allowed. 
5. All participants will be followed for a total of 28 days on the first phase of the trial and at 
60 and 90 days on the second phase. 
6 All participants, without exception, will receive the standard of care for COVID-19 
including the use of remdesivir, dexamethasone, plasma and other, as a component of 
standard of care for patients hospitalized with severe disease, in settings where remdesivir is 
available via the emergency use authorization mechanism. 
Analysis/Interim Monitoring: 
1. Only reasons for study withdrawal are withdrawal of consent and, or loss to 
follow-up 
2. The DSMB will review all SAEs in a narrative and qualitative fashion (not only 
quantitative), to avoid underpowered statistical misconceptions.  
3. Protocol compliance will be monitored by the study team daily discussion. This will 
take place via investigator conference call and will address challenges encountered. 
Trial progress will be monitored by an independent Data and Safety Monitoring 
Board (DSMB) to determine if the study should stop for safety reasons.  
4.2 Scientific Rationale for Study Design 
The purpose of this study is to assess the safety, tolerability, efficacy of intravenously infused 
ascorbic acid therapy for patients with COVID19 and decreased oxygenation. This study will 
provide an opportunity to explore specifically the specific safety of high-dose 
intravenous vitamin c and explore the hypothesis generated by case reports, that high-
dose vitamin C has clinically significant adverse effects on the kidneys.  By administering 
the infusion at the first objective sign of worsening oxygenation, documented by Pulse 
Oximetry Saturation(SpO2)/Fraction of Inspired Oxygen (FiO2) – that is the S/F ratio, 
decreased pulse oximetry at baseline, HDIVC may reduce the inflammatory process and 
development of respiratory failure requiring intubation, which is critical in a pandemic when 
ventilators, ICU beds, and medical staff may be in short supply.  
4.3 Justification for Dose 
Dosing and bio-distribution data in humans show that pharmacological concentrations of 
vitamin C can only be attained following intravenous administration. (29) Oral doses cannot 
achieve therapeutic plasma concentrations. (34-35) Dosage selection for this trial was 
determined both from animal modeling, examining the biological effectiveness in a lung 
injury model system and from the recently conducted randomized double-blind phase 2 
human ARDS (CITRIS-ALI) trial. (11) The 200 mg/kg/24-hour IV (50 mg/kg IV every 6 
hours) dosing protocol was determined from analysis of the CITRIS-ALI (200mg/kg IV 
levels, that was 50 mg/kg IV every 6 hours) plasma ascorbate levels. A special consideration 
is given for patients who will develop KDIGO definition AKI, stage 2 or 3 after the 
infusion. In this scenario, the dosage will be reduce by 50%, for each subsequent 

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infusion, until the AKI resolves completely. We are using a dosing ceiling of 15 grams 
per day, for consideration of vitamin C dosages in obese population. Under no 
circumstance an individual infusion dose will exceed 3.75 grams of vitamin C, or the 
daily infused dose above 15 grams.  
4.4 End of Study Definition 
Active treatment period will continue for 4 days, that is 16 infusions of 50 mg/kg intravenous 
vitamin C, 30-minutes each infusion. The last study-specific bloodwork with be collected at 7 
days. All patients will remain in the study through the end of double-blind period and 
final study blood collection. Participation will end if patient withdraws the consent or is lost 
to follow-up. Clinical data, including a final blood draw, will be collected through day 7. All 
subjects will be followed to day 28 via chart review for collection of clinical outcomes data. 
90-day secondary outcomes will be assessed either during clinic visits or via telephone at 60 
and 90 days. Only acceptable reasons for early study termination include consent 
withdrawal, or loss to follow-up. 
 

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5 - Study Population 
5.1 Inclusion Criteria 
• Adults of 18 years or older  
• Patients hospitalized with a diagnosis of COVID-19 based on central laboratory-
confirmed COVID-19 Novel Coronavirus Disease-2019, based on a positive SARS-
CoV-2 RT-PCR confirmed within 72 hours prior to enrollment of nasal, 
oropharyngeal, or BAL specimen with hypoxemia, (i.e., decrease in oxygenation, as 
outlined below) 
• Pulse oximetry saturation (SpO2) < 93% on room air in WHO COVID-19 ordinal 
scale 3 patients, regardless the need for assisted ventilation, or oxygenation. 
• Any new requirement of supplemental oxygen, with any oxygen device (WHO 
COVID-19 ordinal scale 4-7, regardless of pulse oximetry reading) 
• In patients with supplemental oxygen at home, any increase in the requirement of 
supplemental oxygen.  
• In ICU level of care 
5.2 Exclusion Criteria 
• Age less than 18 years 
• Known allergy to Vitamin C 
• Inability to obtain consent from patient or next of kin 
• Presence of diabetic ketoacidosis 
• ANY history of oxalate stones at any time 
• Patients with Kidney Disease Improving Global Outcomes (KDIGO), CKD stage 
4 (eGFR < 30 ml/min, CKD stage 5 and end-stage renal disease on dialysis 
patients are excluded.  
• Patients with Acute Kidney Injury, stage 3 (see page 28).  
• Pregnant, or lactating 
• Known diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency 
• Patients who received the following medications within 7 days prior to enrollment, or 
plan to receive during enrollment, or 7 days after enrollment: aluminum hydroxide, 
bortezomib, copper, deferoxamine, amphetamines including derivatives such as 
fluphenazine. 
• Patients with active sickle cell crisis  
• Prisoners 
• Patients outside ICU level of care.  
 
5.3.1 Special Considerations: Minorities 
The study will emphasize recruitment of ethnic minorities and patients over 65. Specifically, 
a Spanish language consent will be available, and 24-hour real-time translation services. 
Furthermore, an attempt will be made to obtain consent and agreement with prison warden in 
the Richmond region. Once approval has been signed from prison leadership and the local 
IRB, inmates may be enrolled as well. 
 
5.3.2 Special Considerations: Chronic Kidney Disease and Acute Kidney Injury patients 
Special consideration will be given to avoid excluding patients with acute kidney injury 
(AKI). Recent evidence suggests that AKI develops in up to 60% of high-risk COVID-19 
patients. (33) The receptor for SARS-CoV- 2 is ACE2 receptor, which is expressed in kidney 
much more so than in lung. (33) Autopsy studies in COVID-19 demonstrated acute proximal 

Protocol Version 1.83 
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tubular injury, and peritubular erythrocyte aggregation and glomerular fibrin thrombi with 
ischemic collapse. (33) Therefore, we have the following provisions: 
• Exclude patients with KDIGO CKD stage 4 (eGFR < 30 ml/min) or worse. That 
means patients with KDIGO CKD stage 5 and/or any form of dialysis at baseline are 
also excluded. 
• Exclude patients with pre-existing AKI, stage 3 
• Immediate reduction of each infusion dose by 50% if patients develop KDIGO 
defined AKI stage 2 or higher, until the AKI resolves completely. If the AKI resolves 
completely, normal dosing can be resumed.  
• All AKI and CKD definitions are following the 2012 KDIGO guidelines: Khwaja, A. 
(2012). KDIGO clinical practice guidelines for acute kidney injury.Nephron Clinical 
Practice,120(4), c179-c184. 
 
 
 

Protocol Version 1.83 
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Furthermore, we plan daily assessments of renal safety, including daily creatinine, oxalate, 
and frequent urine oxalate measurements as outlined in detail in the SoA table on page 7.  If 
patients develop AKI, stage 2 or 3 during the first 7 days of the study (4 days of infusion or 3 
subsequent days) the following algorithm will be implemented: 
 
 
 
If new AKI develops: Plan daily creatinine measurement until improvement in the 
serum creatinine or urine output occurs for two consecutive days, at which time less 
frequent assessment as currently proposed in the study protocol can be undertaken. 
 

Protocol Version 1.83 
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5.3.3 Patients receiving are receiving therapeutic fluphenazine.  
Patients who are taking fluphenazine (e.g., Poloxin) will be excluded.  
 
5.3.4 Special Considerations: Obese patients  
Average body weight adults using the VCU protocol for intravenous vitamin C infusion 
receive 14 – 16 grams of vitamin C infused over a 24-hour period. Because the obese 
population of patients are known to be at high risk of COVID-19 pneumonia developing into 
serious respiratory failure we will set a daily ceiling of 15 grams infused into patients with 
BMIs of 40 or above. 
 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. 
Effort will be made to collect enough data from screen fails to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any Serious Adverse Event (SAE).  
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of exclusion criteria such as failure to obtain consent, inability to locate legally authorized 
representative (LAR), or delay in diagnosis may be rescreened. Rescreened participants 
should be assigned the same participant number as for the initial screening. 
5.5 Strategies for Recruitment and Retention 
Non-intubated patients with COVID19 will be recruited from the Emergency Department 
(ED), the medicine inpatient wards, and the intensive care units (ICU) at VCU Medical 
Center and the Central Virginia VA Health System in Richmond, Virginia (RICVA). Both 
institutions are tertiary care medical centers with a large referral base. Study personnel will 
review patients within the electronic medical record to identify potential candidates for 
enrollment. Permission to approach patients and/or their families will be requested from the 
attending physicians in charge of patient care in the ED, inpatient unit, or the ICU. All 
patients meeting the inclusion/exclusion criteria will be approached with consent and will be 
entered into a screening log. If the patient is not enrolled, the screening log will include 
information explaining why enrollment did not occur (exclusion criteria, attending physician 
denial, patient refusal, etc.). 
 
6 - Study Intervention 
6.1 Study Intervention Description 
All study drug doses will be administered via central or peripheral line infusion. Should no 
central or peripheral line be available at the scheduled time of infusion, a call should be 
placed to the pharmacy to determine if the study drug may be co-infused into the line that is 
infusing a different drug. If administering a study drug via co-infusion is contraindicated, 
then study drug infusion may be delayed by a maximum of 8 hours (the nursing assessments 
in COVID-19 patients are done every 4 hours). If the clinical drug administration schedule is 
such that the study drug will not have an available administration time beyond this delay, a 
dedicated new intravenous line (peripheral) should be inserted. Study drug will be blinded 
using an identical appearing placebo. 
6.1.1 Dosing and Administration 
• First study drug dose (L-ascorbic acid, 50 mg/kg infusion over 30 minutes) will be 
considered "Dose 1" and will be administered within the first 8 hours of enrollment or 

Protocol Version 1.83 
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the earliest available time post any clinically indicated procedure which requires the 
patient to be off the unit. Doses will be administered in the ED, medicine inpatient 
unit or ICU. Patients receiving vitamin C will receive 25% of the total daily 
calculated dosing 200 mg/kg/24 hours) infused over 30 minutes every 6 hours for 96 
hours. 
• Subsequent doses will be 50 mg/kg infused over 30 minutes every 6 hours. 
o Timing of Dose 2 will be triggered by the physician order for every 6-hour 
administration and will, therefore, be listed on the bedside medical 
administration record (MAR). As such, the timing of Dose 2 may be out of the 
+/- 3-hour window and will not trigger a protocol deviation. 
o If for any reason any other maintenance dose is not administered within the 
window, the dose will be skipped, and the next scheduled dose will be given 
and documented in the data collection tool. 
6.1.2 Concurrent Medication Infused and Renal Acidification 
Urine pH will be monitored daily according to the Scheduled of Activities table. 
Fluoroquinolones, aminoglycosides, macrolides function optimally at alkaline pH. 
Tetracyclines, nitrofurantoin, many β-lactams exhibit highest activity under acidic conditions. 
Sulfamethoxazole, oxacillin, amoxicillin and clavulanic acid, vancomycin, imipenem, and 
clindamycin are unaffected by pH. (32) See section 6.5.2 for a detailed list of all known 
medication interactions.  
6.2 Preparation/Handling/Storage/Accountability 
6.2.1 Acquisition and accountability 
VCU Health and the VA Investigational Drug and/or Inpatient Pharmacy will coordinate the 
acquisition of sterile L-ascorbic acid (Ascor®) for infusion from McGuff Pharmaceuticals, 
Santa Ana, CA. 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
Ascor vials contain 25,000 mg/50 mL of pH-balanced ascorbic acid and is supplied as 
pharmacy bulk packaging (PBP). The diluted Ascor solution is colorless to pale yellow. The 
placebo will be 50 ml Dextrose 5% Water (D5%W). Sealed amber shrouding will be used 
to cover the IV bag in order to maintain the blind.  
6.2.3 Product Storage and Stability 
Ascor is light sensitive. Light exposure will be minimized, and vials will be stored at 2°C to 
8°C prior to use. Infusion solutions will be prepared by Investigational Pharmacy (IP) during 
weekdays and will be placed in the ward refrigerator which is maintained at 2°C to 8°C. IP 
prepared infusion solutions containing vitamin C or placebo will expire in 24 hours. Infusion 
solutions prepared by ICU Pharmacy (9th floor Critical Care Hospital) after-hours will expire 
in 12 hours. There is published data establishing the stability of admixtures of ascorbic acid 
to be 96 hours stored at room temperature or refrigerated. Dr. Alpha Fowler has unpublished 
data that was obtained prior to an earlier IND trial (IND #113856) which demonstrates the 
stability of samples prepared in the same manner as described below. 
6.2.4 Preparation 
As noted above VCU Health IP will mix L-ascorbic acid once every 24 hours in four 50 ml 
hooded infusion bags using aseptic technique according to USP 797 requirements. All Ascor 
vials utilized will be discarded within 4 hours or sooner as per the Ascor package insert. 
Prepared solutions are stored on the inpatient unit or ICU refrigerator in the dark at 2°C to 
8°C. At designated infusion time, Nursing will infuse the contents of the light-shielded agent 
via infusion pump through tubing over 30 minutes. Prior studies performed have shown that 
L-ascorbic acid prepared for infusion in this way remains stable with no quantifiable 
oxidation or loss of activity. 

Protocol Version 1.83 
39 
For ascorbic acid, the volume of ascorbic acid to be added to the IV bag will be calculated. . 
Under no circumstance an individual infusion dose will exceed 3.75 grams of vitamin C, 
or the daily infused dose above 15 grams. This same amount of fluid will be withdrawn out 
of the D5%W 50 mL bag and discarded. Then, the calculated volume of ascorbic acid will be 
added to the infusion bag. Residual air will be removed from the infusion bag to prevent 
oxidation, and the bag will be shrouded. We commit that all solutions will have a 
pharmacy-approved appropriate osmolarity for peripheral infusions, and the volume of 
placebo will be exactly the same as the control. 
Microbiologic Controls: 
Investigational Pharmacy has an ISO Class 5 laminar airflow hood (Nuaire Class II Type A2 
biological safety cabinet) in a segregated compounding area. This biological safety cabinet is 
recertified every 6 months. Compounding personnel must successfully complete media fill 
testing and gloved, finger-tip sampling as per USP 797 regulations. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
The investigational pharmacist will use a standardized scientific randomization module 
within REDCap (36) Only the study pharmacist will have access to the online secure 
repository. The REDCap module has an auditing trail and log records on who accesses it as 
well as strict security controls.  
 
The prepared infusion bags will have sealed amber shrouding to cover the IV bag in order to 
maintain the blind. 
 
The randomization method will be a block (per site) and stratified and WHO COVID-19 
ordinal outcomes status) randomization.  
We plan to perform block randomization for each participating site. Within this block, there 
will be further stratification of randomization for severity of illness based on WHO COVID-
19 ordinal outcome cutoff as seen in the table below:  
 
 
 
WHO COVID-19 scale 
3-5 at enrollment 
WHO COVID-19 scale 
6-7 at enrollment 
 
 
Stratum A 
Stratum B 

Protocol Version 1.83 
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The goal is for each site to have an equivalent severity among patients randomized to the 
treatment or placebo arm within each stratum. 
6.4 Study Intervention Compliance 
Adherence to the protocol will be assessed and verified using participant drug log, review of 
electronic medical records, and review of the eCRF. 
6.5 Concomitant Therapy 
Any concomitant medications as part of the standard of care (particularly antibiotics, oxygen 
therapy, glucose infusion, insulin, albumin, corticosteroids, N-acetylcysteine, norepinephrine, 
vasopressin) provided will be recorded. 
6.5.1 Rescue Medicine 
Not applicable. 
6.5.2 List of concurrent medications that may be incompatible with intravenous vitamin 
C 
A review of the literature discloses that no known medications are incompatible with 
intravenous vitamin C concurrent administration. Herein we outline three categories of 
interacting medications. Medication that are absolutely contraindicated (none identified). 
Medications that may interact in a harmful way, therefore we may need to consider therapy 
modification. For the study purposes, patients who are taking, or plan to take these 
medications during the period of the study will be excluded. Medication that will require 
monitoring. The table below, summarizes the Vitamin C drug interaction groups.  
Medication interaction 
Interaction 
Category 
Interaction Mechanism 
Reference 
Aluminum Hydroxide 
Therapy 
modification 
Contraindicated for 
study purposes 
Ascorbic Acid may 
increase the absorption of 
Aluminum Hydroxide, 
especially in patients with 
renal failure 
Domingo JL, Gomez M, Llobet 
JM, Richart C. Effect of 
ascorbic acid on gastrointestinal 
aluminium absorption. Lancet. 
1991;338(8780):1467. 
doi:10.1016/0140-
6736(91)92776-x [PubMed 
1683458] 
Bortezomib 
Therapy 
modification 
Contraindicated for 
study purposes 
Ascorbic Acid may 
diminish the therapeutic 
effect of Bortezomib 
Perrone G, Hideshima T, Ikeda 
H, et al, “Ascorbic Acid Inhibits 
Antitumor Activity of 
Bortezomib in 
Vivo,” Leukemia, 2009, 
23:1679-86. 
Copper Depends on 
Dosage Form 
Therapy 
modification 
Contraindicated for 
study purposes 
Copper may decrease the 
serum concentration of 
Ascorbic Acid. 
Prescribing information. Copper 
(cupric chloride). Lake Forest, 
IL: Hospira, Inc., 2004. 
Deferoxamine Depends on 
Dose 
Therapy 
modification 
Contraindicated for 
study purposes 
Ascorbic Acid may 
enhance the adverse/toxic 
effect of Deferoxamine. 
Left ventricular 
dysfunction is of particular 
concern. 
Prescribing information. 
Desferal (deferoxamine 
mesylate). East Hanover, NJ: 
Novartis Pharmaceuticals 
Corporation, September 2010. 

Protocol Version 1.83 
41 
Amphetamines, 
fluphenazine 
Therapy 
modification 
Contraindicated 
for study 
purposes 
Ascorbic Acid may 
decrease the serum 
concentration of 
Amphetamines. 
Documented discussion 
with patient, pharmacy and 
prescribing physician 
required. 
Prescribing information. 
Adderall (dextroamphetamine 
and amphetamine). Wayne, PA: 
Shire US Inc., 3/07. Prescribing 
information. Dexedrine 
(dextroamphetamine). Research 
Triangle Park, NC: 
GlaxoSmithKline, July 2008. 
CycloSPORINE 
(Systemic) 
Monitoring required 
Ascorbic Acid may 
decrease the serum 
concentration of 
CycloSPORINE 
(Systemic). Daily levels 
are required.  
Documented discussion 
with patient, pharmacy and 
prescribing physician 
required. 
Lake KD, Aaronson KD, 
Gorman LE, et al, “Effect of 
Oral Vitamin E and C Therapy 
on Calcineurin Inhibitor Levels 
in Heart Transplant Recipients,” 
J Heart Lung Transplant, 2005, 
24(8):990-4. [PubMed 
16102431] Prescribing 
information. Vyvanse 
(lisdexamfetamine). Wayne, 
PA: Shire US Inc., June 2013. 
Estrogen Derivatives 
Monitoring required 
Ascorbic Acid may 
increase the serum 
concentration of Estrogen 
Derivatives. Documented 
discussion with patient, 
pharmacy and prescribing 
physician required. 
Vihtamaki T, Parantainen J, 
Koivisto AM, et al, “Oral 
Ascorbic Acid Increases Plasma 
Oestradiol During 
Postmenopausal Hormone 
Replacement Therapy,” 
Maturitas, 2002, 42:129-35. 
[PubMed 12065172] 
Warfarin 
Monitoring required 
More frequent 
anticoagulation monitoring 
(daily INR checks) may 
be necessary upon 
initiation of warfarin 
therapy with concomitant 
ascorbic acid. Documented 
discussion with patient, 
pharmacy and prescribing 
physician required. 
Sattar A, Willman JE, Kolluri 
R. Possible warfarin resistance 
due to interaction with ascorbic 
acid: case report and literature 
review. Am J Health Syst 
Pharm. 2013;70(9):782-786. 
[PubMed 23592361] 
Aspirin 
Depending on the 
dose 
Aspirin may decrease the 
serum concentration of 
Ascorbic Acid if aspirin is 
used in the dosing range 
from 600 mg single dose 
up to 3.9 g/day. 
Documented discussion 
with patient, pharmacy and 
prescribing physician 
required. 
Basu TK, “Vitamin C-Aspirin 
Interactions,” Int J Vitam Nutr 
Res Suppl, 1982, 23:83-90. 
[PubMed 6811490] 

Protocol Version 1.83 
42 
Dobutamine, Depends on 
Route 
Depending on the 
dose 
Ascorbic Acid may 
enhance the positive 
inotropic effect of 
Dobutamine. Monitoring 
of mean arterial pressure 
is needed. Documented 
discussion with patient, 
pharmacy and prescribing 
physician required. 
Mak S and Newton GE, 
“Vitamin C Augments the 
Inotropic Response to 
Dobutamine in Humans With 
Normal Left Ventricular 
Function,” Circulation, 2001, 
103(6):826-30. [PubMed 
11171790] 
Indinavir 
Ascorbic Acid may 
decrease the serum 
concentration of 
Indinavir. 
Documented discussion 
with patient, pharmacy and 
prescribing physician 
required. 
Slain D, Amsden JR, Khakoo 
RA, Fisher MA, et al, “Effect of 
High-Dose Vitamin C on the 
Steady-State Pharmacokinetics 
of the Protease Inhibitor 
Indinavir in Healthy 
Volunteers,” Pharmacother, 
2005, 25(2):165-70. [PubMed 
15767232] 
Propranolol 
Ascorbic Acid may 
decrease the serum 
concentration of 
Propranolol. 
Ascorbic Acid may 
decrease the serum 
concentration of 
Propranolol. Documented 
discussion with patient, 
pharmacy and prescribing 
physician required. 
Gonzalez JP, Valdivieso A, 
Calvo R, et al, “Influence of 
Vitamin C on the Absorption 
and First Pass Metabolism of 
Propranolol,” Eur J Clin 
Pharmacol, 1995, 48(3-4):295-
7. [PubMed 7589058] 
Reference: Trissel's ™ 2 Clinical Pharmaceutics Database 
 
6.5.3 List of concurrent medications that should not be admixed, or Y-site administered 
during IV infusion 
No other medication will be Y-site co-administered with intravenous vitamin C without first 
obtaining approval from hospital pharmacy services. Intravenous vitamin C will be 
administered through a dedicated IV-line, tubing and pump. 
The table below includes medications with known and unknown incompatibility. 
Intravenous Medication Y-site administered with IV 
Ascorbic Acid 
Y-Site Incompatibility 
Aminophylline 
Incompatible 
Azathioprine sodium 
Incompatible 
Ceftazidime 
Incompatible 
Ceftriaxone sodium 
Incompatible 
Chloramphenicol sodium succinate 
Incompatible 
Dantrolene sodium 
Incompatible 
Diazepam 
Incompatible 
Diazoxide 
Incompatible 
Erythromycin lactobionate 
Incompatible 
Etomidate 
Incompatible 
Ganciclovir sodium 
Incompatible 

Protocol Version 1.83 
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Hydralazine hydrochloride 
Incompatible 
Hydroxocobalamin 
Incompatible 
Inamrinone lactate 
Incompatible 
Midazolam hydrochloride 
Incompatible 
Minocycline hydrochloride 
Incompatible 
Nitroprusside sodium 
Incompatible 
Papaverine hydrochloride 
Incompatible 
Pentamidine isethionate 
Incompatible 
Pentobarbital sodium 
Incompatible 
Phenytoin sodium 
Incompatible 
Sulfamethoxazole-trimethoprim 
Incompatible 
Thiopental sodium 
Incompatible 
Amphotericin B (conventional) 
Unknown 
Ampicillin sodium 
Unknown 
Ampicillin sodium-sulbactam sodium 
Unknown 
Propofol 
Unknown 
Haloperidol lactate 
Unknown 
Reference: Trissel's ™ 2 Clinical Pharmaceutics Database 
 
6.5.4 Drug or antibiotics interactions that may affected by urine acidification 
Intravenous vitamin C may acidify the urine. Fluoroquinolones and macrolides function 
optimally in alkaline pH and may be affected by acidification of the urine. Fluoroquinolones, 
aminoglycosides, macrolides function optimally at alkaline pH. Tetracyclines, nitrofurantoin, 
many β-lactams exhibit highest activity under acidic conditions. Sulfamethoxazole, oxacillin, 
amoxicillin and clavulanic acid, vancomycin, imipenem, and clindamycin are unaffected by 
pH. Yang et al. (32). 
 
6.6 Plasma Vitamin C quantification method 
Plasma specimens are reduced with dithiothreitol (2mg/ml) followed by precipitation with 
20% trichloroacetic acid then vortex-mixed and centrifuged. Supernate vitamin C levels are 
measured using high-pressure liquid chromatography (HPLC) with UV detection (via cGLP 
bioanalytical validation according to FDA guidelines on bioanalytical method validation). 
Chromatography is performed on a Zorbax SB-AQ, 4.6 x 150 mm, 5 µm column (Agilent 
Technologies, Santa Clara, CA), with a mobile phase using a gradient buffer (dipotassium 
phosphate), ion pairing reagent (tretrabutyl ammonium chloride), and acetonitrile at a flow 
rate 0.850 mL/min. Detection will occur at 265 nm and vitamin C levels quantified using 
peak area analysis and external standardization. Ascorbic acid standards (5 - 2,500 μM) are 
freshly prepared and treated in the same way as the test plasma samples. The limits of 
quantification are 5 μM. 
 
 

Protocol Version 1.83 
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7 - Study Intervention Discontinuation and 
Participant Discontinuation/Withdrawal 
7.1 Discontinuation of Study Intervention 
There is no defined plan to discontinue the patients from the study, however, the PI may stop 
the vitamin C infusions prematurely in the following conditions, while the other interventions 
will continue for safety and study reasons: 
 
The study drug will be stopped without the PI completely discontinue the study assessments 
for the patient (i.e. the patient will still participated in blood draw assessments, blood and 
urine tests per protocol and documentation of outcomes):  
- 
If the patient status improves and patient downgrades level of care from ICU to lower 
levels of care (general or stepdown).  
- 
if participants describe symptoms of nephrolithiasis (kidney stones) that is flank pain 
and hematuria with evidence of kidney stones in the imaging studies. 
- 
do not tolerate the drug due to side effects such as nausea, vomiting, flushing, rash, 
headache, or diarrhea, the PI will  discontinue the study if symptoms are CTCAE v5 
grade 3 or higher and not dose reduce the study drug. In this case the FDA will also 
be informed. 
- 
if a patient develops a metabolic acidosis unexplained by other etiologies (e.g., lactic 
acidosis secondary to septic shock). Determination of the presence of metabolic 
acidosis will be made by the clinical care team.  
- 
Study drug will also be stopped if the primary care team or surrogate decision-maker 
requests stopping the drug for any reasons. Data collection will continue for these 
patients following the withdrawal of study drug. 
 
7.2 Participant Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
Upon withdrawal, all study interventions will cease.  
 
7.3 Lost to Follow-Up 
Loss to follow-up will be documented in the study registry. 
 
8 - Study Assessments and Procedures 
8.1 Efficacy Assessments 
Screening 
Subjects will be evaluated for entry into the study according to stated inclusion and exclusion 
criteria. Individuals who are identified during screening as not eligible for the study need not 
complete all screening procedures. The reason for ineligible status will be documented on the 
Screen Failure Log. 
The following information will be obtained to evaluate each subject's qualifications for 
participation in the study: 
From electronic health record (EHR): 
• Demographic information including gender, date of birth, race, ethnicity 
• Medical and medication history over the past 30 days 
• Documentation of blood for standard of care (SOC) hematology, coagulation, 
clinical chemistry (if available) 

Protocol Version 1.83 
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• Physical examination including height and weight (body mass index will be 
calculated based on these variables), and vital signs (systolic and diastolic blood 
pressure, pulse rate, respiratory rate, pulse oximetry, body temperature), respiratory 
exam (crackles yes/no, wheezing yes/no, increased work of breathing yes/no), 
abdominal exam (abdominal tenderness yes/no) neurological exam (Glasgow Coma 
Scale) 
• 12-lead electrocardiogram (EKG), Chest imaging findings (Chest X-Ray with 
infiltrates yes/no; ground-glass opacities on chest CT yes/no) based on the 
radiological attending report 
• Medical Comorbidities and secondary diagnoses 
• Use of supplemental oxygen (yes/no) 
Study specific 
• If not included in SOC, documentation of negative urine pregnancy testing for 
human chorionic gonadotropin (HCG) if female and of childbearing potential. 
Study assessments 
The following study data will be documented using standard hospitalization care procedures. 
Research staff will collect study data from EHR (including process reports) every 24 hours 
during the study procedure and once a week thereafter.  
8.1.1 Venous Blood Collection Timeline 
Septic patients exhibit subnormal plasma ascorbate levels. Phase I studies performed at 
Virginia Commonwealth University (VCU) show mean ascorbate levels of 17.5 µM (normal 
human ascorbate levels 60 to 70 µM), while some other centers report undetectable plasma 
vitamin C in COVID-19 patients. Baseline ascorbate levels will be drawn, before the 
imitation of any infusion with subsequent trough levels for PK monitoring.  
The target plasma range for modifying pro-inflammatory biomarkers and for attenuating 
vascular injury was obtained from the phase I safety trial and is greater than 500 µm as 
measured 24 hours after initiation of Vitamin C infusion. The day 2 – 7 plasma ascorbate 
levels are expected to be between 500 to 1000 µM based on prior pharmacokinetic studies 
generated during the phase I trial (VCU trial was entitled: Vitamin C Infusion in Human 
Sepsis).  
Blood drawn for ascorbate levels and biomarkers will occur at hour 0 (prior to the first 
infusion), hour 48 (+ or – 3 hours as long as it is drawn prior to Infusion 9), hour 96 (+ 
or – 3 hours as long as it is drawn at least 3 hours post Infusion 16), and hour 168 (+ or 
– 6 hours). 
Schedule 
 
 
Baseline 
(hour 0) 
Treatment 
days 1-4 
(hour 24) 
Treatment 
days 4-7  
Days 
7-14 
Days 
14-21 
Phase 1 
Study 
end  
(day 
28) 
Phase 2 
Day 60 
and  
Day 90 
 
Death from 
ANY cause 
X 
X 
X 
X 
X 
X 
X 
Alive and 
Free of any 
X 
X 
X 
X 
X 
X 
 

Protocol Version 1.83 
46 
respiratory 
failure 
Alive and 
free from 
invasive 
mechanical 
ventilation 
X 
X 
X 
X 
X 
X 
 
AKI (y/n) 
and stage 
X 
X 
X 
X 
X 
X 
 
WHO 
COVD-19 
SCALE 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
medication 
use(a) 
X 
X 
X 
X 
X 
X 
 
Plasma 
levels (b) 
X 
X 
X 
X 
X 
X 
 
Vital signs 
(c) 
X 
X 
X 
X 
X 
X 
 
Clinical 
assessment 
for kidney 
stone 
symptoms 
X 
X 
X 
X 
X 
X 
 
qSOFA score  
X 
X 
X 
X 
X 
X 
 
Ins/Outs 
X 
X 
X 
X 
X 
X 
 
Ventilator 
status / 
oxygen (e) 
X 
X 
X 
X 
X 
X 
 
Ventilator-
free days 
X 
X 
X 
X 
X 
X 
 
AKI-free 
days 
X 
X 
X 
X 
X 
X 
 
24-hour 
urine 
collection 
 
 
X5, X7 
X14* 
X21* 
X28* 
 
Ventilator 
and drip data 
X 
X 
X 
X 
X 
X 
 
AE/tolerance 
(g) 
 
X 
X 
 
 
 
 
Mortality (h) 
X 
X 
X 
X 
X 
Date/ti
me 
 
Discharge (i) 
X 
X 
X 
X 
X 
Date/ti
me 
 
WHO 
COVID-19 
Scale 
X 
X 
X 
X 
X 
X 
 
 
Footnotes: 

Protocol Version 1.83 
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a. Concomitant medication use (if applicable): oxygen therapy (to calculate S/F 
ratio), oxygen device, antibiotics, COVID-19-specific (remdesivir, 
dexamethasone, tocilizumab, sarilumab, canakinumab, hydroxychloroquine, 
azithromycin, convalescent plasma, remdesivir) corticosteroids, albumin, 
thiamine, norepinephrine, vasopressin, and N-acetylcysteine, antiplatelet and 
anticoagulants, muscle relaxants, sedatives (propofol, midazolam) and opioid 
analgesia.  
b. Plasma levels: serum oxalate, creatinine, hematology, coagulation, biomarkers 
(ferritin, C - reactive protein (CRP), lymphocyte count, LDH, d-dimer). If the 
primary team does not obtain these tests, we will obtain them for study purposes 
(dedicated blood draw if needed on day 0 and 7) and as add-on-labs (no study-
specific blood draw on days 1-4). 
c. Vital signs: Temperature, Respiratory Rate, Systolic and Diastolic Blood 
Pressures, Heart Rate, RASS score, Alert/ Not Alert, Oriented/ Not Oriented, 
FiO2, oxygen delivery device.  
d. Ins/Outs: 24-hour oral or IV intake/output and dialysis/ CRRT details at midnight. 
e. Current ventilation status: use of mechanical ventilator or oxygen device (yes/no), 
mode, invasive/ non-invasive ventilation, FiO2, PEEP, Plateau Pressure 
f. Ventilator/CCRT/Vasopressor/Delirium: last 7 days 
g. Adverse Events and tolerance: Interview with patient, may be conducted by 
telephone if feasible to reduce exposure of study personnel 
h. Mortality: date-time of death and all-cause mortality and likely cause of death. 
i. Discharge: Discharge date-time and discharge disposition (home, rehabilitation, 
skilled nursing facility, hospice, transfer to other hospital) 
j. For respiratory failure: was the patient at any time: turned to the prone position to 
facilitate oxygenation, paralyzed, placed on ECMO, had a tracheostomy placed? 
 
Phase 1 End 
• Total ventilator free days, CRRT free days, Vasopressor free days, and Delirium free days. 
• Is patient still hospitalized? 
• For respiratory failure, was the patient at any time: turned to the prone position to facilitate 
oxygenation, paralyzed, placed on ECMO, had a tracheostomy placed? 
• Is patient still alive? If not, date/time and cause of death and code status at time of death. 
Phase 2 follow-up (>=90 days) 
• Is patient still alive? If not, date/time and cause of death and code status at time of death. 
 
8.2 Safety and Other Assessments 
The following data will provide the basis for assessing protocol compliance and safety as 
well as between-group differences in several efficacy variables. Data for each of the variables 
will be recorded on the days shown in the time-events schedule table. This trial will use the 
Common Terminology Criteria for Adverse Events version 5 (CTCAE v. 5) to assess safety 
and severity of symptoms. 
8.2.1 Every 24 hours for as long as the patient is in the hospital: input/output, 
hypoglycemic events, creatinine, worst vital signs, and oxygen requirement, dialysis, 
admission to the ICU or need for mechanical ventilation. COVID-19 WHO ordinal status, 
daily serum chemistries, CBC, magnesium, telemetry ECG tracing monitoring and 
continuous oximetry monitoring. Patients are monitored for gastrointestinal tolerability 
(i.e., nausea, diarrhea) and for other adverse events (i.e., rash, headache) and agent will be 
stopped for CTCAE V5 for grade 3 or higher, while the study monitoring will continue.  

Protocol Version 1.83 
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8.2.2 Every, 24, 48, hours: Acute Kidney Injury-free days, Worst vital signs, Serum 
electrolytes, chemistries, concurrent medications AE/SAE Assessments, Weight, 
Bilirubin, Oxygenation Data, Kidney stone symptoms 
8.2.3 Every 7, 14, 21 and 28 days: Required: Ventilator Free Days to Day 28, All-Cause 
Mortality to Day 28, oxygenation indices, oxygen device, use of dialysis. COVID-19 
WHO ordinal status. 
8.2.4Sixty and 90 Days: All-cause mortality, routine evaluations of organ function, 
functional status 
8.2.5 All patients will be treated at minimum subcutaneous unfractionated heparin for 
thrombo-prophylaxis (5000 units TID). Anticoagulation may be escalated by the treating 
physicians based on clinical and laboratory variables, such as the D-Dimer and the 
thromboelastogram (TEG). If suspicion of clotting arises immediate thromboelastography 
(TEG) will be performed to determine if clotting is ongoing. If TEG supports clotting 
suspicions doppler ultrasound of the appropriate venous site will be performed. 
8.2.6 Assessment of hepatic safety: Hepatic transaminases will be monitored at baseline, 
day 2 and day 3 or the study. Persistent elevations will lead to: 1) discussion with ward 
staff, 2) will lead to right upper quadrant ultrasonography, and 3) Consultation from the 
Hepatology service. 
 
8.3 Adverse Events and Serious Adverse Events 
8.3.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a) 
8.3.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
the investigator, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
8.3.3 Classification of an Adverse Event 
The SAFE EVICT CORONA-ALI trial will utilize the Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0, published: November 27, 2017, which grades 1 
through 5 with unique descriptions of severity for each adverse event based on the 
following: 
Severity of Event 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental activities of daily living (ADL). 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care or ADLs. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
Relationship to Study Intervention 

Protocol Version 1.83 
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All adverse events AEs will have their relationship to study intervention assessed by the 
investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
• Related — The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the study intervention and the AE. 
• Not Related — There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
Expectedness 
The Principal and Sub-Investigators will be responsible for determining whether an adverse 
event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the study intervention. 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate electronic case report form (eCRF). Information to be collected 
includes event description, time of onset, clinician's assessment of severity, relationship to 
study product (assessed only by those with the training and authority to make a 
determination), and time of resolution/stabilization of the event. All AEs occurring while on 
the study must be documented appropriately regardless of relationship. All AEs will be 
followed to an adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as a baseline and not reported as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittently 
require documentation of onset and duration of each episode. 
The study personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 
until resolution or stabilization. 
 
8.3.5 Adverse Event Reporting 
Investigators will report all unanticipated problems that involved risk or harm to a research 
participant AND was not anticipated or foreseen (e.g., not described in the consent form) 
AND is probably or definitely related to or caused by the research to the IRB within 5 
business days of receiving notice of the unanticipated problem. 
Investigators will report all unanticipated problems, defined as a problem that involve risk or 
harm to a research participant AND was not anticipated or foreseen (e.g., not described in the 
consent form) AND is probably or definitely related to or caused by the research, to the 
DSMB within 7 calendar days of the being notified of the event. 
Investigators will also determine if the serious adverse event is unexpected for Vitamin C. 
Unexpected for Vitamin C is defined as any event not listed in the Vitamin C package insert. 
If the investigator determines that any serious and study-related adverse event is unexpected 

Protocol Version 1.83 
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for Vitamin C, the FDA will be notified within 7 calendar days. Such events may also meet 
the definition of Unanticipated Problems as described below. 
CTCAE Grade 3 or higher will trigger a pause in enrollment while the DSMB reviews 
the data to determine whether subsequent enrollment should proceed. 
Examples of untoward clinical occurrences or disease-related events (DRE) that are expected 
in the course of COVID-19 include: 1) transient or worsening hypoxemia, 2) agitation, 3) 
delirium, 4) nosocomial infections, 5) skin breakdown, 6) acute hepatitis, 7) acute kidney 
injury, and 8) worsening of respiratory function. Such events, which are often the focus of 
prevention efforts as part of usual ICU care, will not be considered reportable adverse events 
unless the event is considered by the investigator to be associated with the study drug or 
procedures, or unexpectedly severe or frequent for individual patient sepsis and AH. 
Examples of unexpectedly frequent untoward clinical occurrences would be repeated 
episodes of unexplained hypoxemia. This would be in contrast to an isolated episode of 
transient hypoxemia (e.g., Sp02 ~85%), related to positioning or suctioning. This latter event 
would not be considered unexpected by nature, severity or frequency. These events will be 
captured in the eCRF. 
8.3.6 Adverse Events, Serious Adverse Events, and Unanticipated Problems 
Adverse events (AEs), serious adverse events (SAEs), and unanticipated problems (UPs) 
occurring at VCU will be managed and reported in accordance with VCU/VCUHS Clinical 
Research Standard Operating Procedures #CR-RE-300.1: Adverse Event Management and 
Reporting.  Those occurring at the VA will be managed and reported in accordance with the 
VA’s standard operating procedures. 
All serious adverse events (SAEs) will be followed until a satisfactory resolution or until the 
site investigator deems the event to be chronic or the participant is stable. 
The PI/sponsor will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in 
no case later than 7 calendar days after being informed about the event. In addition, the 
PI/sponsor must notify FDA and all participating investigators in an Investigational New 
Drug (IND) safety report of potentially serious risks, from clinical trials or any other source, 
as soon as possible, but in no case later than 15 calendar days after the PI/sponsor determines 
that the information qualifies for reporting. 

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9 - Statistical Considerations 
Model Set-Up: 
We plan to use a two-sample, unequal-variance 2-tail t-test for comparing the mean 
differences between the two groups, the vitamin C arm and placebo arm. The actual 
interventions will be blinded and will be revealed after the completion of statistical analysis, 
therefore, we will be labeled as group A and group B. No one besides the DSMB and 
independent statistician supporting the DSMB will have access to the comparative data, even 
if the treatment groups are masked as group A and Group B. 
This is a proof-of-concept study, with predetermined sample sizes for each arm, which is 
30 patients for group A and 30 patients for group B, therefore the power analysis is driven 
by the predetermined sample size and did not determine the sample size.  
Therefore, this proof-of-concept study of 60 patients, 30 allocated to the treatment arm and 
30 to the placebo arm, will have 96% power (1-beta () ) to detect an average of 1-point 
difference in the primary outcome, the WHO COVID-19 ordinal scale, with an alpha error 
probability () of 4% (0.04). This is by applying a two-tail, t-test with unequal variances (see 
figure below). 
  
 
-3
-2
-1
0
1
2
3
4
5
6
7
0
0.1
0.2
0.3
critical t = 2.0997
α
2
β

Protocol Version 1.83 
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For binary secondary outcomes, we plan to use the chi-squared test, with 1-degree of 
freedom. The expected effect size for an alpha level of 0.05 and power of 80% is 0.36, as 
shown in the figure below. 
 
10
20
30
40
50
60
70
80
90
100
110
120
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
 = 0.0401181
α err prob
t tests - Means: Difference between two independent means (two groups)
Tail(s) = Two. Effect size d = 1. Allocation ratio N2/N1 = 1. α err prob = 0.0401181
Total sample size
10
20
30
40
50
60
70
80
90
100
110
120
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
α err prob
 = 1
Effect size d
t tests - Means: Difference between two independent means (two groups)
Tail(s) = Two. Power (1-β err prob) = 0.959882. Allocation ratio N2/N1 = 1. Effect size d = 1
Total sample size
10
20
30
40
50
60
70
80
90
100
110
120
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Effect size w
 = 0.0501
 = 0.0001
α err prob
χ² tests - Goodness-of-fit tests: Contingency tables
Df = 1. Power (1-β err prob) = 0.8
Total sample size

Protocol Version 1.83 
53 
 
In contrast, for a constant hypothetical effect size of 0.2, a phase 3 trial will require at least 
200 patients to achieve a power of 80% and an alpha of 0.05 (yellow line, figure below). 
 
Planned Interim Analyses:  
No planned interim analyses will be conducted in this study. The results will be 
analyzed after the 60th patient has finished enrollment and has been discharged from the 
hospital (phase 1). There are no provisions to stop the trial early for efficacy. 
Missing Data 
The primary outcome, the WHO-COVID-19 scale is encompassing missing data from death 
or hospital discharge. Missing laboratory or clinical data due to patient death, or discharge 
will not be imputed given this practice will introduce systematic bias, since they are not 
missing at-random. For organ-system data, the highest scores will be attributed after patient 
death, since death causes cessation of all organ function, and any imputation method will 
underestimate the severity. For missing-at-random data, multiple imputation with a pattern-
mixture model with control-based pattern imputation will used, with 50 imputed data sets, in 
order to compensate for data that may be missing at random. 
 
2
4
6
8
10
12
14
16
18
0
1
2
3
4
5
6
critical χ² = 3.8415
α
β
0.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
0
100
200
300
400
500
600
Total sample size
 = 0.101
 = 0.051
 = 0.001
α err prob
χ² tests - Goodness-of-fit tests: Contingency tables
Df = 1. Effect size w = 0.2
Power (1-β err prob)

Protocol Version 1.83 
54 
10 - Supporting Documentation and Operational 
Considerations 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Informed Consent Process 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant. Due to the infectious nature of COVID-19, we will follow the FDA 
guidance dated March 2020 and updated May 12, 2020, to obtain informed consent. In order 
to protect members of the research team the consent process will be conducted verbally using 
the existing the same remote system currently being used in the hospital for communication 
with patients regarding their clinical care. If the participant agrees to participate in the study, 
their consent will be documented either using an electronic signature, a wet signature which 
is photographed, attestation by an impartial witness and the investigator that the participant 
consented, or sterilization of the paper consent. Informed consent will be documented in the 
EHR prior to starting intervention/administering study intervention. 
 
Informed consent is a process that is initiated prior to the individual's agreeing to participate 
in the study and continues throughout the individual's study participation. Consent forms will 
be Institutional Review Board (IRB) approved and the participant will be asked to read and 
review the document. The investigator will explain the research study to the participant and 
answer any questions that may arise. A verbal explanation will be provided in terms suited to 
the participant's comprehension of the purposes, procedures, and potential risks of the study 
and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to consenting. However, given the 
time sensitive nature, participants will be given a maximum of 4 hours to make a decision. 
The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate.  
 
The participant will provide informed consent prior to any procedures being done specifically 
for the study. Participants will be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. Participants will be informed of other 
COVID-19 trials that are being performed. Should another drug become available to treat 
COVID-19 that is safe and effective the drug to subjects enrolled in this trial will be offered. 
A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document 
(including the date) and consent provided before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
Some of the patients approached for participation in this research protocol will have 
limitations of decision-making abilities due to their critical illness. Hence, some patients will 
not be able to provide informed consent. Accordingly, informed consent will be sought from 
the potential subject's legally authorized representative (LAR) in compliance with Federal 
Regulations 45 CFR part 46. Only those individuals who are authorized to serve as LARs per 
VCU IRB Written Policies and Procedures #XI-3 will be eligible to provide consent on 
behavior of patients to participate in this study. Because all participants are inpatients in the 
hospital, the study will use the same LARs for research consent as are acting as LARs for the 
purposes of treatment. 

Protocol Version 1.83 
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10.1.1.b Informed Consent with DocuSign Part 11  
In concordance with the latest FDA guidance on consent purposes, the study is offering 
electronic Informed Consent. This will be offered through DocuSign Part 11. The consent 
forms will be identical in Spanish and English; however, the signatures will be electronic. 
The electronic informed consent (eIC) will only be offered to Legally Authorized 
Representatives (LAR) and not in face-to-face consent with patients.  For face-to-face 
encounters only the paper consent forms will be used. 
 
The consents will be offered in order to facilitate the following: 
• Legally Authorized Representative (LAR) may not be able to travel on site in a timely 
manner. 
• LAR may not be comfortable visiting the hospital  
• LAR may not be adherent to social distancing/ face masks which make it impossible 
for study personnel to interact.  
 
The following elements will be followed for the informed consent process, in concordance 
with the VCU IRB requirements: 
 
a) A remote discussion is required prior to sending the DocuSign Part 11 consent 
b) The consent will be emailed or faxed for the LAR to review prior to the discussion 
c) DocuSign consent cannot be used for in-person interactions. Only the paper ICF. 
d) A remote consent discussion is held via phone, Zoom, etc. and the LAR’s questions 
are answered.  
e) If the person indicates they are willing, the study team member collects the person’s 
name and email address.  
f) The study team member goes into their Part 11 DocuSign account, creates an 
envelope, and sends it to the participant. An access code will also be set and 
communicated to the LAR. 
g) The LAR clicks the DocuSign email and creates an account password to log in. 
h) They review and sign the consent document electronically. 
i) The DocuSign envelope is routed to the person obtaining consent for signature and 
then to the Principal Investigator. 
j) Once all signatures are obtained, all persons receive an email and can download a 
copy of the signed form. 
k) The study team (PI, regulatory contact) ensure that the DocuSign Part 11 consent is 
accessible any time an auditing is requested and a physical copy is held in the study’s 
regulatory binder in a dedicated section of DocuSign Part 11 Informed Consents. 
 
 
10.1.2 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants and 
IRB. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and will provide 
the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
(primary outcome, or AKI-free days), or any safety concerns 

Protocol Version 1.83 
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• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB and/or Food and Drug Administration (FDA). 
10.1.3 Data Confidentiality and Participant Policy 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators and their staff. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the PI. 
All research activities will be conducted in as private a setting as possible. 
Representatives of the Institutional Review Board (IRB) and regulatory agencies may inspect 
all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
The study participant's contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
FDA requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored in a secure, electronic database. This will not 
include the participant's contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study 
data entry and study management systems used by clinical sites and by research staff will be 
secured and password protected. At the end of the study, all study databases will be de-
identified and archived. 
10.1.4 Future Use of Stored Human Specimens and Data 
Specimens will be added to the Virginia Commonwealth University Registry of SARS-CoV-
2 (VCU-RS). The consent process will include the use of completely deidentified and 
tabulated data for post-hoc studies.  
10.1.5 Safety Oversight 
Safety oversight will be monitored by the DSMB and co-PI (s) to ensure accurate recording 
of the data and reporting of any clinically significant AEs to the IRB or appropriate federal 
authorities. 
The Data and Safety Monitoring Board (DSMB) will be comprised of physicians, ethicists, 
and statisticians from several universities outside of VCU. No one besides the DSMB and 
independent statistician supporting the DSMB will have access to the comparative data, even 
if the treatment groups are masked as group A and Group B. The DSMB charter will be 
submitted for FDA review. The DSMB will have access to masked data to evaluate the 
benefit-risk of patients enrolled in the SAFE-EVICT-CORONA-ALI trial. The DSMB 
charter will be submitted for FDA review, specifying the DSMB members. We will include 
detailed procedures to maintain trial integrity (e.g., personnel, firewalls). We will additionally 
give the expected enrollment rate and the amount of time to clean and analyze interim data 
for DSMB review. With the rate of new COVID-19 patient admission we will propose to 
hold a DSMB review every month. The DSMB charter will lay out the steps to ensure 
review of early interim data which will ensure patient safety. 
 
10.1.6 Key Roles and Study Governance 
Not relevant 

Protocol Version 1.83 
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10.1.7 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and verifiable, 
and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s). 
• Monitoring for this study will be performed by an internal monitoring team, who may 
or may not be part of the study team. 
• On-site monitoring will occur annually at the time of IRB continuing review and 
involve a random review of certain data to assess for data accuracy, protocol 
compliance, and deviations. 
10.1.8 Quality Assurance and Quality Control 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. As mentioned 
in the statistical section 9.5, for missing at random data, we will employ imputation methods 
that may include multiple imputations, or pattern mixture models, depending on the 
appropriateness of each scenario. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices 
(GMP)). 
The investigational site will provide direct access to all trial-related sites, source 
data/documents, and reports for the purpose of inspection by local and regulatory authorities. 
10.1.9 Data Handling and Record Keeping 
A screening log will be created and stored in a password-protected document on a secure 
REDCap (18) network. Data will be entered into a password-protected software. Entry logs 
and audit trails are kept within the system, as well as complete tracing on who entered/ 
modified what and when. Difference levels of access provided.  
The study team will enter the data in REDCap after consent is obtained (31). The PI and co-
PIs will supervise the accuracy and integrity of the data.  
Study documents should be retained for a minimum of 2 years after study completion. 
10.1.10 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. Noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  
10.1.11 Publication and Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
Data will be shared through the VCU registry for protocols approved by VCU’s IRB. 
Data may be shared with a national COVID-19 registry. 
10.1.12 Conflict of Interest Policy 

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The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the design and conduct of this trial. 
 

Protocol Version 1.83 
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10.3 Protocol Amendment History 
Version 
Date 
Description of Change  
Brief Rationale 
1.51 
08/14 
Change of protocol after FDA PIND 
feedback 
Focusing on a phase 2, safety 
proof-of-concept study 
1.6 
9/10 
Feedback from FDA (RI) 
Revised inclusion and 
exclusion criteria for AKI, CKD, 
dosage ceiling of 15 gr daily 
added. Oxalate measurement 
as secondary outcome 
changed to day 5. Dose 
reduction of 50% for patients 
with AKI stage 2 or 3. 
1.7 
9/20 
Feedback from FDA 
Addition of echocardiogram as an 
exploratory outcome in COVID-19 
sepsis patients 
Evaluating the effect of 
vitamin c in the myocardial 
function and GLS. Correction 
of errors. Ascorbic acid 
measurement, adding 
outcome of alive-and-free of 
respiratory failure, and alive-
and-free of ventilation. Added 
daily assessments and labs to 
day 7. Consideration to 
change the primary outcome 
to mortality adjusted for 
prespecified outcomes. 
1.8 
11/5 
Removal of echocardiogram 
Removal of cf-DNA from secondary 
outcomes 
Removal of Syndecan-1 from 
secondary outcomes  
Removal of troponin 
Budget restriction 
1.82 
2/7/2021 
Due to hospital staffing in the 
middle of the COVID-19 pandemic 
we were informed by the VCU 
Health Clinical Research Team that 
the study can only be undertaken 
in ICU level of care. Therefore, we 
include in the exclusion criteria 
“non-ICU patients” 
Reported Staff Restrictions 
1.83 
5/22/2021 
Clarifications requested by the IRB 
on inconsistencies when infusions 
are stopped, status, and clarify 
discontinuation vs. withdrawal.  
After revision of protocol 1.82 
this was affected 
 
 
 
 
 
 
 
 
 
 
 
 

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References 
1. WHO, WHO Director-General's opening remarks at the media briefing on COVID-19 
- 11 March 2020. 2020; 
 
2. Dong, E, Du, H, Gardner, L. An interactive web-based dashboard to track COVID-19 
in real time. Lancet Infect Dis 2020; doi: 10.1016/S1473-3099(20)30120-1.  
 
3. Ferguson, NM Laydon, D Nedjati-Gilani, G Imai, N Ainslie, K Baguelin, M Bhatia, S 
Boonyasiri, A Cucunubá, Z Cuomo-Dannenburg, G Dighe, A. Imperial College 
COVID-19 Response Team Impact of non-pharmaceutical interventions (NPIs) to 
reduce COVID-19 mortality and healthcare demand.  
 
4. Society of Critical Care Medicine,. United States Resource Availability for COVID-
19 United States Resource Availability for COVID-19. 2020;  
 
5. Fink S. Worst-Case Estimates for U.S. Coronavirus Deaths - The New York Times. 
The New York Times  
 
6. American Hospital Association. Fast Facts on U.S. Hospitals, 2020. 2020;  
 
7. Zhu, Na Zhang, Dingyu Wang, Wenling Li, Xingwang Yang, Bo Song, Jingdong 
Zhao, Xiang Huang, Baoying Shi, Weifeng Lu, Roujian Niu, Peihua Zhan, Faxian 
Ma, Xuejun Wang, Dayan Xu, Wenbo Wu, Guizhen Gao, George F Tan, Wenjie 
China Novel Coronavirus Investigating and Research Team. The New England 
Journal of Medicine A Novel Coronavirus from Patients with Pneumonia in China, 
2019. N Engl J Med 2020; 8:727 - 733. doi: 10.1056/NEJMoa2001017.  
 
8. Huang, Chaolin Wang, Yeming Li, Xingwang Ren, Lili Zhao, Jianping Hu, Yi Zhang, 
Li Fan, Guohui Xu, Jiuyang Gu, Xiaoying Cheng, Zhenshun Yu, Ting Xia, Jiaan Wei, 
Yuan Wu, Wenjuan Xie, Xuelei Yin, Wen Li, Hui Liu, Min Xiao, Yan Gao, Hong 
Guo, Li Xie, Jungang Wang, Guangfa Jiang, Rongmeng Gao, Zhancheng Jin, Qi 
Wang, Jianwei Cao, Bin. The Lancet Clinical features of patients infected with 2019 
novel coronavirus in Wuhan, China. Lancet 2020; 10223:497 - 506. 
doi:10.1016/S0140-6736(20)30183-5.  
 
9. Wang, Dawei Hu, Bo Hu, Chang Zhu, Fangfang Liu, Xing Zhang, Jing Wang, Binbin 
Xiang, Hui Cheng, Zhenshun Xiong, Yong Zhao, Yan Li, Yirong Wang, Xinghuan 
Peng, Zhiyong. The Journal of the American Medical Association Clinical 
Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected 
Pneumonia in Wuhan, China. JAMA 2020; doi: 10.1001/jama.2020.1585.  
 
10. Intravenous Vitamin C Employed as Adjunctive Therapy in Recurrent Acute 
Respiratory Distress Syndrome (ARDS): A Case Report | A54. CRITICAL CARE 
CASE REPORTS: ACUTE HYPOXEMIC RESPIRATORY FAILURE/ARDS.  
 
11. Fowler, A, Truwit, D, Hite, RD, Morris, PE, DeWilde, C, Priday, A, Fisher, BJ, 
Thacker, LR, Natarajan, R, Brophy, DF, Sculthorpe, R, Nanchal, R, Syed, A, Sturgill, 
J, Martin, GS, Sevransky, J, Kashiouris, M, Hamman, S, Egan, KF, Hastings, A, 

Protocol Version 1.83 
62 
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; 
13:1261 - 1270. doi: 10.1001/jama.2019.11825.  
 
12. 1989 - Sawyer, Marino [ABSTRACT antioxidant therapy & survival in ARDS]  
 
13. Fowler, AA, Syed, AA, Knowlson, S, Sculthorpe, R, Farthing, D, DeWilde, C, Larus 
CA, Martin E. Brophy, DF, Gupta, S Medical Respiratory Intensive Care Unit 
Nursing Fisher, BJ, Natarajan, R. Journal of Translational Medicine Phase I safety 
trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014; 
32. doi: 10.1186/1479-5876-12-32. 
 
14. Vincent, JL, Marshall, JC, Namendys S, François SA, Martin-Loeches B, Lipman, I, 
Reinhart J, Antonelli, K, Pickkers, M, Njimi, P, Jimenez, H, Sakr, E, Yasser ICON 
investigators. Respiratory medicine Assessment of the worldwide burden of critical 
illness: the intensive care over nations (ICON) audit. Lancet Respir Med 2014; 5:380 
- 386.  
 
15. Fujii, TL, Young N, Frei PJ, Eastwood DR, French GM, Deane CH, Shehabi AM, 
Hajjar Y, Oliveira LA, Udy G, Orford AA, Edney A, Hunt SJ, Judd AJ, Bitker HL, 
Cioccari L, Naorungroj L, Yanase T, Bates F, McGain S, Hudson F, Al-Bassam EP, 
Dwivedi W, Peppin DB, McCracken C, Orosz P, Bailey J, Bellomo M. Effect of 
vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and 
free of vasopressor support among patients with septic shock: VITAMINS 
randomized clinical trial.  JAMA 2020; doi: 10.1001/jama.2019.22176. 
 
16. Web MD. Side Effects Halt Use of Chloroquine Vs. COVID-19. URL:  
https://www.webmd.com/lung/news/20200407/side-effects-halt-use-of-chloroquine-
vs-covid-19. Cited on May 5, 2020 
 
17. Trankle, CR, Pucket L, Swift-Scanlan T, Dewilde C, Priday A, Sculthorpe R, 
Ellenbogen KA, Fowler A, Koneru J.  Vitamin C intravenous Treatment in the setting 
of atrial fibrillation ablation: results for the randomized double-blinded, placebo-
controlled CITRIS-AF pilot study J Am Heart Assoc. 2020 Feb 4; 9(3): e014213. 
 
18. Cheng, Richard Z. "Can early and high intravenous dose of vitamin C prevent and 
treat coronavirus disease 2019 (COVID-19)?" Medicine in Drug Discovery 5 (2020): 
100028. 
 
19. National Cancer Institute. https://www.cancer.gov/about-
cancer/treatment/cam/hp/vitamin-c-pdq cited on April 27, 2020 
 
20. Petition for the President of the United States from Change.org 
https://www.change.org/o/the_coronavirus_ivc_project cited on May 5th, 2020. 
 
21. 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 

Protocol Version 1.83 
63 
for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit 
Care Med. 2017 Feb 4;6(1):85-90.  
 
22. Kashiouris, M. G., L’Heureux, M., Cable, C. A., Fisher, B. J., & Leichtle, S. W. 
(2020). The emerging role of vitamin C as a treatment for sepsis. Nutrients, 12(2), 
292. 
 
23. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic 
acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-
100. 
 
24. Hemilä H. Vitamin C supplementation and respiratory infections: a systematic 
review.Mil Med. 2004;169(11):920-5. 
 
25. Mohammed BM, Fisher BJ, Kraskauskas D, Farkas D, Brophy DF, Fowler AA,  
Natarajan N. Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap 
Formation. Nutrients. 2013; 5(8): 3131–3150. doi: 10.3390/nu5083131 
 
26. Suwarto S, Sasmono RT, Sinto R, Ibrahim E, Suryamin M. Association of Endothelial 
Glycocalyx and Tight and Adherens Junctions With Severity of Plasma Leakage in 
Dengue Infection. J Infect Dis. 2017;215(6):992-999. doi: 10.1093/infdis/jix041, 
PMID: 28453844. 
 
27. Fowler AA 3rd1, Fisher BJ1, Kashiouris MG1. Vitamin C for Sepsis and Acute 
Respiratory Failure-Reply. JAMA. 2020;323(8):792-793. doi: 
10.1001/jama.2019.21987. 
 
28. Lamarche, Jorge, et al. "Vitamin C-induced oxalate nephropathy." International 
journal of nephrology 2011 (2011). 
 
 
29. Buehner, Michelle, et al. "Oxalate nephropathy after continuous infusion of high-dose 
vitamin C as an adjunct to burn resuscitation." Journal of Burn Care & Research 37.4 
(2016): e374-e379. 
 
30. Fontana, Francesco, et al. "Oxalate nephropathy due to excessive vitamin C 
administration in two patients with COVID-19." Kidney International Reports (2020). 
 
 
31. Yanase, Fumitaka, et al. "Harm of IV high-dose vitamin C therapy in adult patients: a 
scoping review." Critical care medicine 48.7 (2020): e620-e628. 
 
32. Yang L, Wang K, Li H, Denstedt JD, Cadieux PA. The influence of urinary pH on 
antibiotic efficacy against bacterial uropathogens. Urology. 2014;84(3):731.e1-
731.e7317. doi:10.1016/j.urology.2014.04.048 
 
 
33. Batlle, Daniel, et al. "Acute kidney injury in COVID-19: emerging evidence of a 
distinct pathophysiology." Journal of the American Society of Nephrology (2020). 
 

Protocol Version 1.83 
64 
34. Padayatty, SJ, Sun, H, Wang, Y, Riordan, H, Hewitt D, Katz, SM, Wesley A, Levine, 
M. Annals of Internal Medicine Vitamin C pharmacokinetics: implications for oral 
and intravenous use.  Publication: Ann Intern Med Publication date: 2004; Issue: 
7:Page/Line: 533 - 537. doi: 10.7326/0003-4819-140-7-200404060-00010. 
 
35. Levine, M, Padayatty, SJ, Espey, MG. Advances in nutrition (Bethesda, Md.) Vitamin 
C: a concentration-function approach yields pharmacology and therapeutic 
discoveries.  Publication: Adv Nutr Publication date: 2011; Issue: 2:Page/Line: 78 - 
88. doi: 10.3945/an.110.000109. 
 
36. Harris, Paul A., et al. The REDCap consortium: Building an international community 
of software platform partners. Journal of biomedical informatics Publication date: 
2019; 95: 103208.