Vitamin C Infusion for TReatment in Sepsis and Alcoholic Hepatitis
Phase: PHASE2
Conditions: Alcoholic Hepatitis, Sepsis
Sponsor: Virginia Commonwealth University

 
 
Title: Vitamin C Infusion for TReatment In Sepsis and Alcoholic Hepatitis 
 
NCT #: NCT03829683 
 
Document date: 01/21/2020 
 
Document Type: Protocol and SAP 
 
 
 

Vitamin C Infusion for TReatment In Sepsis and 
Alcoholic Hepatitis 
 
CITRIS-AH 
 
Protocol Number: 0001 
Principal Investigators: Arun J. Sanyal and Alpha A. Fowler 
Virginia Commonwealth University 
IND Sponsor: Federal Food and Drug Administration  
IND # 142244 
Funded by: National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
 
Version Number:  12 
 
21 January 2020 
 
 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 11 
2.3.1 
Known Potential Risks ................................................................................................... 11 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 13 
4.1 
Overall Design .................................................................................................................................... 13 
4.2 
Scientific Rationale for Study Design.............................................................................................. 14 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 14 
5.1 
Inclusion Criteria ................................................................................................................................ 14 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations .................................................................................................................... 16 
5.4 
Screen Failures .................................................................................................................................. 17 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 17 
6 
STUDY INTERVENTION ............................................................................................................................ 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 17 
6.1.1 
Study Intervention Description ..................................................................................... 17 
6.1.2 
Dosing and Administration ............................................................................................ 18 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 18 
6.2.1 
Acquisition and accountability ...................................................................................... 18 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 18 
6.2.3 
Product Storage and Stability ....................................................................................... 18 
6.2.4 
Preparation ...................................................................................................................... 19 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 19 
6.4 
Study Intervention Compliance ........................................................................................................ 19 
6.5 
Concomitant Therapy ........................................................................................................................ 20 
6.5.1 
Rescue Medicine ............................................................................................................ 20 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 20 
7.1 
Discontinuation of Study Intervention ............................................................................................. 20 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 20 
7.3 
Lost to Follow-Up ............................................................................................................................... 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 21 
8.1 
Efficacy Assessments ....................................................................................................................... 21 
8.2 
Safety and Other Assessments ....................................................................................................... 23 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 23 

  
 
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 23 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 23 
8.3.3 
Classification of an Adverse Event .............................................................................. 24 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 24 
8.3.5 
Adverse Event Reporting .............................................................................................. 25 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 26 
8.4 
Unanticipated Problems .................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 26 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 26 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 27 
9.1 
Statistical Hypotheses ....................................................................................................................... 27 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 28 
9.4.1 
General Approach .......................................................................................................... 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 
9.4.3 
Safety Analyses .............................................................................................................. 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 29 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 29 
10.1.1 
Informed Consent Process ........................................................................................... 29 
10.1.2 
Study Discontinuation and Closure ............................................................................. 30 
10.1.3 
Confidentiality and Privacy ........................................................................................... 31 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.5 
Key Roles and Study Governance .............................................................................. 32 
10.1.6 
Safety Oversight ............................................................................................................. 33 
10.1.7 
Clinical Monitoring .......................................................................................................... 33 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 33 
10.1.9 
Data Handling and Record Keeping ............................................................................ 33 
10.1.10 
Protocol Deviations ........................................................................................................ 34 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 34 
10.1.12 
Conflict of Interest Policy .............................................................................................. 35 
10.2 
Abbreviations ...................................................................................................................................... 36 
10.3 
Protocol Amendment History ........................................................................................................... 38 
11 
REFERENCES ............................................................................................................................................. 39 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the NIAAA 
Terms and Conditions of Award. The Principal Investigator will assure that no deviation from, or changes 
to the protocol will take place without prior agreement from the Investigational New Drug (IND) 
sponsor, funding agency and documented approval from the Institutional Review Board (IRB), 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. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Vitamin C Infusion for TReatment In Sepsis and Alcoholic Hepatitis 
Study Description: 
It is our long-term goal to identify relevant “druggable” targets for 
alcoholic hepatitis (AH) and to translate this knowledge in to effective 
strategies to prevent and treat AH. This proposal will focus on one key 
area of unmet need in the field i.e. those with alcoholic hepatitis who have 
active infection and sepsis.  
 
We hypothesize that in patients with sepsis and alcoholic hepatitis, a 96-
hour infusion of vitamin C (ascorbic acid, AscA, 200mg/kg/24 hours) will 
improve hepatic function, be well tolerated, and will attenuate biomarkers 
of inflammation, vascular injury, and encourage fibrinolysis. 
Objectives: 
 
To assess the efficacy of a 96-hour intravenous vitamin C infusion protocol 
(200 mg/kg per 24 hours) in patients with established alcoholic hepatitis 
(AH) and sepsis. In this course of performing this proof of concept phase II 
trial we will explore three hypotheses: 
 
Hypothesis 1A: Vitamin C infusion will significantly attenuate hepatic 
dysfunction as measured by the model for end stage liver disease (MELD) 
score in patients with alcoholic hepatitis and sepsis. 
 
Hypothesis 1B: Vitamin C infusion will be safe and tolerable in patients 
with alcoholic hepatitis and sepsis. 
 
Hypothesis 1C: Vitamin C infusion will attenuate biomarkers of 
inflammation (C-Reactive Protein, procalcitonin), vascular injury 
(Thrombomodulin, Angiopoietin-2), while inducing the onset of a 
fibrinolytic state (Tissue Factor Pathway Inhibitor). 

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Endpoints: 
Primary Endpoint: Change in MELD score at 96 hours as compared to 
baseline when compared to placebo.  
 
Secondary Endpoints: 
• 
SOFA Score and components at hours 48, 96, 168 
o PaO2/FiO2 
o SpO2/FiO2 
o Platelets 
o Total Bilirubin 
o Vasopressor status 
o Glasgow Coma Score 
o Creatinine or Urine Output 
• 
CLIF-SOFA scores and components at hours 48, 96, 168 
o Total Bilirubin 
o Creatinine 
o Renal replacement therapy (yes/no) 
o West-Haven grade for hepatic encephalopathy (HE) 
o INR 
o Mean arterial pressure (MAP) 
o Use of vasopressors (yes/no) 
o PaO2 or SpO2 
o FiO2 
o Use of mechanical ventilation (yes/no) 
• 
Lille score 
o Age 
o Albumin (on admission) 
o Bilirubin (on admission, hour 96, 168) 
o Creatinine (on admission) 
o Prothrombin time (on admission) 
• 
Maddrey Discriminate Function (MDF) at hours 96, 168 
o Prothrombin time (hours 96, 168) 
o Total bilirubin (hours 96, 168) 
o PT control/reference level (assuming 12 seconds) 
• 
Liver enzymes and function tests at hours 48, 96, 168 
o AST, ALT, total bilirubin, alkaline phosphatase, albumin 
• 
MELD-Na Score at hours 48, 96, 168 
o INR, creatinine, bilirubin, sodium 
• 
Documented tolerability at hours 24, 48, 96 
o Need for dose reduction, headache, dizziness, dry mouth, 
nausea, vomiting, flushing, rash, hypotension, treatment 
related adverse events 
• 
Documented safety at hours 24, 48, 96  
o QTc Interval (EKG) 
o Crystalluria (Urinalysis with microscopy and pH testing) 
• 
Serum Biomarkers 
o Procalcitonin, C-reactive protein, thrombomodulin, 
thromboelastography (TEG), Receptor for Advanced 

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Glycation End Products, Tissue Factor Pathway Inhibitor at 
study hours 0, 48, 96, 168 (When feasible) 
• 
Ascorbate level at hour 0, 48, 96, 168 (When feasible) 
• 
Need for escalation of support i.e. need for ventilator or 
pressor support when these are not needed at baseline 
• 
ICU-free days at day 28 
• 
All-cause mortality to day 28 and day 90 
• 
Hospital-free days at day 90 
Study Population: 
A total of 20 adult subjects with alcoholic hepatitis and suspected or 
documented sepsis will be enrolled in this study.  All participants will be 
enrolled at the Virginia Commonwealth University Health System (VCUHS). 
Phase: 
Phase II 
Description of 
Sites/Facilities Enrolling 
Participants: 
Subjects will be recruited from the Emergency Department (ED), inpatient 
medicine unit admitted to the Digestive Health Service (DHS), and 
Intensive Care Units (ICU) at VCUHS. 
Description of Study 
Intervention: 
Participants will be randomized to receive either intravenous Vitamin C 
(sterile L-ascorbic acid mixed in 5% dextrose in water) or placebo (5% 
dextrose in water).  Active treatment will continue for 96 hours, discharge 
from study hospital, study withdrawal, or death, whichever comes first. 
Study Duration: 
Years 1-4 
Participant Duration: 
90 days 
1.2 
SCHEMA 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
Hour 0 
 
 
Total N=20:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; document. 
Perform baseline assessments, including MELD score. 
Perform baseline blood draw. Baseline EKG. 
After baseline assessments, administer first dose of Vitamin C or Placebo 
Vitamin C 
N=10 
Placebo 
N=10 
participants 
Randomize 

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Hour 6 
 
 
Hour 12 
 
 
Hour 18 
 
 
Hour 24 
 
 
Hour 30 
 
 
Hour 36 
 
 
Hour 42 
 
 
Hour 48 
 
 
 
Hour 54 
Administer second dose of Vitamin C or Placebo 
Administer third dose of Vitamin C or Placebo 
Administer fourth dose of Vitamin C or Placebo 
Administer fifth dose of Vitamin C or Placebo, EKG, Assess for AEs 
Administer sixth dose of Vitamin C or Placebo 
Administer seventh dose of Vitamin C or Placebo 
Administer eighth dose of Vitamin C or Placebo 
Collect MELD score.  Assess for AEs. Collect SOFA & CLIF-SOFA components. EKG.  
Blood draw for biomarkers and ascorbate. (When feasible)    
Administer ninth dose of Vitamin C or Placebo 
Administer tenth dose of Vitamin C or Placebo 

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Hour 60 
 
 
Hour 66 
 
 
Hour 72 
 
 
Hour 78 
 
 
Hour 84 
 
 
Hour 90 
 
 
Hour 96 
 
Hour 168 
 
 
 
Day 28 
Calculate ICU Free Days 
Administer eleventh dose of Vitamin C or Placebo 
Administer twelfth dose of Vitamin C or Placebo 
Administer thirteenth dose of Vitamin C or Placebo. EKG. 
Administer fourteenth dose of Vitamin C or Placebo 
Administer fifteenth dose of Vitamin C or Placebo 
Administer sixteenth dose of Vitamin C or Placebo 
Collect MELD score.  Assess for AEs. Collect SOFA & CLIF-SOFA components. EKG. 
Blood draw for biomarkers and ascorbate. (When feasible) 
Collect MELD, SOFA, CLIF-SOFA components. Blood draw for biomarkers and 
ascorbate. (When feasible)   

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Day 90 
 
 
                          END STUDY 
 
 
Calculate Hospital Free Days 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Assessments 
Hour 
0 
Q 24 hrs 
1st 7 days 
or in ICU 
Hour 
48 
Hour 
96 
Hour 
168 
Day 
28 
Day 
90 
VS: BP, HR, MAP, RR, Temp., O2 
sats, CVP, Glasgow Coma Scale, 
West-Haven Scale 
S 
 
S 
S 
S 
Body Weight 
S 
 
S 
S 
Suspected or known site of sepsis 
S 
 
S 
S 
S 
R 
R 
I/Os Total and Urine and urinalysis 
for crystalluria 
S 
R 
R 
R 
 
 
 
Assessment of Renal Function with 
serum creatinine, urine output and 
Use of Dialysis 
S 
 
S 
S 
S 
S 
Calculate MELD Score (post study by 
biostatistician) 
S 
 
S 
S 
S 
Labs: 
Arterial Blood Gases, Na+, K+, BUN, 
Cr, WBC, Hgb, Hct, Platelets, 
PT/INR 
S 
 
S 
S 
S 
Bilirubin Total, AST, ALT, ALP, 
albumin 
S 
 
S 
S 
S 
Need for Vasopressors or Inotropes: 
Epi, Nor-epi, Phenylephrine, 
Vasopressin, Dopamine 
S 
 
S 
S 
S 
All concomitant medications 
including: 
Methylprednisone, Hydrocortisone, 
N-acetylcysteine, Antibiotics, 
Thiamine, Albumin 
S 
 
S 
S 
S 
AE/SAE Assessments 
R 
 
R 
R 
R 
Blood for Biomarkers and TEG 
R 
 
R 
R 
R 
ICU Free Days 
 
R 
Hospital Free Days 
 
R 
Glucose Monitoring 
S 
S 
S 
S 
S 
 
 
EKG Monitoring 
S 
R 
R 
R 
 
 
 
All-Cause Mortality 
 
 
 
 
 
R 
R 
 
S = Standard of Care 
R = Research 
 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Alcoholic hepatitis is a clinical syndrome characterized by development of rapid onset of jaundice and 
systemic inflammation in the setting of heavy alcohol (1). Recent guidelines have proposed a 
standardized definition of AH consisting of the clinical development of hepatitis in the setting of heavy 
alcohol use, along with a serum bilirubin >3 mg/dL, aspartate aminotransferase (AST) >50 IU/ml and 
<500 IU/ml, an AST: alanine aminotransferase (ALT) ratio of >1.5, and exclusion of other causes of acute 
hepatitis such as viral, autoimmune, or metabolic etiologies (2). The diagnosis of AH is associated with 
high rates of mortality (3). Various scoring systems such as the Maddrey Discriminate Function (MDF) 
Model for End Stage Liver Disease (MELD), and Lille Model have been developed to predict mortality in 
alcoholic hepatitis patients (4,5). 
 
Recent data indicated the mortality due to alcoholic cirrhosis is increasing, in particular younger people 
age 25-34 (6). The main driver of morbidity and mortality in AH patients are infections (7). However, 
clinical trials of AH exclude patients with suspected or documented infection (8). There are currently no 
FDA approved therapies for AH. Current guidelines by the American Association for the Study of Liver 
Disease (AASLD) recommend corticosteroids for the treatment of severe AH (9). However, 
corticosteroids only have a short-term mortality benefit at 28 days and are associated with higher risks 
of infection, so therefore contraindicated in patients with AH and suspected or documented sepsis (10). 
 
In this study, we will test the novel hypothesis that high-dose ascorbic acid (AscA or Vitamin C) will 
improve outcomes of AH patients with sepsis.  
 
 
2.2 
BACKGROUND  
 
AH is associated with numerous pathophysiological 
mechanisms that increase predisposition to sepsis 
(Figure 1) (11). High levels of alcohol consumption 
impair the gut epithelial barrier and increase 
bacterial translocation and endotoxemia (12). In 
animal models, alcohol ingestion also increases 
markers of oxidative stress (13). Activated Kupffer 
cells and hepatocytes are the likely source of free 
radicals (14,15). Oxidative stress mediates alcohol 
induced liver injury via cytochrome P-450 system 
and leads to mitochondrial damage, activation of 
apoptosis, and up regulation of lipid synthesis (16, 
17,18,19). There is also a release of damage and 
pathogen associated molecular pattern (DAMP and 
PAMP) signals that enhance activation of the innate immune system (20) These signals set up a systemic 
inflammatory state which is further amplified by the systemic response to infection (21) At the same 
time, there are changes in neutrophil, lymphocyte and macrophage function that impair the ability to 
clear infection while enhancing oxidative stress and tissue injury (22 23). 

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Use of High Dose Ascorbic Acid in Patients with AH and Sepsis 
 
Vitamin C or Ascorbic acid (AscA) has been shown to have pleotropic effects in sepsis such as reducing 
oxidative stress, improving neutrophil function and bacterial clearance, reducing systemic inflammatory 
cytokines, and improving endogenous 
catecholamine synthesis (Figure 2) (24, 25, 26, 
27). AscA cannot be synthesized in humans 
and serum levels are dependent on diet (28). 
Serum levels of AscA are reduced in patients 
with sepsis and lower levels correlate with 
higher mortality (29). AscA levels in serum and 
liver tissue have been shown to be reduced in 
patients with alcoholic liver disease (30). In 
critically ill patients, intravenous 
administration of AscA is necessary to 
maintain supra-physiological levels (31, 32). In 
a phase 1 randomized clinical trial of patients 
with severe sepsis, high dose intravenous AscA 
was safe with no adverse events and 
demonstrated a reduction in inflammatory 
markers and organ dysfunction compared with 
placebo (33). Previous clinical trials in AH have 
only administered anti-oxidants via the oral route and excluded patients with infection (34). Therefore, 
the purpose of this clinical trial is to examine the safety, tolerability, and efficacy of high dose 
intravenous AscA in patients with severe AH and sepsis. 
 
Preliminary Data To Support the Use of AscA in AH and Sepsis 
 
AscA prevents pulmonary neutrophil infiltration in a feces-induced peritonitis (FIP) model of sepsis 
(Figure 3). 
 
 
 
 
FIP
FIP-AscA
Figure 2a: AscA (200 mg/kg) infused 30 min following onset of feces 
induced peritonitis (FIP) attenuates sepsis-mediated acute lung injury in 
wild type mice at 16 hours. (H&E stain, 40X magnification)
Figure 3a: AscA (200 mg/kg) infused 30 min following onset of feces
Induced peritonitis (FIP) attenuates sepsis-mediated acute lung 
injury in wild type mice at 16 hours. (H&E stain, 40X magnification)
FIP-AscA
Figure 2b: AscA (200 mg/kg) infused 30 min after of feces induced 
peritonitis significantly attenuated neutrophil sequestration in murine 
lung at 16 hours. (Anti-murine PMN monoclonal antibody, 40X Mag)
FIP
Figure 3b: AscA (200 mg/kg) infused 30 min after feces induced 
peritonitis significantly attenuated neutrophil sequestration in 
muring lung at 16 hours. (Anti-murine PMN monoclonal 
antibody, 40X Mag)

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AscA Increased Clearance of Bacteria from Circulation in a Preclinical Model of Sepsis 
 
In the same murine model of sepsis, blood was obtained by cardiac 
puncture at the time of euthanasia using sterile technique varying 
time points after induction of feces induced peritonitis with or 
without associated AscA administration (Figure 4).  10 µl of blood was 
plated on agar plates and colonies counted after overnight 
incubation.  AscA treated mice had a highly significant decrease in 
colony counts compared to untreated mice (p< 0.01). Bronchoalveolar 
lavage in these mice also demonstrated an increased in alveolar 
protein content after induction of FIP and protection from AscA (data 
not shown). 
 
Human Data to Support the Safety and Efficacy of AscA in Humans with Sepsis 
 
A phase I, randomized, double blind, placebo-
controlled trial, testing the safety of parenteral 
vitamin C in patients with severe sepsis was 
initiated at the VCU Medical Center. All patients 
enrolled, regardless of study arm, received full 
ICU standard of care. Patients were randomized 
to placebo (5% dextrose/water, D5W), or low 
dose vitamin C (50 mg/kg/24hr), or high dose 
vitamin C (200 mg/kg/24hr). The calculated 24 
hour dosage was divided into four and 
administered intravenously (in 50 ml D5W) over 
30 minutes every 6 hours for 96 hours. Vital 
signs were monitored every 5 minutes during 
infusion and for 45 minutes afterwards by 
bedside ICU Nursing and the investigative team. 
Plasma AscA was measured by HPLC at varying 
time points after entry (Figure 5).  At entry, the levels were sub-normal in all cases.   
 
While they did not change in the placebo arm, both high-dose 
and low dose AscA achieved steady state within 24 hours.  AscA 
improved SOFA scores (Fig 6). The SOFA scores were plotted 
over time of entry.  While the placebo arm remained relatively 
flat with a small trend upwards, both low and high dose AscA 
decreased the SOFA scores over the 96 hours of infusion.  
 
Figure 4: Blood cultures from septic mice after 
FIP onset. AscA treated mice (200 mg/kg) show 
significantly lower colony forming units per 10 µl 
of blood compared to untreated septic animals.
Figure 7: Patients with severe sepsis have low plasma 
ascorbate levels. Intermittent intravenous vitamin C infusion 
produces rapid, sustained increases in plasma ascorbate 
levels.
Figure 5: Patients with severe sepsis have low plasma 
ascorbate levels. Intermittent intravenous vitamin C 
infusion produces rapid, sustained increases in plasma 
ascorbate levels.
Figure 8: High dose vitamin C significantly 
reduces sequential organ failure assessment 
(SOFA) scores during the 96 hour treatment 
period when compared to placebo.
Figure 6: High dose vitamin C significantly 
reduces sequential organ failure assessment 
(SOFA) scores during the 96 hour treatment 
period when compared to placebo.

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AscA produced a trend towards decreased mortality (Figure 7):  In 
this pilot study which was not powered to evaluate mortality, there 
was a trend for decreased mortality at day 28.  These data formed 
the basis for an ongoing phase 2B trial of AscA for severe sepsis 
funded by the NHLBI and led by the Dr. Fowler (co-PI).  
 
AscA decreased 
hsCRP and 
procalcitonin:  
In the placebo 
arm, the CRP (left panel) and procalcitonin (right 
panel) remained flat and then either decreased 
(CRP) or showed an increase (procalcitonin).  In 
contrast, both doses of AscA reduced both hsCRP 
and procalcitonin (Figure 8). 
 
 
 
 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Potential Physical Risks of Ascorbic Acid Infusion: dry mouth, nausea, vomiting, dizziness, headache, 
pseudohyperglycemia (if checked with point of care glucose testing), crystalluria. 
 
Potential Psychological, Social, Legal Risks of Ascorbic Acid Infusion: No psychological, social or legal 
risks are identifiable from an extensive literature search.  
 
Risks of Blood Draws:  All patients will have blood drawn for research purposes. Most blood will be 
drawn through indwelling catheters. Risks of drawing blood percutaneously are uncommon and include 
bleeding and bruising. 
 
Glucose Monitoring Plan: 
 
Guidance for blood glucose monitoring in patients enrolled in the CITRIS-AH Trial: 
 
Ascorbic acid is known to artefactually raise POC blood glucose readings by all POC devices except the 
StatStrip glucometer. However, it does not raise blood glucose readings from a basic metabolic panel or 
glucose results using the gas lab.  Thus, extreme care must be taken to assure an accurate blood glucose 
level from a metabolic laboratory (BMP) or arterial blood gas panel before initiating any insulin therapy, 
including sliding scale or scheduled insulin. 
Inpatient units not using the StatStrip POC glucometer should follow the guidelines below. 
 
Guidance for blood glucose monitoring in patients enrolled this study: 
Figure 9: Vitamin C infusion reduces 28-
day mortality in Patients with Severe 
Sepsis
Figure 7: Vitamin C infusion 
reduces 28-day mortality in 
patients with severe sepsis
Figure 10: Intravenous vitamin C rapidly lowers inflammatory biomarkers 
(CRP, PCT) in patients with severe sepsis.
Figure 8: Intravenous vitamin C rapidly lowers inflammatory 
biomarkers (CRP, PCT) in patients with severe sepsis

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• 
Critical care and Inpatient Unit (Main 9 West) Nursing and Physician leadership at all study sites 
must be informed of vitamin C’s effect on point of care (glucometer) blood glucose and arterial 
blood gas glucose point of care values. 
• 
In-service training will be documented in the Study Training Log 
• 
Bold signage will be displayed on all study instructions, data collection forms, and at the 
patient’s head of bed, stating: 
 STOP! Do not use Accuchek or other Point of Care devices to measure glucose on this 
patient 
 Use only metabolic or gas lab glucose screening methods 
 This patient is enrolled in a study with Vitamin C, which artefactually increases POC glucose 
testing 
 Do Not Initiate or Utilize Sliding Scale, Scheduled Insulin, or Continuous Insulin Infusion 
Without Laboratory Confirmation of Blood Glucose 
• 
Those receiving insulin infusion or sliding scale insulin as a part of standard of care will have 
metabolic glucose screening on the schedule determined by the attending physician 
• 
Blood glucose monitoring for insulin administration guidance should only be by a metabolic or 
blood gas laboratory measured blood glucose results, whether or not the study patient is 
receiving insulin  
• 
Study personnel will follow each study patient closely to monitor insulin use to ensure that point 
of care glucose screening is suspended for the research subject. 
• 
Point of care glucose testing may resume 36 hours after the last infusion of study drug. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Most observational studies suggest a mortality benefit from prior or in-patient Vitamin C use after 
hospitalization for serious infections.  None of the observational trials have reported significant Vitamin 
C-related toxicity.  An animal model of acute lung injury with intravenous LPS and feces induced 
peritonitis demonstrate significantly less lung injury with Vitamin C, which may result in shortening the 
time patients require mechanical ventilation. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The identifiable risks arising from exposure to intravenous ascorbic acid infusion are low. In preliminary 
data analyzed at VCU for another intravenous Vitamin C in sepsis study, we extensively outlined the 
potential benefits brought by attenuation of acute lung injury and organ failure associated with bacterial 
sepsis. Given the low risk associated with ascorbic acid infusion and the potential high likelihood of 
benefit we assess the risk/benefit ratio to be low (i.e., that benefit far outweighs risk). 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
Primary 
 
 
Vitamin C infusion will significantly 
attenuate hepatic dysfunction as 
measured by the model for end stage 
liver disease (MELD) score 
Change in MELD score at 96 hours as 
compared to baseline when compared to 
placebo.  
 
MELD score is an 
independent positive 
predictor of mortality in 
patients with AH.  
Secondary 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
Vitamin C infusion will be safe and 
tolerable in patients with severe 
alcoholic hepatitis 
.  
Documented side effects and serious 
adverse events at hours 24, 48, 96 when 
compared with hour zero in high dose 
ascorbic acid versus placebo.  
 
AscA infusion may cause 
dry mouth, nausea, 
vomiting, dizziness, 
headache, flushing, rash, 
diarrhea. AscA can be 
excreted from kidney and 
lead to crystalluria, so will 
monitor urine pH via 
urinalysis. Will also 
monitor EKGs for QTc 
changes.  
 
Secondary 
 
 
Vitamin C infusion will attenuate 
biomarkers of inflammation (C-
Reactive Protein, procalcitonin), 
vascular injury (Thrombomodulin, 
Angiopoietin-2), while inducing the 
onset of a fibrinolytic state (Tissue 
Factor Pathway Inhibitor) 
Modulation of available biomarkers 
 
Changes in these 
biomarkers may provide 
mechanistic insight into 
how vitamin C attenuates 
inflammation 
Secondary  
 
 
Vitamin C Infusion will improve clinical 
endpoints in this patient population 
.  
Change in SOFA Score and Components 
at hours 48, 96, 168 
 
Change in CLIF-SOFA scores and 
Components at hour 48, 96, 168 when 
compared to placebo 
 
Change in MELD-Na, MDF, Lille scores at 
hour 48, 96, 168 when compared to 
placebo 
 
Ascorbate level at hour 0, 48, 96, 168 
(When feasible) 
 
ICU-free days at day 28 
 
All-cause mortality to day 28, 90 
 
Hospital-free days at day 90 
 
 
CLIF-SOFA, MDF, MELD, 
and Lille scores are 
associated with mortality 
in alcoholic hepatitis. 
Ascorbate levels are 
associated with mortality 
in sepsis patients in the 
ICU. AH patients have 
prolonged 
hospitalizations and are 
frequently in the ICU. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Randomization of 20 subjects with AH and sepsis to receive either Placebo (50 ml of 5% dextrose in 
water every 6 hours for 96 hours, or 16 total doses) or Vitamin C (sterile L-ascorbic acid for injection at 

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200 mg/kg per 24 hours with entire calculated 24 hour dose diluted in 200 ml of 5% dextrose in water). 
One fourth of the 24 hour calculated dosage will be administered in 30 minute intravenous infusions and 
occur every 6 hours for a total of 16 doses. Standard of care therapy will be followed in both arms.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The purpose of this study is to assess the efficacy of intravenously infused ascorbic acid therapy for 
patients with alcoholic hepatitis (AH) and sepsis. By restricting the population to those we believe to 
have both infection and AH, this study targets a disease process and population that has the highest 
mortality rate and has been studied in animal models. By focusing on sepsis associated with AH, we have 
selected a group that has a higher disease burden than AH alone and thus likely to have both increased 
mortality and an increased opportunity for benefit, including a reduction in hepatic dysfunction and ICU 
length of stay. In choosing the MELD score as the primary outcome, we will be able to discriminate 
between hepatic function improvement and risk of mortality. By using secondary endpoints such as 
CLIF-SOFA, documentation of serious adverse events, and biomarkers of inflammation, vascular injury, 
and coagulation, as the primary outcomes, we will be able to detect changes in clinical outcomes, assess 
safety and tolerability of ascorbic acid therapy in alcoholic hepatitis, and potential mechanistic insights 
that are important for demonstrating proof of concept. 
 
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 (32). 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 I human sepsis safety trial. The 
200 mg/kg/24 hour IV dosing protocol was determined from quantification of plasma ascorbate levels 
and from assessing the impact on SOFA scores. Further, the dosage was selected following observation 
of the 200 mg/kg/24 hour regimen on biomarker levels. 
 
4.4 
END OF STUDY DEFINITION 
Active treatment will continue until 96 hours, discharge from study hospital, study withdrawal, or death, 
whichever comes first.  All subjects will be followed to day 90 for collection of outcomes data even 
though the study intervention will be completed by 96 hours from randomization at the latest. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
The inclusion and exclusion criteria listed for the CITRIS-AH trial are listed below. The definitions of 
alcoholic hepatitis and severe sepsis for this study are derived and defined as previously published in the 
reference literature. 
 
Patients must have a diagnosis from the attending physician or hepatologist of definite or probable 
alcoholic hepatitis based on NIAAA criteria (2) and suspected or proven infection, and meet 2 out of 4 of 
the criteria for Systemic Inflammatory Response (SIRS) due to infection or be accompanied by at least 1 
criterion for sequential organ failure assessment (SOFA): 
 
 

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1. Alcoholic hepatitis: 
a. Definite NIAAA alcoholic hepatitis 
i. Clinical diagnosis and histological confirmation of features of alcoholic hepatitis 
1. Histological diagnosis: liver biopsy with steatohepatitis, lobular 
inflammation, Mallory-Denk bodies, hepatocyte degeneration or 
ballooning, “chicken-wire” or portal fibrosis 
2. Clinical diagnosis: 
a. Chronic alcohol use for at least 5 years (may be intermittent 
abstinent) 
b. >1 standard drink per day in women and >2 in men 
c. AUDIT score >15 
d. Heavy alcohol use for at least 6 months  
i. “Heavy use” = average >3 drinks per day (40g) for 
women and average 4 drinks (50-60g) per day for men 
e. Onset of jaundice within the past 8 weeks 
f. Less than 8 weeks of abstinence before onset of jaundice 
g. Serum bilirubin >3 mg/dL 
h. AST >50 
i. 
AST/ALT ratio >1.5 and levels <400 IU/L 
b. Probable NIAAA alcoholic hepatitis criteria 
i. Clinical diagnosis based on heavy alcohol use >5 years 
ii. Active alcohol use until 4 weeks prior to presentation 
iii. average >3 drinks per day (40g) for women and average 4 drinks (50-60g) per 
day for men  
iv. Sudden onset or worsening of jaundice (bilirubin >3 mg/dL) within past 60 days 
v. AST/ALT ratio >1.5 and levels <400 IU/L 
vi. Absence of other causes of liver disease 
1. Negative autoimmune markers (ANA < 1:160, SMA <1:80) 
2. Negative viral hepatitis markers (HAV A IgM, HBV sAg, HBV c IgM, HCV 
Ab, HCV RNA) 
3. No recent exposure to drugs with DILI potential, as determined by 
attending physician or hepatologist medication review 
c. Patients with potential cofounders may be offered transjugular liver biopsy to assess for 
histological characteristics of alcoholic hepatitis and ruling out other features of chronic 
liver disease as a part of standard of care 
2. Suspected or proven infection: (e.g., thorax, urinary tract, abdomen, skin, sinuses, central 
venous catheters, and central nervous system.) 
3. The presence of a systemic inflammatory response: Defined as: fever: >38ºC (any route) or 
hypothermia: <36ºC (core temp only), tachycardia: heart rate > 90 beats/min or receiving 
medications that slow heart rate or paced rhythm, leukocytosis: >12,000 WBC/µL or leukopenia: 
<4,000 WBC/µL or >10% band forms. Respiratory rate > 20 breaths per minute or PaCO2 < 32 or 
invasive mechanical ventilation. 
4. The presence of sepsis associated organ dysfunction as assessed by SOFA: (any of the following 
thought to be due to infection)  
a. Sepsis associated hypotension (systolic blood pressure (SBP) < 90 mm Hg or an SBP 
decrease > 40 mm Hg unexplained by other causes or use of vasopressors for blood 
pressure support (epinephrine, norepinephrine, dopamine =/> 5mcg, phenylephrine) 
b. Arterial hypoxemia (PaO2/FiO2 ≤ 300) or supplemental O2 > 6LPM. 

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c. Lactate > upper limits of normal laboratory results 
d. Urine output < 0.5 ml/kg/hour for > two hours despite adequate fluid resuscitation 
e. Platelet count < 100,000 per mcL 
f. Coagulopathy (INR > 1.5) 
g. Bilirubin > 2 mg/dL 
h. Glasgow Coma Scale < 11 or a positive CAM ICU score 
5. Negative urine or serum toxicology and acetaminophen drug screen 
 
 
 
 
5.2 
EXCLUSION CRITERIA 
 
1. Known allergy to Vitamin C 
2. Inability to obtain consent 
3. Age < 18 years 
4. No indwelling central or peripheral venous or arterial catheter in patients requiring insulin in a 
manner that requires glucose being checked more than twice daily (e.g. continuous infusion, 
sliding scale)  
5. Presence of diabetic ketoacidosis 
6. Patient or surrogate or physician not committed to full support (not excluded if patient would 
receive all supportive care except for cardiac resuscitation); 
7. Pregnancy or breast feeding (as documented by urine or serum pregnancy testing) 
8. Moribund patient not expected to survive 24 hours 
9. Active or history of kidney stone 
10. History of chronic kidney disease, stage IIIb or above 
11. History of glucose-6-phosphate dehydrogenase (G6PD) deficiency 
12. Active malignancy, except non-melanoma skin cancer 
13. Uncontrolled upper or lower gastrointestinal bleeding 
14. Possible alcoholic hepatitis or other confounding cause of acute hepatitis such as viral, 
metabolic, autoimmune 
15. History of decompensated cirrhosis as indicated by variceal bleeding within 3 months, tense 
ascites, or hepatocellular carcinoma (HCC) 
16. History of liver or other organ transplantation 
17. Initial ALT or AST greater than 5 times the upper limit of normal 
18. Positive urine or serum toxicology screen and acetaminophen level 
19. Non-English speaking 
20. Ward of the state (inmate, other) 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable to this study. 
 
 

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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. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 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). Subjects will be documented in 
the Study Screening Log when all Inclusion Criteria are met.   
 
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 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 
Patients with sepsis and AH will be recruited from the Emergency Department (ED), the medicine 
inpatient Digestive Health Service (DHS), and the intensive care units (ICU) at Virginia Commonwealth 
University Health System (VCUHS). VCUHS is a large tertiary care medical center with a large referral 
base. Annually over 11,000 patient contacts are made for liver disease and 15% of these are for alcohol 
related liver disease. 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 (DHS), or 
the ICU. All patients meeting the inclusion/exclusion criteria will be approached with a 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.). If a patient is enrolled in the ICU and meets ICU discharge criteria based on the decision of the ICU 
attending physician, the patient will be transferred to the DHS inpatient team on Main 9 West (M9W) 
unit in order to continue the study drug infusion. 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 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 scheduled time of infusion, a call should be placed to pharmacy to 
determine if study drug may be piggybacked into the line that is infusing a different drug.  If 
administering study drug via piggyback is contraindicated, then study drug infusion may be delayed by a 
maximum of 6 hours. If clinical drug administration schedule is such that study drug will not have an 
available administration time beyond this delay, a dedicated new line (peripheral or central) should be 
inserted. Study drug will be blinded using an identical appearing placebo.   
 
 

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6.1.2 DOSING AND ADMINISTRATION 
 
1) First study drug dose (L-ascorbic acid or placebo) will be considered “Dose 1” and will be 
administered within 6 hours of randomization or the earliest available time post any clinically 
indicated procedure which requires the patient to be off the unit. All doses will be administered in 
the medicine M9W inpatient unit or ICU.  Patients receiving vitamin C will receive 25% of the total 
daily calculated dosing (200mg/kg/24 hours) and will be infused over 30 minutes for this first dosing. 
2) Subsequent doses which represent 25% of the day’s total dose will be infused every six hours 
through 96 hours (+/- 3 hours).  
a) Timing of Dose 2 will be triggered by the physician order for q 6 hour administration and will 
therefore be listed on the bedside MAR.  As such, timing of Dose 2 may be out of the +/- 3 hour 
window and will not trigger a protocol deviation. 
b) If for any reason any other maintenance dose is not administered within window, the dose will 
be skipped and the next scheduled dose will be given and documented in the data collection 
tool.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
VCU Investigational Drug Services (IDS) Pharmacy will coordinate acquisition of sterile L-ascorbic acid for 
infusion from the manufacturer.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
ASCOR vials contain 25,000 mg/50mL of ascorbic acid and is supplied as pharmacy bulk packaging (PBP). 
The diluted ASCOR solution should appear colorless to pale yellow. Amber shrouding will be used to 
cover the IV bag. The product labeling will be blinded as to what the actual product is.  For example, the 
drug name and dose will be indicated as per the following:  "Caution: New Drug—Limited by Federal (or 
United States) law to investigational use. Ascorbic acid ____mg or placebo in 50cc D5W". The placebo is 
a 50 mL bag of 5% dextrose in water. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
ASCOR is light sensitive so light exposure should be minimized and stored per package insert 
instructions: 
 
Store under refrigeration (2°C to 8°C); protect from light with amber IV bag cover. Infusion solutions 
prepared by the IDS Pharmacy in the Main Pharmacy IV admixture suite will expire in 24 hours if 
refrigerated and light-protected.  Infusion solutions prepared by the ICU Pharmacy after-hours will 
expire in 12 hours, if refrigerated and light-protected. 
 
There is published data establishing the stability of admixtures of ascorbic acid to be at least 24 hours 
stored at room temperature or refrigerated. Also, 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. 
 
In the event that amber tubing is not available in hospital pharmacy stock (due to shortage or supply 
chain delays), clear infusion tubing may be used. The manufacturer of ASCOR has unpublished stability 
data showing minimal product oxidation for up to 96 hours when exposed to ambient light.  

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6.2.4 PREPARATION 
IDS or ICU (after hours) Pharmacy will mix “study drug” or placebo once every 24 hours in four 50 ml 
hooded infusion bags and stored in the M9W unit or ICU in the dark at 4ºC. The prepared IV bags will 
have the IV tubing attached and primed by the bedside (M9W or ICU) nursing staff.  At designated 
infusion time, M9W or ICU Nursing will infuse the contents of the light-shielded agent via infusion pump 
through light-shielded tubing over 30 minutes. Prior studies performed at VCUHS have shown that L-
ascorbic acid prepared for infusion in this way remains stable with no quantifiable oxidation. 
 
Study drug / placebo will be prepared in 50 ml D5W bags, USP, using aseptic technique according to USP 
797 requirements.  All ASCOR pharmacy bulk package vials utilized will be discarded within 4 hours or 
sooner as per the ASCOR package insert. 
 
For ascorbic acid, the volume of ascorbic acid to be added to the IV bag will be calculated. This same 
amount of fluid will be drawn out of the D5W 50 mL bag and discarded.  Then, the calculated volume of 
ascorbic acid will be added to the IV bag.  As much air as possible will be removed from the IV bag using 
an empty syringe with needle attached (in order to prevent oxidation).  The IV bag will be covered with a 
light-protective shroud.   
 
For placebo, a 50cc bag of dextrose 5% in water will have the excess air removed from the IV bag as for 
the ascorbic acid bags (to maintain the blind).  The IV bag will be covered with a light-protective shroud 
(to maintain the blind). 
 
Microbiologic Controls:    
 
Main Pharmacy IV sterile admixture suite consists of an ISO Class 5 open architecture compounding 
workbench, with an ISO Class 7 positive pressure buffer zone, and an ISO Class 8 positive pressure 
anteroom.  There is continuous monitoring of temperature, humidity, and air pressure.  The 
environmental controls are recertified every 6 months, including viable active air samples.  The 
pharmacy staff monitors monthly surface samples.  Compounding personnel must successfully complete 
media fill testing and gloved, fingertip sampling as per USP 797 regulations.  The ICU Pharmacy (used for 
after-hours dispensing) 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.  
ICU 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 
After informed consent is given, a randomized assignment will be made by the VCU Investigational 
Pharmacy in random batches of 2, 4, or 8 subjects.  Eligibility forms confirming eligibility will be 
transmitted via the OnCore clinical trials software and verified by the VCU Investigational Pharmacy 
prior to randomization. Investigational Pharmacy at VCUHS will administer either Vitamin C therapy or 
placebo. The randomization will be stratified to one of the two study arms. 
 
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.   
 

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6.5 
CONCOMITANT THERAPY 
Any concomitant medications as part of standard of care (particularly glucose infusion, insulin, albumin, 
corticosteroids, N-acetylcysteine, and antibiotics) provided will be recorded.  
 
6.5.1 RESCUE MEDICINE 
Not applicable.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If subjects do not tolerate the drug due to side effects such as nausea, vomiting, flushing, rash, 
headache, diarrhea, develops crytalluria on urinalysis, or QTc prolongation >50% baseline, we will 
reduce the subsequent doses by 50%. If the QTc is greater than 550 msec at any time, the drug will be 
discontinued. 
 
Loss of indwelling venous/arterial catheter or peripheral intravenous access will also trigger the stopping 
of Vitamin C infusions but subjects will remain on study. Blood glucose monitoring will continue via the 
central laboratory for 36 hours after the last infusion via peripheral IV draws or peripheral sticks. 
Biomarker sampling via peripheral IV and/or peripheral stick is allowable as it occurs only 4 times 
throughout the study and likely only once (if at all) after the patient has been discharged from the unit 
and is without a central line. 
 
The study drug will be discontinued if a patient develops a metabolic acidosis unexplained by other 
etiologies (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 discontinued if primary care team 
or surrogate decision maker request withdrawal. Data collection will continue on these patients 
following withdrawal of study drug. 
 
Requests to unblind a patient's study treatment can be made to the study (investigational) pharmacist 
or clinical care team.  Unblinding study treatment should occur only in the case of an emergency when 
knowledge of the study treatment is essential for subject care to treat a serious adverse event and 
prevent further harm or death. 
 
If possible, a decision to unblind should be discussed with the Principal Investigator or a sub-Investigator 
prior to unblinding the study treatment.  
 
If a blind is broken (either intentionally or unintentionally), the circumstances should be documented as 
to who, what, when, and why and all documentation shall be kept by the study pharmacist. 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
 
 

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7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 4-8 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
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 or performed to evaluate each subject’s qualifications for 
participation in the study: 
• 
Demographic information including gender, date of birth, race, ethnicity 
• 
Medical and medication history over the past 30 days 
• 
Alcohol consumption history 
• 
Collection of blood for chemistry, hematology, coagulation, microbiology, in female patients, a 
pregnancy test (urine pregnancy test or blood human chorionic gonadotropin (hCG) 
• 
Urinalysis and urine and/or drug/toxicology screening, including acetaminophen 
• 
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, body temperature), skin exam (jaundice yes/no, spider angiomata yes/no), abdominal 
exam (ascites yes/no, hepatosplenomegaly yes/no) neurological exam (Glasgow Coma Scale, 
West-Haven Hepatic Encephalopathy Scale, asterixis yes/no) 
• 
Review inclusion and exclusion criteria 
• 
Signed, written informed consent 
 
Assessments at Baseline (Hour 0): 
• 
Collection of concomitant medications (if applicable); including corticosteroids, albumin, 
thiamine, antibiotics, and N-acetylcysteine use 
• 
Collection of blood for hematology, coagulation, clinical chemistries 
• 
Vital signs and abbreviated physical exam, including Glasgow Coma Scale and West-Haven Scale 
• 
 
12-Lead EKG 

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• 
        Documentation of negative urine or serum drug screen, negative acetaminophen serum level,     
and negative urine or serum pregnancy testing for human chorionic gonadotropin (hCG) if female 
 
Treatment Day 1 (Hour 24): 
• 
Collection of concomitant medications (if applicable) 
• 
Collection and monitoring of vital signs: blood pressure, temperature, heart rate, oxygen 
saturation 
• 
Abbreviated physical exam 
• 
Collection of blood for standard of care (SOC) hematology, coagulation, clinical chemistry, and 
biomarkers 
• 
Document urine volume, urinalysis 
• 
12-Lead EKG 
• 
AE review and reporting 
 
Treatment Day 2 (Hour 48): 
• 
Collection of concomitant medications (if applicable) 
• 
Collection and monitoring of vital signs: blood pressure, temperature, heart rate, oxygen 
saturation 
• 
Abbreviated physical exam 
• 
Collection of blood for hematology, coagulation, clinical chemistry, biomarkers 
• 
Document urine volume, urinalysis 
• 
12-Lead EKG 
• 
AE review and reporting 
 
Treatment Day 3 (Hour 72): 
• 
Collection of concomitant medications (if applicable) 
• 
Collection and monitoring of vital signs: blood pressure, temperature, heart rate, oxygen 
saturation 
• 
Abbreviated physical exam 
• 
Collection of blood for standard of care: hematology, coagulation, clinical chemistry  
• 
Document urine volume 
• 
12-Lead EKG 
• 
AE review and reporting 
 
Treatment Day 4 (Hour 96): 
• 
Collection of concomitant medications (if applicable) 
• 
Collection and monitoring of vital signs: blood pressure, temperature, heart rate, oxygen 
saturation 
• 
Abbreviated physical exam 
• 
Collection of blood for SOC hematology, coagulation, clinical chemistry, and biomarkers 
• 
Document urine volume, urinalysis 
• 
12-Lead EKG 
• 
AE review and reporting 
 
Study Day 7 (Hour 168): 
• 
Collection of concomitant medications (if applicable) 
• 
Collection and monitoring of vital signs: blood pressure, temperature, heart rate, oxygen 
saturation 

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• 
Collection of blood for SOC hematology, coagulation, clinical chemistry, and biomarkers 
 
Study Day 28 
• 
Phone call or chart review to document morbidity and mortality 
 
Study Day 90 
• 
Surviving subjects will be asked to come for a close out visit. However, this population is notorious 
for compliance issues and if they do not come in a phone call and chart review will be done along 
with assessment via national death register 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Assessment of hepatic safety: We will follow the current guidance from FDA for assessment of liver 
safety in those with pre-existing hepatic impairment. Evaluation of Drug Induced Severe Hepatitis 
(eDISH): eDISH plots will be overlaid from placebo and drug treated arms at the end of the study to look 
for DILI signals. Those cases with bilirubin > 3x ULN and ALT > 8x ULN will be studied individually and 
adjudicated for DILI. These data will be provided to the DSMB for concordance with DILI assessment and 
to IRB and regulatory agencies. 
 
For individual cases, the following rules will be followed for drug discontinuation for DILI: 
 
Since the study population will have evidence of severe liver injury coming in to the trial, these 
modifications are proposed. 
 
If AST or ALT rise by > 50% from baseline, but are less than 8 times the upper limit of normal and this is 
associated with less than 3 mg/dl rise in bilirubin, a hepatic panel will be repeated within 24 hours.  If 
the AST and ALT continue to rise or bilirubin rises by 3 mg/dl or more, the study drug will be 
discontinued. 
 
If AST or ALT exceed 8 times the upper limit of normal at any time or bilirubin rises by 3 or more mg/dl 
from baseline within a 48-hour time frame, the study drug will be discontinued.   
 
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 either the 
investigator or sponsor, 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, 

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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 following subsections will include a discussion of how AEs will be classified. 
8.3.3.1 SEVERITY OF EVENT 
All AEs will be assessed by the study clinician using a protocol defined grading system.  Describe the 
method of grading an AE for severity. For example, many toxicity tables are available for use and are 
adaptable to various study designs. Selection of a toxicity table or severity scale should be made in 
consultation with the study Medical Monitor. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician 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. 
 
8.3.3.3 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. 
 

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All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). 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 diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
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 intermittent 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 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 IRB in the required reporting time frame. The IRB 
at VCUHS will be notified within 5 business days of receiving notice of the unanticipated problem.   
 
VCU will report all unanticipated problems, defined as problems 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 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. 
 
Examples of untoward clinical occurrences, or disease-related events (DREs) that are expected in the 
course of AH include: 1) transient hypoxemia, 2) agitation, 3) delirium or hepatic encephalopathy, 4) 
nosocomial infections, 5) skin breakdown, 6) gastrointestinal bleeding, 7) acute kidney injury, and 8) 
worsening of hepatic 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 
an 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. 

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8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study 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 the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria from the time of consent to through study hour 168 until resolved, withdrawn from 
the study, death, or lost to follow up: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing IRB and to the DCC. The UP 
report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 

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• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 48 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 5 business days of 
the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 5 business days of the IRB’s receipt of the report of 
the problem from the investigator. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Our null hypothesis (H0) is that intravenous infusion of vitamin C at 200 mg/kg/day will not result in 
decrease in MELD score from admission to day 4 when compared to placebo. 
 
Our alternative hypothesis (H1) is that intravenous infusion of vitamin C at 200 mg/kg/day will 
significantly reduce MELD scores at day 4 compared with MELD on admission in patients with alcoholic 
hepatitis and sepsis.  
 
9.2 
SAMPLE SIZE DETERMINATION 
We anticipate an average MELD of 29 on enrollment, with a standard deviation of 5 points, which is 
based on previous analysis of VCU patient data with alcoholic hepatitis and sepsis. If we assume an 
alpha of 0.05 and power of 80%, we will need to enroll 8 patients in each arm in order to detect a 25% 
decrease in MELD on day 4. Therefore, we will overpower and enroll 10 patients in each arm given 
uncertainties of power calculation. Changes from baseline to day 4 will also be compared across arms by 
Wilcoxon test.  Power calculations were made with NQuery 4.0. 
 
9.3 
POPULATIONS FOR ANALYSES 
We will perform the following analyses for the study: 
 
• 
Intention-to-Treat (ITT) Analysis Dataset:  all randomized participants 
• 
Modified Intention-to-Treat Analysis Dataset: participants who took at least one dose of study 
intervention and/or have some particular amount of follow-up outcome data 
• 
Safety Analysis Dataset: subset of participants for whom safety analyses will be conducted (e.g., 
participants who took at least one dose of study intervention 
• 
Per-Protocol Analysis Dataset: participants in the full analysis (ITT) set who complied with the 
protocol sufficiently to ensure that these data would be likely to represent the effects of study 
intervention and will be the primary analysis for all outcomes 

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9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Continuous variables will be compared across groups using ANOVA or a Kruskal Wallis ANOVA 
depending on their distribution. Changes from baseline to time of measurement will be compared by 
analysis of covariance. Categorical variables will be measured by Fisher’s Exact test. Correlations will be 
assessed by Spearman’s coefficient. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Change in MELD from baseline to day 4. Changes from baseline to time of measurement will be 
compared by analysis of covariance. 
 
We will use the following MELD formula: 
Original MELD Score = (0.957 * ln(Serum Cr) + 0.378 * ln(Serum Bilirubin) + 1.120 * ln(INR) + 0.643 ) * 10 
(if hemodialysis, value for Creatinine is automatically set to 4.0) 
 
Note: If any score is <1, the MELD assumes the score is equal to 1. 
 
9.4.3 SAFETY ANALYSES 
Adverse Events 
Adverse events will be classified into standard terminology using the Medical Dictionary for Regulatory 
Activities (MedDRA). Adverse events will be listed by reported verbatim term and MedDRA-preferred 
term, start and stop date and time, study day, duration, severity, relationship to study drug, and 
seriousness. Additionally, data may be grouped for analysis by different levels of the MedDRA hierarchy. 
The incidence of AEs, the incidence of treatment- related AEs, and the severity of AEs will be tabulated 
by cohort (Vitamin C or placebo). The number and percentage of patients with SAEs and treatment-
related SAEs and patients who withdraw due to an AE will be tabulated by cohort (Vitamin C or placebo). 
 
Clinical Laboratory Testing 
Clinical laboratory test parameters will be listed for individual patients. Baseline for clinical laboratory 
parameters will be defined as the last evaluation before the start of the initial dosing with study drug. 
Summary statistics, including mean absolute change from baseline, will be calculated for each 
parameter and summarized. 
 
Vital Signs 
Vital signs results (systolic and diastolic blood pressure, pulse rate, and body temperature) will be listed 
for individual patients. Each vital sign measure will be tabulated by evaluation time point. Baseline for 
vital signs measurements will be defined as the last evaluation before the beginning of the first study 
drug infusion (Vitamin C or placebo, which will generally be Baseline, pre-dose). Summary statistics, 
including mean absolute change from baseline, will be determined and tabulated for each measure. 
 
Physical Exams 
Physical examination findings at baseline will be listed. Clinically significant changes will be recorded as 
AEs. Symptoms of interest previously reported with intravenous Vitamin C based on the package insert 
will be recorded daily, including dizziness, headache, nausea, vomiting, flushing, rash, or diarrhea. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
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 signing. 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 sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. 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 the form signed, 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. 
 
Many of the patients approached for participation in this research protocol will have limitations of 
decision-making abilities due to their critical illness. Hence, most patients will not be able to provide 
informed consent.  Accordingly, informed consent will be sought from the potential subject’s legally 
authorized representative. 
 
Regarding proxy consent, the existing federal research regulations (‘the Common Rule’) state at 
45 CFR 46.116 that: “no investigator may involve a human being as a subject in research…unless the 
investigator has obtained the legally effective informed consent of the subject or the subject’s legally 
authorized representative”; and defines at 45 CFR 46 102 (c) a legally authorized representative (LAR) 
as: “an individual or judicial or other body authorized under applicable law to consent on behalf of a 
prospective subject to the subject’s participation in the procedures(s) involved in the research.”  OHRP 
defined examples of “applicable law” as being state statutes, regulations, case law, or formal opinion of 
a State Attorney General that addresses the issue of surrogate consent to medical procedures.  Such 
“applicable law” could then be considered as empowering the surrogate to provide consent for subject 
participation in the research.  

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According to a previous President’s Bioethics Committee (National Bioethics Advisory Committee), an 
investigator should accept as an LAR…a relative or friend of the potential subject who is recognized as an 
LAR for purposes of clinical decision making under the law of the state where the research takes place. 
Finally, OHRP has opined in their determination letters that a surrogate could serve as a LAR for research 
decision making if such an individual is authorized under applicable state law to provide consent for the 
“procedures” involved in the research study. 
 
According to the Belmont Report, respect for persons incorporates at least two ethical convictions; first, 
that individuals should be treated as autonomous agents, and second, that persons with diminished 
autonomy are entitled to protection. One method that serves to protect subjects is restrictions on the 
participation of subjects in research that presents more than minimal risks. Commentators and Research 
Ethics Commission have held the view that it is permissible to include incapable subjects in research that 
involves more than minimal risk as long as there is the potential for beneficial effects and if the research 
presents a balance of risks and expected direct benefits similar to that available in the clinical setting.  
Several U.S. task forces have deemed it is permissible to include incapable subjects in research.  For 
example, the American College of Physicians’ document allows surrogates to consent to research 
involving incapable subjects only “if the net additional risks of participation are not substantially greater 
than the risks of standard treatment.”  Finally, the National Bioethics Advisory Committee (NBAC) stated 
“that an IRB may approve a protocol that presents greater than minimal risk but offers the prospect of 
direct medical benefits to the subject, provided that…the potential subject’s LAR gives permission…” 
 
Consistent with the above ethical sensibilities regarding the participation of decisionally incapable 
subjects in research and the previous assessment of risks and benefits in the previous section, the 
present trial presents a balance of risks and potential direct benefits that is similar to that available in 
the clinical setting, with the exception of the additional blood draws. 
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, investigator, funding agency, 
the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory 
authorities>.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor 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 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests 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 sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product 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 sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the <specify name of Data Coordinating Center>. 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 <specify name of Data Coordinating Center> research 
staff will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the <specify name of Data Coordinating Center>. 
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data will be stored in the central repository of the NIAAA Alcoholic Hepatitis Network (AlcHepNet) and 
the VCU lab of Arun Sanyal. The AlcHepNet clinical trial data base and biospecimen databank will be 
located at the University of Massachusetts Amherst Medical Center. The data will be de-identified and 
linked to CITRIS-AH study ID number. Future data will be stored indefinitely. At the time of patient 
screening, a separate informed consent process will occur for enrollment in the NIAAA AlcHepNet 
Observational Registry. In addition, the CITRIS-AH informed consent form will contain a section to 
document patient enrollment in the AlcHepNet Registry. 
 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Principal Investigator 
Alpha Fowler, MD 
Arun Sanyal, MD 
Virginia Commonwealth University 
Virginia Commonwealth University 
P.O. Box 980050 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
804-828-9071 
804-828-4060 
alpha.fowler@vcuhealth.org 
arun.sanyal@vcuhealth.org 
 
 
 
 
 
University of Massachusetts Medical School Data Coordinating Center Contacts 
DCC Director 
DCC Project Manager/ 
Biostatistician 
DCC Database Developer/ 
Programmer 
Bruce Barton, PhD 
Aimee Kroll-Desrosiers, MS 
Peter Lazar 
AS5-2071 
368 Plantation Street 
Worcester, MA 01605 
AS5-2067 
368 Plantation Street 
Worcester, MA 01605 
AS5-2063 
368 Plantation Street 
Worcester, MA 01605 
508-856-8191 
508-856-3540 
508-856-8344 
bruce.barton@umassmed.edu 
aimee.kroll@umassmed.edu 
peter.lazar@umassmed.edu 
 
Sub-Investigator 
Sub-Investigator 
Sub-Investigator 
Velimir Luketic, MD 
Mohammad Siddiqui, MD 
Richard Sterling, MD 
Virginia Commonwealth 
University 
Virginia Commonwealth University 
Virginia Commonwealth 
University 
P.O. Box 980341 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
804-828-4060 
804-828-4060 
804-828-4060 
velimir.luketic@vcuhealth.org 
Mohammad.siddiqui@vcuhealth.org 
Richard.sterling@vcuhealth.org 
 
Sub-Investigator 
Sub-Investigator 
Trainee/Fellow 
Richard Stravitz, MD 
Scott Matherly, MD 
Brian Davis, MD  
Virginia Commonwealth 
University 
Virginia Commonwealth University 
Virginia Commonwealth 
University 
P.O. Box 980341 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
804-828-4060 
804-828-4060 
804-828-4060 
Richard.stravitz@vcuhealth.org 
Scott.matherly@vcuhealth.org 
Brian.davis1@vcuhealth.org 
 
Research Nurse 
Research Coordinator 
Stephanie Taylor 
Rebecca Collen 
Virginia Commonwealth 
University 
Virginia Commonwealth University 

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P.O. Box 980341 
Richmond, VA 23298 
P.O. Box 980341 
Richmond, VA 23298 
804-828-4060 
804-828-4060 
Stephanie.taylor@vcuhealth.org 
Rebecca.collen@vcuhealth.org 
 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including gastroenterology, hepatology, and/or pulmonary 
critical care. Members of the DSMB should be independent from the study conduct and free of conflict 
of interest, or measures should be in place to minimize perceived conflict of interest.  The DSMB will 
meet at least every 4 weeks after enrollment of the first subject and until the last enrolled subject 
completes treatment period to assess safety and efficacy data on each arm of the study. The DSMB will 
also continue to monitor the study every 4-8 weeks until the last subject completes the 90 day end-of-
study time period. The DMSB will operate under the rules of an approved charter that will be written 
and reviewed at the organizational meeting of the DSMB. At this time, each data element that the DSMB 
needs to assess will be clearly defined. The DSMB will provide its input to the study team. 
 
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 random 
review of certain data to assess for data accuracy, protocol compliance, and deviations. 
• 
The VCU Compliance office will be provided copies of monitoring reports. 
 
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. 
 
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 monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  

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10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at VCU under the supervision of the site 
investigators. The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by the University of Massachusetts Medical School Data Coordinating Center. The data 
system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 6 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. The 
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.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
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: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 

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10.1.12 
CONFLICT OF INTEREST POLICY 
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.  The study 
leadership in conjunction with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has 
established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
 
 

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10.2 ABBREVIATIONS 
 
ABG 
Arterial Blood Gas 
AE 
Adverse Event 
AH 
Alcoholic hepatitis 
AKI 
Acute Kidney Injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibody 
ANA 
Anti-nuclear antibody 
ANCOVA 
Analysis of Covariance 
AscA 
Ascorbic Acid (Vitamin C) 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DILI 
Drug Induced Liver Injury 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 

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NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIRS 
Systemic Inflammatory Response Syndrome 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2 
8/26/2018 
Changed title to CITRIS-AH from 
CITRIS-AI 
Standardized terminology 
3 
8/27/2018 
Added additional secondary 
endpoint clinical features 
Clarified clinical details of 
secondary endpoints 
4 
8/28/2018 
Added justification of endpoints, 
clinical data for inclusion criteria 
Refinement of primary and 
secondary endpoints needed 
5 
8/29/2018 
Added additional background data 
on AscA 
Previous drafts lacked detailed 
background AscA data 
6 
8/30/2018 
Added patient recruitment locations 
Clarification needed 
7 
8/31/2018 
Added detailed study assessment 
and procedures 
Fixed missing elements  
8 
9/15/2018 
Clarified screening procedures 
Changes per IRB request 
9 
11/15/2018 
Added DILI assessment, changed IND 
exemption to IND pending, IV tubing 
to be primed at bedside 
Changes per discussion with 
research team and pharmacy 
9.1 
11/18/2018 
Reformatted to DCC NIH template 
Additional details on AE, SAE 
definition, research team 
contacts 
10.1 
12/20/2018 
Added additional exclusion criteria, 
specified drug labeling, toxicology 
assessments, pregnancy assessment, 
DSMB meeting times 
Changes requested by FDA 
11 
02/25/2019 
added crystalluria monitoring, 
biomarkers to be collected “when 
feasible” 
Reconciled section 1.3 with 8.1 
12 
1/21/2020 
Include statement about using clear 
IV tubing if amber tubing is not 
available 
Manufacturer of ASCOR has 
stability data to support use of 
clear tubing when needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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