Conditions: Covid19
Keywords: outpatient famotidine n-acetyl cysteine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this trial is to assess the safety and toxicity profile of the combination of famotidine and oral n-acetyl cysteine in adult outpatients with newly diagnosed SARS-CoV-2 infection.

Detailed description:
This is a phase I trial enrolling subjects with newly diagnosed SARS-CoV-2 infection who do not require hospitalization. Exclusion criteria have been written to exclude patients who would be expected to have increased risk from either medication alone. Subjects will be assigned a dose combination of famotidine and n-acetyl cysteine. In addition to assessing the safety and toxicities profiles of the combination of drugs we will be measuring certain endpoints to assess possible efficacy. These endpoint include the following: rates of hospitalization; time to complete remission of symptoms, e.g, fever, respiratory symptoms, etc.; severity of symptoms with validated survey instruments; cytokine values in serum and urine; and markers of inflammation and oxidative stress.

Arms:
arm 1: N-Acetyl Cysteine 600 mg three times daily arm 2: N-Acetyl Cysteine 1,200 mg three times daily arm 3: N-Acetyl Cysteine 600 mg three times daily Famotidine 20 mg three times daily arm 4: N-Acetyl Cysteine 1,800 mg three times daily arm 5: N-Acetyl Cysteine 1,200 mg three times daily Famotidine 20 mg three times daily arm 6: N-Acetyl Cysteine 600 mg three times daily Famotidine 40 mg three times daily arm 7: N-Acetyl Cysteine 1,800 mg three times daily Famotidine 20 mg three times daily arm 8: N-Acetyl Cysteine 1,200 mg three times daily Famotidine 40 mg three times daily arm 9: N-Acetyl Cysteine 600 mg three times daily Famotidine 80 mg three times daily arm 10: N-Acetyl Cysteine 1,800 mg three times daily Famotidine 40 mg three times daily arm 11: N-Acetyl Cysteine 1,200 mg three times daily Famotidine 80 mg three times daily arm 12: N-Acetyl Cysteine 1,800 mg three times daily Famotidine 80 mg three times daily

Interventions: intervention 1: Famotidine intervention 2: N-Acetyl cysteine
Intervention descriptions: intervention 1: Oral Famotidine intervention 2: Oral N-Acetyl Cysteine

Protocol document:
Prot_SAP_000.pdf: 
PI Name: John Joseph O’Connell, MD 
 
Additional authors: 
Larisa D Coldebella Perino, MD; Jennica Siddle, MD; Phillip Moschella, MD, PhD; Arwen BL 
Declan, MD, PhD; Angelo Perino, MD; Amanda Schnee, MD; Deborah Kunkel, PhD; Corey 
Andrew Kalbaugh, PhD;  Lior Rennert, PhD; Alex Ewing, PhD; Prerana Roth, MD;  Michael 
Cohen, PharmD; Halee Bryant Vaughn; David Y Pritchett; Benjamin R Hutto; Josiah N 
McDonald; Angela Orsky, DNP; Timothy F McTigue, MD;  and W. Jeffery Edenfield, MD  
  
Study Title:  A Phase I Clinical Trial of the Combination of Famotidine (FAM) and Oral N-Acetyl 
Cysteine (NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-
CoV-2 Infection 
  
Protocol Date: 18 August 2020 
 
 
 
 
 
 
 
 
 


page 2 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
  
Table of Contents 
I) 
Specific Aims 
 
 
 
 
 
 
 
page    3 
II) 
Background and Significance  
 
 
 
 
page    4 
 
i) Background 
 
 
 
 
 
 
 
page   4 
 
 a) Biochemical Rationale 
 
 
 
 
 
page   4 
 
1. Angiotensin Converting Enzyme 2 (ACE2) is SARS-CoV-2 Virus Binding Site 
 
2.   The type II Transmembrane Serine Protease (TMPRSS2) is critical in SARS-CoV-2 
 
 
Infection and its Expression is upregulated by ROS and Decreased by NAC 
 
 
3.   Intra-Epithelial Lymphocytes are a Critical 1st Line of Defense to Coronaviruses 
 
4.  Famotidine inhibits Histamine Suppression of Intra-Epithelial Lymphocytes 
 
5. Contribution of Mast Cells to SARS-CoV-2 Induced Inflammation  
 
 
6. ACE2 Depletion Results in Oxidative Stress, Tissue Fibrosis and Thrombosis 
 
7. NAC Reduces Oxidative Stress and Prevents Tissue Fibrosis and Thrombosis 
 
8. NAC Reduces Viral Replication which is increased by Oxidative Stress 
 
b) Clinical Rationale  
 
 
 
 
 
page 13 
 
1.  Chronic Oxidative Stress is Associated with Conditions which are Risk  
 
 
Factors for Severity SARS-CoV-2 Infection and Death 
 
2. Clinical Pathology of SARS-CoV-2 Infection – Thrombosis and Fibrosis  
 
3. MERS Leads to Lung Fibrosis 
 
4. SARS Leads to Lung and Heart Fibrosis with Downregulation of ACE2 
 
5. ACE2 Protects from Severe Acute Lung Failure 
 
6.   NAC Significantly Reduces Duration in ICU in ARDS and Ventilator Associated 
 
 
Pneumonia (VAP) 
 
7. NAC Reduces Tissue Damage from Viral Replication 
 
8. NAC Dramatically Reduces Severity of H1N1 Influenza Viral Infection 
 
9. Side Effect Profile of NAC 
 
10. Side Effect Profile of FAM 
 
11. Possible Reduction in Absorption of NAC due to increased Gastric pH 
 
12. Possible Synergistic Effect between FAM and NAC via enhancement of Lymphocytes 
 
 
and IL-2 production 
 
13. Possible Synergistic Effect between FAM and NAC to counteract effect of IL-6 
 
 
 in Prolongation of the QT Interval 
 
14. Depletion of LC3-I is rate limiting in Coronavirus infection and NAC’s demonstrated  
 
 
ability to dramatically increase LC3-II to LC3-I ratio 
 
ii) Clinical Significance 
 
 
 
 
 
page 27 
III) Research Design and Methods 
 
 
 
 
page 29 
IV) Protection of Human Subjects  
 
 
 
 
page 33 
V) 
Adequacy of Protection against Risks 
 
 
 
page 35 
VI) Subject Safety and Minimizing Risks  
 
 
 
page 42 
VII) Consultants 
 
 
 
 
 
 
 
page 43 
VIII) Facilities Available 
 
 
 
 
 
 
page 44 
IX) Appendices 
 
 
 
 
 
 
 
page 45 
X) 
References  
 
 
 
 
 
 
 
page 71 


page 3 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
I) SPECIFIC AIMS 
      i) Aim 1 
The primary outcome is to assess the safety and toxicity profile of the combination of 
famotidine and oral n-acetyl cysteine in adult outpatients with newly diagnosed SARS-CoV-2 
infection. 
    ii) Hypothesis 1  
We hypothesize that the combination of famotidine and n-acetyl cysteine are a safe 
combination of therapies in adult outpatients with newly diagnosed SARS-CoV-2 infection. 
  iii) Aim 2 
The secondary outcome is to assess whether certain markers (e.g., IL-1β, IL-2, IL-6, Tryptase, 
Glutathione, F2-Isoprostane/Creatinine, N-methylhistamine, CAP-SYM 18, IPSS and CURB-65) 
are predictive of outcomes and/or treatment response. 
   iv) Hypothesis 2 
We hypothesize that treatment with the combination of n-acetyl cysteine and famotidine in 
addition to the potential for reducing the primary endpoint of risk of hospitalization may also 
affect specific markers of infection which may prove useful surrogates for predicting the 
severity of the infection. 
 
 


page 4 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
II) BACKGROUND AND SIGNIFICANCE 
      i) Background 
N-Acetyl Cysteine (NAC) is a prodrug to L-cysteine which is a precursor to the biologic 
antioxidant glutathione.  Administration is FDA approved for acetaminophen poisoning for 
which it is nearly 100% effective if given with 8 hours1 and works through replenishing 
glutathione stores.2   
Famotidine is a histamine-2 (H2) receptor antagonist.  Administration is approved in adult 
and pediatric patients 40 kg and above for the treatment of active duodenal ulcer, active 
gastric ulcer, symptomatic non-erosive gastroesophageal reflux disease (GERD), and 
erosive esophagitis due to GERD if diagnosed by biopsy.  Administration is also approved in 
adults for the treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison 
Syndrome, multiple endocrine neoplasias) and for the reduction of the risk of duodenal 
ulcer recurrence.  
There have been no studies on the use of the combination of FAM and NAC in the 
treatment of outpatients who test positive for SARS-CoV-2 infection. 
a) Biochemical rationale 
 Angiotensin Converting Enzyme 2 (ACE2) is SARS-CoV-2 Virus Binding Site 
ACE2 is also one of the primary receptors for SARS‐CoV invasion into the human body.3,4 
The recent outbreak causing novel coronavirus pneumonia (COVID‐19) is caused by the 
virus (2019‐nCoV, SARS‐CoV‐2) which has also been shown to invade human alveolar 
epithelial cells through mainly ACE2.5 
 The type II Transmembrane Serine Protease (TMPRSS2) is Critical in SARS-CoV-2 
Infection and its Expression is Upregulated by ROS and Decreased by NAC 
It has recently been demonstrated that the SARS-CoV-2 virus binds to the ACE2 receptor   
and the serine protease TMPRSS2 is critical for Spike protein priming. 6  In SARS-CoV it had 
been previously demonstrated that TMPRSS2 can cleave and activate the SARS-CoV Spike 
protein which then allows the viral membrane to fuse with the cell membrane.7 
In normal porcine epithelial cells it has been demonstrated that oxidative stress enhanced 
paracellular permeability of the cell layer which was accompanied by predominantly 
cytoplasmic occurrence of TMPRSS2 embedded in cell membrane under physiological 
conditions. These results support that ROS can influence paracellular gate opening via 
multifaceted mode of action and that an altered distribution pattern of TMPRSS2 and 
relocalized transmembrane serine protease activity may contribute to weakening of 
epithelial barrier integrity under acute oxidative stress.8  Thus, it would be reasonable to 
hypothesize that cells exposed to oxidative stress may be more susceptible to SARS-CoV-2 
infection through its interaction with TMPRSS2. 
In fact, it has been demonstrated in-vitro that oxidation inhibition reduces the expression 
of TMPRSS2.  Furthermore, ROS was demonstrated to significantly increase the mRNA 


page 5 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
expression of TMPRSS2 and the addition of n-acetyl cysteine was demonstrated to 
significantly reduce the expression of mRNA level of TMPRSS2.9  
 Intra-Epithelial Lymphocytes are a Critical 1st Line of Defense to Coronaviruses 
The defense of a mucosal surface against viral infection is dependent in part on the 
leukocyte population resident at that site. It has been demonstrated that intraepithelial 
leukocytes (IEL) taken from the bovine intestinal epithelium were able to inhibit bovine 
coronavirus (BCV) replication, and this activity was markedly enhanced by interleukin-2 and 
tumor necrosis factor.10   It was further demonstrated that the IEL mediated higher levels 
of IL-2-activated, antibody-dependent, and lectin-dependent cytotoxicity than did 
lymphocytes from mesenteric lymph nodes, Peyer's patches, or the spleen. 
Further evidence of the role of IELs in the defense against coronaviruses has been 
demonstrated in mice when exposed to the enteric murine coronavirus (MHV-Y).  A potent 
in-vitro cytotoxic activity was demonstrated by mucosal leukocytes, especially IEL, and 
spleen cells for MHV-Y-infected syngenic and allogeneic target cells.11  Targets infected12 
with Pichinde virus, an enveloped nonenterotrophic virus, were not lysed by IELs. 
 Famotidine inhibits Histamine Suppression of Intra-Epithelial Lymphocytes 
Histamine has been demonstrated to significantly decrease IL-2 production in IELs as well 
as splenocytes.  It has been further demonstrated that famotidine, but not histamine 1 or 3 
receptor antagonists, competes with the inhibitory effect of histamine on the production of 
IL-2 and other cytokines in IELs.13   
Therefore, since IEL activity against the bovine coronavirus was markedly enhanced by IL-2, 
and famotidine competes with the inhibition of IEL production of IL-2 by histamine, a 
mechanism of action by which famotidine may be beneficial in patients infected with the 
SARS-CoV-2 is suggested. 
 Contribution of Mast Cells to SARS-CoV-2 Induced Inflammation 
Mast cells (MCs) express TLR which can be quickly recognized by pathogens including 
viruses.  Viral activated MCs release early inflammatory chemical compounds including 
histamine, tryptases and chimase; while late activation provoke the generation of pro-
inflammatory IL-1 family members including IL-1, IL-6 and IL-33.12  While there is 
substantial evidence for mast cell mobilization and activation of effector cells following 
viral challenge, mast cells have also been implicated in inappropriate inflammatory 
responses, long term fibrosis and vascular leakage associated with viral infections.14  
Therefore, strategies to modulate the activity of mast cells but not entirely suppress them 
may take advantage of the positive effects of mast cells in helping the immune system to 
fight a SARS-CoV-2 infection while potentially mitigating the negative effects caused by the 
release of chemical mediators of inflammation and the secretion of pro-inflammatory 
cytokines that can substantially aggravate the pathological state of the patient.12 
 ACE2 Depletion Results in Oxidative Stress, Tissue Fibrosis and Thrombosis 
Distribution of ACE2 throughout the Body 


page 6 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
In an non-disease status the ratio of ACE to angiotensin converting enzyme 2 (ACE2) 
appears to be relatively stable with ACE far more abundant.15   In fact, ACE2 has been 
found in rats to co-regionalize with ACE throughout a body’s tissues.16  Thus, as would be 
expected, the endothelium of human lungs express a not insignificant amounts of ACE2 but 
remarkably surface expression of ACE2 is also found in lung alveolar epithelial cells.17  In 
fact, lung tissue has high RAS activity and is the leading site of Angiotensin II synthesis.3   
Other locations which express ACE2 include enterocytes of the small intestine; and arterial 
smooth muscle cells, arterial, and venous endothelial cells, within the stomach, small 
intestine, colon, spleen, liver, kidney and brain.17  
Intra-organ Renin-Angiotensin System (RAS)      
Apart from the circulating RAS, the existence of local or intra-organ RASs have been 
described in a number of organs, including the heart, brain, kidney, lung, pancreas and 
liver.18–22  These local systems have been shown to be responsive to various stimuli of 
physiological and pathophysiological importance.  Moreover, the locally generated 
angiotensin peptides fragments have a plethora of actions and have been implicated in cell 
growth, anti-proliferation, apoptosis, reactive oxygen species (ROS) generation, hormonal 
secretion, pro-inflammatory and pro-fibrogenic actions (see figure 1).18,23 
 
 
Mechanism of action of ACE2 – Serves a counter balance to ACE and reduces ROS 
The renin angiotensin system (RAS) plays an important role in inflammation and fibrosis. 
The classical axis of the RAS, formed by angiotensin converting enzyme (ACE), angiotensin II 
(Ang II) and angiotensin receptor type 1 (AT1), activates several cell functions and 
Figure 1: A cartoon drawing23 of the putative ACE2-angiotensin-(1-7)-Mas axis, a counter-regulatory 
arm of the RAS that produce effects that oppose those of the ACE-angiotensin II-AT I receptor axis. 


page 7 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
molecular signaling pathways related to tissue injury, inflammation and fibrosis. In sharp 
contrast, the RAS axis composed by angiotensin converting enzyme 2 (ACE2), angiotensin-
(1-7) and Mas receptor exerts opposite effects in relation to inflammatory response and 
tissue fibrosis.24 
In vitro, angiotensin II significantly increases the NADPH oxidase-4 (NOX4) level and 
reactive oxygen species (ROS) which is attenuated by NAC.25,26  ACE2 deficiency has been 
shown in-vitro to increase ROS.27,28 ACE2 overexpression has likewise been shown in-vitro 
to decrease ROS.29  Thus, in conditions of chronic ROS it would be expected that both ACE 
and ACE2 would be more prevalent.  This has been observed in patients with congestive 
heart failure where the level of soluble ACE2 was found to correlate with increased 
oxidative stress-mediated endothelial dysfunction.30  
Tissue Fibrosis – Reduced by ACE2 Expression 
Angiotensin II, the main effector peptide of the RAS (renin–angiotensin system), has been 
shown to be a key mediator of tissue fibrosis in a number of diseases, including chronic 
heart and kidney diseases and diabetes.31  Recent studies indicate that angiotensin II may 
also play a central role in the pathogenesis of chronic liver disease and that the RAS is a 
promising potential target for anti-fibrotic therapies.18   Even more recently, the RAS was 
demonstrated to mediate intestinal fibrosis in patients with inflammatory bowel disease 
and Angiotensin (1-7) was shown to reduce colonic myofibroblast proliferation in a dose-
dependent manner.32  
ACE2 Inhibits NOX4-Dervied ROS-Mediated Pathway to Reduce Fibrosis and Cell Death 
The activation of the NOX-dependent generation of superoxide induced by Angiotensin II 
has emerged as a critical pathogenic factor in the development of pulmonary fibrosis.33 
NOX4-dependent generation of ROS (especially hydrogen peroxide [H2O2]) is required for 
TGF-β1-induced ECM generation and platelet-derived growth factor (PDGF)-induced 
migration of lung fibroblasts.34,35  It was recently demonstrated that the ACE2/Ang(1–
7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the 
NOX4-derived ROS-mediated RhoA/Rock pathway.25 
In addition to reducing tissue fibrosis, activation of the ACE2/Ang-(1-7)/Mas pathway has 
been shown to reduce NOX4 expression and reduce oxygen glucose deprivation induced 
tissue swelling, ROS production, and cell death in the mouse brain with angiotensin II 
overproduction.36   
Angiotensin (1-7) Prevents Pulmonary Fibrosis by Inhibiting TGF-β1-Smad Signaling Pathway 
Accumulating evidence indicates that angiotensin (1-7) protects against pulmonary fibrosis 
in animal models but not only by the NOX4-derived ROS-mediated pathway.  Angiotensin 
(1-7) also effectively inhibits epithelial-mesenchymal transition (EMT) induced by 
transforming growth factor- β1 (TGF-β1) in human alveolar epithelial cells by inhibiting 
TGF-β1 phosphorylation of Smad2 and Smad3 and suppressing the expression of 
downstream target genes of TGF- β1-Smad signaling (see figure 2).37 


page 8 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
 
 
ACE2 Protection against Thrombosis 
Lung vascular injury is the most important initial cause of acute lung injury (ALI) and 
ARDS.38  In the setting of both infectious and noninfectious lung injury, neutrophils 
accumulate in the lung microvasculature and become activated, leading to degranulation 
and the release of several toxic mediators, including proteases, reactive oxygen species, 
pro-inflammatory cytokines, and pro-coagulant molecules, which result in increased 
vascular permeability and a sustained loss of normal endothelial barrier function.38 
There is growing evidence indicating that the counter-regulator axis of the renin-
angiotensin system (RAS), composed of Angiotensin-Converting Enzyme 2 (ACE2), 
Angiotensin-(1–7) and the Mas receptor, has protective effects against thrombosis.39  
The initial study demonstrating the direct antithrombotic effect of Ang-(1–7) was 
performed by Kucharewicz et al.40 They observed that the intravenous infusion of Ang-(1–
7) reduced the weight of the thrombus induced by the ligature of the abdominal vena cava 
in renovascular hypertensive rats.40,41 However, Ang-(1–7) did not have any observed effect 
in normotensive rats.41   
In addition to this activity on endothelial cells, evidence suggests that Ang-(1–7) may also 
directly modulate platelet activity. In 2008, the presence of the Mas receptor on platelets 
was detected and more importantly, it was demonstrated that the Mas receptor activation 
by Ang-(1–7) increased the production of NO in platelets.42 Furthermore, it has been 
reported that incubation of platelet preparations with increasing concentrations of Ang-(1–
7) reduced their adhesion to fibrillar collagen.40 
ACE2 is also involved in the pathophysiological formation of a thrombus.39 A decrease in 
ACE2 activity, but not in ACE2 protein expression, was associated with increased thrombus 
Figure 2. Schematic summary of the proposed mechanism of TGF-β1 induction of epithelial 
mesenchymal transition (EMT) in alveolar epithelial cells and inhibition by Angiotensin (1-7).37 


page 9 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
formation in spontaneously hypertensive rats.43 Supporting that finding, the 
pharmacological activation of ACE2 was associated with a marked reduction of thrombus 
formation in spontaneously hypertensive rats.43  In addition, pre-treatment with,DX-600, 
an ACE2 inhibitor (see figure 3), increased the thrombus formation in both hypertensive 
and normotensive rats.43  Moreover, ACE2 also modulates platelet activity, since its 
activation decreased platelet attachment to injured microvessels.43 
 
 
 NAC Reduces Oxidative Stress and Prevents Tissue Fibrosis and Thrombosis 
Mechanism of action of NAC – restoration of glutathione depletion from oxidative stress  
N-acetyl-cysteine (NAC), is known to rapidly increase glutathione (GSH) synthesis in 
acetaminophen posioning2. GSH acts as a nucleophilic scavenger of electrophilic xenobiotic 
compounds and their metabolites, converting electrophilic centers via enzymatic 
conjugation into thio-ether bonds. In addition, GSH, as the only substrate of selenium-
dependent GSH peroxidase44,45 and also as a chemical reducing agent and antioxidant, has 
an extremely important role. By virtue of these features GSH is considered to be an 
outstanding protector of biological structures and function. GSH is synthesized 
intracellularly from the amino acids glycine, glutamate, and the thiol providing amino acid 
cysteine.  Cell membranes in general are impermeable to the tripeptide glutathione. 
Hence, GSH is synthesized intracellularly only from the single amino acid constituents or 
their precursors.44–46  Since glycine and glutamate are abundantly available in the 
intracellular space, an adequate supply and transmembrane transport of cysteine into the 
cell becomes the rate-limiting step in the biosynthesis of GSH. The administration of 
exogenous N-acetyl cysteine (NAC) effectively meets intracellular needs of cysteine for 
Figure 3. Schematic illustration showing the mechanism for the anti-thrombotic effect of 
ACE2/Ang(1-7)/Mas axis.43 


page 10 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
the synthesis of GSH by supplementing precursor pools in a more physiological 
way.44,47,48 
Any single GSH moiety, once it is conjugated to electrophils and transported out in this 
form, and also when oxidized, is not immediately available for subsequent needs. Oxidized 
glutathione is reduced once again to the functional form via the glutathione reductase 
pathway. Under these conditions the loss of glutathione remains reversible. Conjugated 
GSH, however, is exported from the cell and processed to mercapturic acids, which are 
excreted in the urine. In these reactions, GSH is lost irreversibly and can be replaced only 
via ex novo synthesis. Irreversible loss of GSH occurs preferentially following oxidative 
stress. Under conditions of intense oxidative stress, the rate of glutathione disulfide (GSSG) 
formation - through oxidation of GSH - is such as to surpass, and possibly exhaust, the 
intracellular glutathione reductase capacities; as a consequence, an accumulation of 
intracellular GSSG will result. GSSG in turn, being toxic to the intracellular milieu beyond a 
critical concentration, is exported from the cell and hence lost to the reductase 
pathway.44,45,48 
NAC Inhibits NOX4-Dervied ROS-Mediated Pathway to reduce Fibrosis 
In-vitro, Angiotensin II significantly increased the NOX4 level and ROS production in lung 
fibroblasts, which stimulated cell migration and a-collagen I synthesis through the 
RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC). 25  In vivo, 
constant infusion with Ang(1–7) shifted the RAS balance toward the ACE2/Ang(1–7)/Mas 
axis, and alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway 
by reducing NOX4-derived ROS.25  Thus, the NOX4-derived ROS pathway, which when 
inhibited appears to alleviate bleomycin-induced lung fibrosis in-vivo, has been shown to 
be inhibited in-vitro by NAC. 
NAC Inhibits TGF-β Regulation of NOX4 to Reduce IL6 Release in Airway Smooth Muscle Cells 
TGF-β induces the expression of NOX4 which is accompanied by an elevation of ROS levels 
and IL6 release from airway smooth muscles cells (ASMCs) which is reversed by NAC 
through inhibition of Smad3 phosphorylation (see figure 4).49  This suggests an important 
pathway by which NAC could reduce the severity of sudden acute respiratory syndrome 
in those infected with SARS-CoV-2 as it was recently observed in patients admitted to the 
hospital with symptomatic SARS-CoV-2 infection that IL-6 level was strongly associated 
with the need for mechanical ventilation, the maximal IL-6 level predicted for respiratory 
failure with high accuracy with the risk of respiratory failure 22 higher in patients with IL-
6 levels greater the 80 pg/mL compared to patients with lower IL-6 levels.50 


page 11 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
 
 
NAC Mitigates Toll-Like Receptor Activation to Reduce IL-1β and IL6 
While the data in humans likely doesn’t support NAC as effective in reversing progression 
of pre-existing idiopathic pulmonary fibrosis (IPF),51,52 it is felt there may be specific 
clusters of IPF patients where NAC may have a role.  In fact, NAC exposure was shown to be 
associated with improved transplant-free survival in ANA positive patients with usual 
interstitial pneumonia (UIP).53  The mechanism in which this was felt possible was that NAC 
may have mitigated Toll-Like Receptor (TLR) activation by self-antigen/autoantibody 
complexes in ANA seropositive patients with UIP.   The binding of SARS-CoV-2 to the TLR 
causes release of pro-IL-1β which is followed by production of active mature IL-1β, a 
mediator of lung inflammation and fibrosis.54 In a guinea pig model, decreased expression 
of IL-1β was significant with NAC and was observed only in animals treated with NAC as 
compared to saline or ascorbic acid.55 In a model of mouse ischemia-reperfusion, NAC prior 
to ischemia lead to a significant decrease in IL-1β levels after ischemia and significant 
decrease in IL-1β as well as IL-6 levels in bronchoalveolar lavage fluid after reperfusion.56  
In a human placebo-controlled trial of oral NAC (600 mg twice daily) for 8 weeks in 
continuous ambulatory peritoneal dialysis patients, administration of NAC significantly 
diminished IL-6 (p=0.002) and IL-1 (p=0.01).57 
Thrombosis – Reduced by NAC 
Treatment with glutathione depletion agents has been shown in rabbits to significantly 
inhibit fibrinolytic activity in the arterial wall by induction of a significant reduction of the 
activity of tissue plasminogen activator and a significant increase in plasminogen activator 
inhibitor which suggests a modulatory role of glutathione in the release and/or clearance 
of components of the fibrinolytic system.58   This suggests that NAC could have a role in 
preventing inhibition of fibrinolytic activity in disease states that could otherwise lead to a 
depletion of glutathione. 
Figure 4. Schematic summary of the proposed mechanism of TGF-β mediated regulation 
of oxidant/antioxidant balance and IL-6 release in ASMCs and reversal by NAC.49 


page 12 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
In fact, in-vitro data exists that demonstrates that NAC reduces platelet activation induced 
by oxidized low-density lipoproteins.59  The reduction in platelet activation by NAC 
appeared to be through its effect of increasing activity of the PI3K/AKT/mTOR pathway to 
reduce platelet autophagy thus inhibiting platelet aggregation (see figure 5). 
 
 
In-vivo studies also demonstrate that NAC can reduce formation of thrombosis.  In a mouse 
model of Type I Diabetes, in which the diabetic blood and brain became progressively more 
susceptible to platelet activation and thrombosis,  the effects of diabetes were partly or 
completely reversed by NAC.60   
In a large-vessel thromboembolic stroke model in mice, intravenous NAC administration 
was demonstrated to promote lysis of arterial thrombi resistant to conventional 
approaches such as recombinant tissue-type plasminogen activator, direct thrombin 
inhibitors, and anti-platelet treatments. It is important to note that NAC did not worsen 
hemorrhagic stroke outcome, suggesting that it exerts thrombolytic effects without 
significantly impairing normal hemostasis.61 The results of this study demonstrate 
significant improvements in cerebral arterial occlusion events through a thrombolytic 
mechanism involving NAC. This effect appears to be mediated by the reduction of disulfide 
linkages that stabilize the high molecular weight forms of von Willebrand Factor (VWF).62 
 
In well-established murine and baboon models for TTP, prophylactic administration of NAC 
was effective in preventing severe TTP signs in mice, but NAC was not effective in resolving 
preexistent acute TTP signs in mice and baboons.63  Taken together with other studies, this 
suggests that NAC may be more effective in the acute setting or in preventing thrombosis 
rather than in the chronic setting. 
In a human study of obese insulin-resistant subjects, NAC was found to reduce platelet 
aggregation ex-vivo; however, it required significantly higher concentrations of NAC with 
much longer exposer to NAC when compared to non-obese controls without insulin 
resistance.64 
Figure 5. Schematic illustrating proposed mechanism by which ROS induce autophagy to promoted 
ox-LDL-induced platelet activating by inhibiting the PI3K/AKT/mTOR pathway is inhibited by NAC.59 


page 13 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
We therefore conclude that if NAC can reduce severity of SARS-CoV-2 infection in regards 
to thrombosis formation, it most likely would be effective if given early in the course of 
infection before significant thrombotic events have occurred and that higher doses and 
longer duration of dosing may be necessary in certain subjects such as the obese with 
insulin resistance.  
 NAC Reduces Viral Replication which is Increased by Oxidative Stress 
Oxidative Stress Increases Viral Replication 
Inflammation has been shown to promote acute viral infection.65   CMV virus enhancers 
were discovered, to an extent not previously recognized, to employ a path of least 
resistance by directly harnessing, within a short temporal window, the activation of anti-
viral signaling in macrophages to drive viral gene expression and replication.65 
Positive-sense single stranded RNA viruses have also been shown to utilize oxidative stress 
during infection to help control genome RNA capping and genome replication.66 
NAC decreases Viral Replication through Reactive Oxidative Species Pathway 
There is a plethora of in-vitro data demonstrating that NAC reduces viral replication, 
activation of latent virus or damage to infected cells in a multitude of viruses to include 
HBV,67 CMV,68 Coxsackievirsus B,69 RSV,70,71 H5N1,72 EBV,73 rotavirus,74 HCV,75 Rubella 
Virus,76 rhinovirus,77 KSHV,78 porcine circovirus,79 Enterovirus 7180 and 
Adenovirus.81  Additionally there is in-vitro data showing that reduction of oxidative stress 
by other anti-oxidants such as glutathione, which isn’t easily absorbed orally unlike NAC, 
reduces viral replication in VZV82 and HSV.83,84  
The mechanism of action appears to be via the ROS/p53 signaling pathways.85  Because this 
pathway is common to viral replication across a broad spectrum of viruses to specifically 
include positive-sense single stranded RNA viruses, we anticipate that NAC will likely also 
significantly reduce viral replication of SARS-CoV-2, a positive sense single stranded RNA 
virus. 
b) Clinical rationale 
1. Chronic Oxidative Stress is Associated with Conditions which Are Risk Factors for 
Severity of SARS-CoV-2 Infection and Death 
Patients with risk factors for increased oxidative stress or decreased cellular immunity, e.g., 
African ethnicity86, male gender87, elderly88,89, obesity90, hypertension91, atherosclerosis92, 
COPD93, and DM94 appear to have a much more virulent and potentially lethal SARS-CoV-2 
infection.95–97  In, fact recent evidence demonstrates that 94.3% of patients hospitalized in 
New York with SARS-CoV-2 infection had at least one high risk factor and 88% had more 
than one risk factors.98 
Since ACE and ACE2 are both upregulated with oxidative stress and viral replication is 
increased with oxidative stress  (see figure 6),99 we hypothesis that severity of SARS-CoV-2 
infection is likely far more virulent in patients with these conditions because the SARS-CoV-
2 virus binding site, ACE2, serves as marker of those cells most hospitable for viral 
replication and the severity of tissue injury increases with ACE2 depletion (see figure 7).100   


page 14 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
We further hypothesis that the earlier in the course of infection that attempts are made to 
reduce binding to ACE2 and to reduce oxidative stress the greater the potential exists to 
reduce the severity of the SARS-CoV-2 infection. 
 
 
 
 
Figure 6: A cartoon drawing99 of the increased but relatively balanced levels of ACE and ACE2 due 
to chronic oxidative stress. 
Figure 7: A cartoon drawing100 of the increased severity of SARS-CoV-2 infection due to the sudden 
downregulation of otherwise increased levels of ACE2 due to conditions of chronic oxidative stress. 


page 15 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
2. Clinical Pathology of SARS-CoV-2 Infection – Thrombosis and Fibrosis 
Elevation of IL6 is Strongly Associated with Need for Ventilation and Respiratory Failure 
Since the early descriptions, it appeared that the progressive worsening lung function of 
patients infected with SARS-CoV-2 is potentially driven by host immune response.101  
Recent analysis of 40 patients admitted to a single institution with PCR proven 
symptomatic SARS-CoV-2 infection were analyzed for baseline clinical and laboratory 
findings and elevated interleukin-6 (IL-6) was strongly associated with the need for 
mechanical ventilation (p=1.2·10-5).50  In addition, the maximal IL-6 level (cutoff 80 pg/ml) 
for each patient during disease predicted respiratory failure with high accuracy (p=1.7·10-8, 
AUC=0.98). The risk of respiratory failure for patients with IL-6 levels of ≥ 80pg /ml was 22 
times higher compared to patients with lower IL-6 levels. 
Pathologic Findings - Massive Pulmonary Interstitial Fibrosis and Hemorrhagic Infarct 
COVID‐19 patients, and SARS patients, often develop a severe acute respiratory syndrome 
and appear to have typical ARDS pathology in the lung. 102  In a critical patient with COVID-
19, histological examination demonstrated bilateral diffuse alveolar damage with cellular 
fibromyxoid exudates (figure 8A, B). The right lung showed evident desquamation of 
pneumocytes and hyaline membrane formation, indicating acute respiratory distress 
syndrome. The left lung tissue displayed pulmonary edema with hyaline membrane 
formation, suggestive of early-phase ARDS (figure 8B). Interstitial mononuclear 
inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. 
Multinucleated syncytial cells with atypical enlarged pneumocytes characterized by large 
nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the 
intraalveolar spaces, showing viral cytopathic-like changes.103  No obvious intranuclear or 
intracytoplasmic viral inclusions were identified.  In fact, the pathological features of SARS-
CoV-2 infection greatly resemble those seen in SARS and Middle Eastern respiratory 
syndrome (MERS) coronavirus infection.102,104,105 


page 16 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
 
 
Microvascular COVID-19 Lung Vessel Obstructive Thrombo-Inflammation 
In addition to the severe respiratory distress syndrome associated with SARS-CoV-2 
infection, the infection appears associated with a transient increased risk of venous 
thromboembolic events.  In the absence of major predisposing factors for venous thrombo-
embolism, the severe COVID-19 pneumonia may be a precipitating factor for acute venous 
thrombo-embolism and acute pulmonary embolism.106 
In a recent Dutch trial, a 31% incidence of thrombotic complications in 184 ICU patients 
with COVID-19 infections was reported.107  It seems clear that more than standard 
anticoagulantion may be needed as a report of 388 patients from Milan in which 100% of 
ICU patients and 75% of general ward patients received thromboprophylaxis a cumulative 
rate of 21% of thromboembolic events were observed.108 
Figure 8. Pulmonary interstitial histopathology associated with critical patient 
A: Massive pulmonary interstitial fibrosis. B: Pulmonary hemorrhagic infarct. C: Vascular wall thickening 
and lumen stenosis. D: Boangiitis obliterans are surrounded by inflammatory cells. E: Interstitial plasma 
cells infiltrating. F: Lung interstitial fibrosis by Masson stain.102 


page 17 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
In a study of patients with severe COVID-19 characterized by respiratory failure (n=5) and 
purpuric skin rash (n=3), examination of skin and lung tissue demonstrated there exists at 
least a subset of sustained, severe COVID-19 patients who experience a catastrophic 
microvascular injury syndrome mediated by activation of complement pathways and an 
associated pro-coagulant state.109  Based on this study and observations of others, the use 
of MicroCLOTS (microvascular COVID-19 lung vessels obstructive thrombo-inflammatory 
syndrome) has been suggested as new name for severe pulmonary coronavirus disease 
2019 (COVID-19). 101 It has been hypothesized that, in predisposed individuals, alveolar 
viral damage is followed by an inflammatory reaction and by microvascular pulmonary 
thrombosis. This progressive endothelial thrombo-inflammatory syndrome may also 
involve the microvascular bed of the brain and other vital organs, leading to multiple organ 
failure and death.101 
Clinical Benefit from Anticoagulation 
In a study of 449 patients with severe COVID-19, 99 of them received heparin (mainly with 
low molecular weight heparin, LMWH) for 7 days or longer. The D-dimer, prothrombin time 
and age were positively, and platelet count was negatively, correlated with 28-day 
mortality in multivariate analysis.  No difference on 28-day mortality was found between 
heparin users and nonusers (30.3% vs 29.7%, P=0.910). But the 28-day mortality of heparin 
users were lower than nonusers in patients with SIC score ≥4 (40.0% vs 64.2%, P=0.029), or 
D-dimer > 6 fold of upper limit of normal (32.8% vs 52.4%, P=0.017).110  
Not consistent with DIC rather Hypercoagulability with Severe Inflammatory State 
In a separate study, whole blood from 24 patients admitted into the intensive care unit 
because of COVID-19 was collected and evaluated with thromboelastography by the TEG 
point-of-care device on a single occasion and six underwent repeated measurements on 
two consecutive days for a total of 30 observations.  The results of this cohort of patients 
with COVID-19 were not consistent with acute DIC, rather they support hypercoagulability 
together with a severe inflammatory state.111 
Recently, a group from Switzerland report a case of an ICU COVID-19 patient in which they 
observed a massive elevation of VWF, with VWF antigen at 555% (normal42- 136 %) and 
VWF activity of 520% (normal 42–168%), accompanied by an increase of Factor VIII clotting 
activity of 369% (normal 55–164%).  They conclude, “We would like to emphasize the 
significance of anticoagulation in severe COVID-19 disease, by adding our observation of 
highly pathological data on anti-phospholipid-antibodies, von Willebrand Factor (VWF) and 
Factor VIII.”112 
 
Taken together, given that NAC has demonstrated fibrinolytic properties, anti-platelet 
aggregation properties and the ability to reverse crosslinking of platelets through VWF, we 
propose that giving NAC early in the course of infection could go a long way to reduce the 
severity of a SARS-CoV-2 infection in regards to thromboembolic events. 
 


page 18 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
3. MERS-CoV infection Leads to Lung Fibrosis   
Symptoms caused by MERS-CoV are similar to those of SARS-CoV infection but unlike SARS-
CoV and SARS-Cov2, the MERS-CoV uses the species-specific receptor, human dipeptidyl 
peptidase 4 (hDPP4), for its entry into host cells.113,114  In a stable murine model of hDPP4-
transgenic mice infected with MERS-CoV, histopathological signs indicative of progressive 
pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory 
monocytes, and macrophage polarization as well as elevated expression of profibrotic 
molecules and acute inflammatory response were observed in the lung.115  In humans, 
DPP4 is continuously expressed in epithelial cells116 and human tracheobronchial 
epithelium, bronchial epithelium and renal epithelium have undergone cytopathic changes 
when infected with MERS-CoV in culture.117  
Patients with MERS often present to a hospital with systemic and lower respiratory tract 
(LRT) signs and symptoms of disease which usually include fever, chills or rigors, dry or 
productive cough, shortness of breath and one or more comorbidities including diabetes, 
chronic kidney disease, chronic heart disease, recent surgery, hypertension, chronic lung 
disease, asthma, obesity, smoking, malignant disease or steroid use.117  These 
comorbidities are all associated with conditions of chronic oxidative stress and of interest 
DPP4 like ACE2 appears to be a marker for NOX4-derived ROS.   Inhibiting DPP4 in high 
glucose-induce endothelial dysfunction,118 cardiac hypertrophy ,119 chronic kidney 
disease,120  perivascular adipose tissue,121 and oxidized-LDL- induced endothelial 
dysfunction,122  has been demonstrated to reduce ROS and NOX-4 expression.  In fact, in 
cardiac hypertrophy, it was demonstrated that the inhibition of DPP4 significantly 
suppresses angiotensin II induced increase in NOX4 mRNA.119  
Therefore, due to high risk for severe acute respiratory distress, increased risk of severity 
due to very similar comorbidities, and receptor binding domains (albeit different for MERS-
CoV) that serve as for markers of cells most likely to enhance viral replication via a NOX4-
derived ROS pathway, MERS appears very similar clinically and pathologically to COVID-19. 
4. SARS Leads to Lung Fibrosis and Heart Fibrosis with Downregulation of ACE2 
SARS-CoV infection leads to Increased Pulmonary Fibrosis via the EGFR Signaling Pathway 
which is blocked by NAC 
Many survivors of SARS-CoV infection develop pulmonary fibrosis (PF), with higher 
prevalence in older patients.  Based on this observation a study using mouse models of 
SARS-CoV pathogenesis identified that the wound repair pathway, controlled by the 
epidermal growth factor receptor (EGFR), is critical to recovery from SARS-CoV-induced 
tissue damage.  In mice with constitutively active EGFR [EGFR(DSK5) mice], it was found 
that SARS-CoV infection caused enhanced lung disease. Importantly, it was show that 
during infection, the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor 
(HB-EGF) were upregulated, and exogenous addition of these ligands during infection lead 
to enhanced lung disease and altered wound healing dynamic.123 
Of particular note, it has been demonstrated in non-small cell lung (NSCLC) cancer cells 
exposed to cigarette smoke extract (CSE) that CSE stimulated ROS generation leading to  


page 19 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
EGFR-TKI resistance via promotion of EGFR signaling which was suppressed by NAC.124   A 
similar effect of NAC has been demonstrated in human head and neck cancer cells and the 
induced cytotoxicity by a TKI was demonstrated via a NOX4-dervied ROS pathway.125  In 
EGFR-sensitive NSCLC cell lines, exposure to oxidative stress has been demonstrated to 
result in tyrosine kinase inhibitor (TKI) resistance by abnormal activating EGFR 
phosphorylation and disrupting the classical dimer structure of EGFR.126 
Thus, the signaling pathways discussed earlier, in which Angiotensin (1-7) inhibits 
pulmonary fibrosis and in which NAC inhibits IL-6 expression, appears to increase 
pulmonary fibrosis in mice infected with SARS-CoV and is inhibited by NAC in cancer cell 
lines.  
SARS-CoV Infection Leads to Downregulation of ACE2 and Severe Acute Lung Injury 
Additionally, in a study of ACE2 knockout (KO) mice and wild type mice treated with either 
SARS-CoV or recombinant SARS spike protein, wild‐type mice exhibited significantly 
reduced ACE2 expression in the lungs with either treatment. These wild type mice showed 
increased severity of pathological conditions in acute lung injury.  Treating ACE2 KO mice 
with SARS‐CoV resulted in only a very low quantity of virus being recovered and a slight 
reduction in leukocyte infiltrate score relative to uninfected ACE2 KO mice.  In contrast 
there was a significant increase in the leukocyte infiltrate score in ACE2 wild type mice 
infected with SARS-CoV compared to wild type mice not infected.  Therefore, the 
downregulation of ACE2 expression in SARS‐CoV infection may play a causal role in the 
pathogenesis of SARS, which provides a reasonable explanation for the progression of SARS 
patients into ARDS.3,127 
 SARS-CoV Infection Leads to Heart Fibrosis with Downregulation of ACE2 
Many patients with SARS, in addition to suffering a severe acute respiratory syndrome, also 
suffered from cardiac disease including arrhythmias, sudden cardiac death, and systolic and 
diastolic dysfunction.128,129  Autopsy heart samples from 20 patients who succumbed to the 
SARS crisis in Toronto were used to investigate the impact of SARS on myocardial structure, 
inflammation and ACE2 protein expression.  Reverse transcriptase PCR analysis showed 
35% had positive SARS-CoV genome detected in their heart.  Importantly, the duration of 
the illness was significantly shortened in patients with detectable virus in their heart (3.9 
versus 43.2 days; p < 0.05). Staining showed increased myocardial inflammation and 
interstitial fibrosis in patients who had SARS-CoV detected in their hearts.  Additionally, the 
presence SARS-CoV in the heart was associated with marked down-regulation of ACE2 
protein expression.128 
Based on these autopsy findings, an in-vivo study was performed on mice which were 
infected with the human strain of the SARS-CoV and encephalomyocarditis virus and were 
examined for ACE2 mRNA and protein expression. Pulmonary infection with the human 
SARS-CoV in mice led to an ACE2-dependent myocardial infection with a marked decrease 
in ACE2 expression confirming a critical role of ACE2 in mediating SARS-CoV infection in the 
heart.128 


page 20 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
5.  ACE2 Protects from Severe Acute Lung Failure 
Injection of recombinant human ACE2 (rhuACE2) protein into acid aspiration-treated ACE2 
KO mice decreased degree of lung injury.  Acid aspiration-treated wildtype mice were also 
rescued by rhuACE2.  Catalytically inactive ACE2 did not rescue the severe lung phenotype 
in ACE2 KO mice and had no effect on the severity of acute lung injury in wild type animals.  
In contrast to ACE2 KO mice, ACE KO mice were partially protected against acute lung 
injury by acid-aspiration.   In addition inactivation of ACE on ACE2 KO mice rescued the 
mice from severe lung failure.  Thus it was shown that ACE promotes acute lung injury 
pathology and ACE2 alleviates it.130 
6. NAC Significantly Reduces Duration in ICU in ARDS and Ventilator Associated Pneumonia (VAP) 
It appears in chronic progressive conditions such as idiopathic pulmonary fibrosis, NAC may 
be unlikely to reverse lung fibrosis and its potential to prevent further progression of lung 
fibrosis is uncertain.51,131  However, in conditions of acute pneumonitis and prevention of 
acute lung injury, NAC appears more promising.132–135  
In a recent meta-analysis of five randomized trials in patients with ARDS demonstrated that 
time in the ICU was significantly shortened in patients randomized to receive NAC.132  
While this meta-analysis did not show a survival advantage to NAC, the numbers of 
patients in the trials was relatively small and the cause of respiratory failure was likely 
varied and perhaps not always due to viral pneumonia or other causes of oxidative stress.  
Additionally, the dose of IV NAC in these trials were significantly lower than the maximum 
tolerated dose of 450 mg/kg136 and the number of days NAC was administered seems 
somewhat short in several of the trials.  Despite these limitations it is quite notable that 
there was still significant benefit found in reducing the number of days in the ICU. 
In a separate randomized double-blind placebo controlled trial for the prophylaxis of 
ventilator-associated pneumonia (VAP), in 60 mechanically ventilated patients at high risk 
of developing VAP, 30 were randomized to receive a dose of 600 mg twice daily via NG 
tube.137  Patients treated with NAC were significantly less likely to develop clinically 
confirmed VAP compared with patients treated with placebo (26.6% vs. 46.6%; P = 0.032). 
Patients treated with NAC had significantly less ICU length of stay (14.36 ± 4.69 days vs. 
17.81 ± 6.37 days, P = 0.028) and less hospital stay (19.23 ± 5.54 days vs. 24.61 ± 6.81 days; 
P= 0.03) than patients treated with placebo. Time to VAP was significantly longer in the 
NAC group (9.42 ± 1.9 days vs. 6.46 ± 2.53 days; P = 0.002). The incidence of complete 
recovery was significantly higher in the NAC group (56.6% vs. 30%; P = 0.006). No adverse 
events related to NAC were identified. 
In our proposed trial of non-hospitalized patients, we propose oral dosing twice a day 
based on data demonstrating  oral dosing results in increased levels of glutathione in 
bronchoalveolar lavage fluid one to three hours after administration of 600 mg of oral NAC 
which fell by 16 to 20 hours.138  
7. NAC Reduces Tissue Damage from Viral Replication 
Reduces TissueIn-Vivo Activity of NAC to Reduce Tissue Damage from Viruses 


page 21 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
NAC has more recently been shown to reduce viral replication in animal models139 and 
reduces apoptosis due to increased reactive oxidative species (ROS) in healthy cells of 
animals infected with virus (shown in the liver of mice infected with the dengue virus139, 
lungs of mice infected with H9N2 swine flu140, and in the intestines of piglets infected with 
a lethal porcine coronavirus, porcine epidemic diarrhea virus (PEDV)).85,141,142   
Porcine Coronavirus, Porcine Epidemic Diarrhea Virus (PEDV), severity in 2013-2014 
For the last four decades, PEDV infection has resulted in significant economic losses in the 
European and Asian pig industries, but in 2013–2014 the disease was also reported in the 
US, Canada and Mexico. As a result of the significant impact of PEDV, the US pig industry 
lost almost 10% of its domestic pig population after only a 1 year-epidemic period, 
amounting to approximately 7 million piglets.143 
Porcine Coronaviruses Bind to the Aminopeptidase N Receptor on Small Intestine Paneth Cells 
Inducing Mitochondrial Damage and ROS Causing Paneth cell decrease and Accelerated Viral 
Replication 
Transmissible gastroenteritis virus (TGEV) is an enteropathogenic coronavirus, that like 
PEDV, causes severe lethal watery diarrhea and dehydration in piglets.  PEDV has been 
shown to recognize protein receptor aminopeptidase N from pig and human and sugar co-
receptor N-acetylneuraminic acid.144  TGEV shares aminopeptidase N as its receptor 
binding domain (RBD) but unlike, PEDV doesn’t appear to use N-acetylneuraminic acid as a 
co-receptor.145,146  Initial invasion by TEGV into Paneth cells through the aminopeptidase N 
(APN) receptor has been demonstrated to induce mitochondrial damage and ROS 
generation, ultimately causing Paneth cell decrease and loss of Notch factors (DII4 and 
Hes5), which are essential for Lgr5 ISCs self-renewal and differentiation.  Interestingly, loss 
of Notch signaling induced goblet cells differentiation at the cost of absorptive enterocytes 
and promoted mucins secretion, which accelerated TGEV replication.147 
Intestinal Damage from Porcine Coronaviruses Reduced by NAC  
Studies have indicated that TGEV infection induces cell apoptosis in host cells. A more 
recent study, further investigated the roles and regulation of reactive oxygen species (ROS) 
in TGEV-activated apoptotic signaling. The results showed that TGEV infection induced ROS 
accumulation, whereas UV-irradiated TGEV did not promote ROS accumulation.  In 
addition, TGEV infection lowered mitochondrial transmembrane potential, which was 
inhibited by ROS scavengers, pyrrolidinedithiocarbamic (PDTC) and N-acetyl-L-cysteine 
(NAC).  Furthermore, the two scavengers significantly inhibited the activation of p38 MAPK 
and p53 and further blocked apoptosis occurrence through suppressing the TGEV-induced 
Bcl-2 reduction, Bax redistribution, cytochrome c release and caspase-3 activation.  These 
results suggest that oxidative stress pathway might be a key element in TGEV-induced 
apoptosis and TGEV pathogenesis.141  
NAC and PDTC have also been demonstrated to result in significant Inhibition of apoptosis 
induced by PEDV.  Moreover, further inhibition tests were established to prove that p53 
was regulated by ROS in PEDV-induced apoptosis.85 


page 22 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
In addition to in-vitro data demonstrating inhibition of apoptosis by either porcine 
coronavirus, TGEV or PDEV, there is in-vivo data demonstrating significant effect of NAC.   A 
trial of thirty-two 7-day-old piglets randomly allocated piglets to one of four treatments in 
a 2 × 2 factorial design consisting of a liquid diets with or without  50 mg/kg BW NAC 
supplementation and oral administration of 0 or 104.5 TCID50 (50% tissue culture infectious 
dose) PEDV. On day 7 of the trial, half of the pigs (n = 8) in each dietary treatment received 
either sterile saline or PEDV (Yunnan province strain) solution at 104.5 TCID50 per pig. On 
day 10 of the trial, d-xylose (0.1 g/kg BW) was orally administrated to all pigs. One hour 
later, jugular vein blood samples were collected, and then all pigs were killed to obtain the 
small intestine. PEDV infection increased diarrhea incidence, while reducing average daily 
weight gain. PEDV infection also decreased plasma d-xylose concentration, small intestinal 
villus height, mucosal I-FABP and villin mRNA levels but increased mucosal MX1 and GCNT3 
mRNA levels (P < 0.05). Dietary NAC supplementation ameliorated the PEDV-induced 
abnormal changes in all the measured variables. Moreover, NAC reduced oxidative stress, 
as indicated by decreases in plasma and mucosal H2O2 levels. Collectively, these novel 
results indicate that dietary supplementation with NAC alleviates intestinal mucosal 
damage and improves the absorptive function of the small intestine in PEDV-infected 
piglets.142 
Lung Damage from H9N2 swine flu reduced by NAC 
The effects of NAC on H9N2 swine influenza virus-induced acute lung injury (ALI)were 
investigated in mice inoculated intranasally with 107 50% tissue culture infective doses  
(TCID50) of H9N2 which demonstrated  that pulmonary inflammation, pulmonary edema, 
MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6, IL-1β and CXCL-10 in BALF 
were attenuated by NAC. Moreover, NAC significantly inhibited the levels of TLR4 protein 
and TLR4 mRNA in the lungs. These results suggest that antioxidants like NAC represent a 
potential additional treatment option that could be considered in the case of an influenza 
A virus pandemic.140 
8. NAC Dramatically Reduces Severity of H1N1 Influenza Viral Infection 
In a study to evaluate the effect of long-term treatment with NAC on influenza and 
influenza-like episodes, 262 subjects (78% > or = 65 years old, and 62% suffering from non-
respiratory chronic degenerative diseases) were enrolled in a randomized, double-blind 
trial involving 20 Italian Centers.  Subjects were randomized to receive either placebo or 
NAC tablets (600 mg) twice daily for 6 months. NAC treatment was well tolerated and 
resulted in a significant decrease in the frequency of influenza-like episodes, severity, and 
length of time confined to bed.  Both local and systemic symptoms were sharply and 
significantly reduced in the NAC group.  Frequency of seroconversion towards A/H1N1 
Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected 
subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo 
group.  Evaluation of cell-mediated immunity showed a progressive, significant shift from 
anergy to normoergy following NAC treatment. 88 
 


page 23 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
9. Side effect profile of NAC 
NAC has been used for over five decades and has an extremely favorable side effect profile.  
It has been studied extensively in innumerable Phase I, II and III trials.  Phase I trials of oral 
n-acetyl cysteine have generally reported minor side effects to include intestinal gas, 
diarrhea, heartburn, bad taste, nausea, fatigue, flushing, stomach aches, constipation, 
burping, hiccups and bloating.148,149 A recent meta-analysis of Phase III trials in patients 
with COPD receiving NAC revealed very common AEs of respiratory tract infection 
(10.85%); common AEs of GI disorders (4.16%) and pruritus (1.08%); and uncommon AEs of 
cerebrovascular disorders (0.9%), dizziness (0.72%) and musculoskeletal disorders 
(0.54%).150  
A recent double-blinded placebo-controlled phase III randomized trial of 60 mechanically 
ventilated patients at high-risk of developing ventilator-associated pneumonia (VAP) were 
randomized between NAC (600 mg twice daily) and placebo via NG tube. Patients treated 
with NAC were significantly less likely to develop clinically confirmed VAP compared with 
patients treated with placebo (26.6% vs. 46.6%; P = 0.032). Patients treated with NAC had 
significantly less ICU length of stay (14.36 ± 4.69 days vs. 17.81 ± 6.37 days, P = 0.028) and 
less hospital stay (19.23 ± 5.54 days vs. 24.61 ± 6.81 days; P = 0.03) than patients treated 
with placebo. Time to VAP was significantly longer in the NAC group (9.42 ± 1.9 days vs. 
6.46 ± 2.53 days; P = 0.002). The incidence of complete recovery was significantly higher in 
the NAC group (56.6% vs. 30%; P = 0.006). No adverse events related to NAC were 
identified in this trial. 
A total of 262 subjects of both sexes (78% ≥65 yrs, and 62% suffering from non-respiratory 
chronic degenerative diseases) were enrolled in a multi-center, randomized, double-
blinded trial. Subjects were randomized to receive either placebo or NAC tablets (600 mg) 
twice daily for 6 months. NAC treatment was well tolerated and resulted in a significant 
decrease in the frequency of influenza-like episodes, severity, and length of time confined 
to bed. Both local and systemic symptoms were sharply and significantly reduced in the 
NAC group. Frequency of seroconversion towards A/H1N1 influenza virus was similar in the 
two groups, but only 25% of virus-infected subjects under NAC treatment developed a 
symptomatic form, versus 79% in the placebo group.88 The treatment with 600 mg NAC 
twice daily was well-tolerated in the large majority of subjects, with only 9% reporting 
adverse events, a figure which was not significantly different from that of the placebo 
group (5%).   
A recent Phase I trial was conducted in which 30 subjects with retinitis pigmentosa 
received NAC in three cohorts of 10 subjects.  Each cohort received 600, 1200 or 1800 mg 
of NAC bid for 12 weeks and then tid for 12 weeks.  There were 11 drug related AEs found 
of which 9 were GI adverse events.  8 AEs resolved spontaneously without dose reduction 
and 3 AEs resolved with dose reduction from tid to bid dosing.  The maximum tolerated 
dose in this trial was 1800 mg twice a day.149 
 


page 24 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
10. Side effect profile of FAM 
The main risks to Famotidine which have been occurred in greater than or equal to 1% of 
subjects in clinical trials are: headache; dizziness; and constipation.   
Other adverse reactions that were reported in less than 1 % of subjects in clinical trials 
include: fever, abnormal weakness or lack of energy; fatigue; heart palpitations; elevated 
liver enzymes; vomiting; nausea; abdominal discomfort; decreased appetite; dry mouth; 
decreased platelet counts in your blood; swelling of the tissue around your eyes; rash; eye 
redness and irritation; difficulty breathing; muscle pain; joint pain; seizure; hallucinations; 
depression; anxiety; decreased interest in sexual intercourse; difficulty falling asleep; 
prolonged sleeping; dry skin; flushing; ringing in your ears; altered sense of taste; and 
difficulty in men with achieving erections capable of intercourse.  The following have also 
been reported during post-approval use of famotidine: changes to your heart by effecting 
the rhythm in which it beats; jaundice; inflammation and possible damage to your liver; 
decreased levels of white blood cells, red blood cells or platelets which could be life 
threatening; allergic reaction which could be life-threatening; rapid swelling of soft tissues 
often involving tissue around the face, limbs or genitals; hives; muscle damage; muscle 
cramps; confusion; agitation; tingling, numbness, or burning sensation in the skin often 
involving hands, feet, arms, or legs; pneumonia; and rash and blistering which could be life 
threatening. 
In a recent prospective trial of patients with Parkinson’s disease, doses of famotidine were 
escalated from 80 mg/day to 120 mg/day to 160 mg/day.   No significant adverse effects 
were observed.151 
11. Possible Reduction in Absorption of NAC due to increased Gastric pH 
It is conceivable that due to the reduction in gastric pH that oral NAC may not be absorbed 
as effectively when given in combination.  In order to mitigate this theoretical possibility, 
we have proposed a phase I trial of the combination of the two investigational drugs with 
twelve possible combinations described in greater detail below.  Three arms are with NAC 
alone.  Additionally, while the trial design should allow us to evaluate the possibility of a 
decreased effectiveness of NAC in combination with FAM, we make the following 
observations to conclude that it is unlikely that the increased gastric pH will decrease the 
absorption of NAC. 
 It has been demonstrated that if NAC is absorbed in its protonated form, NACH2, this 
would have to occur in the stomach because very little NAC exists in this form at a pH 
greater than 4.0.152  Thus, if NAC is only absorbed in the stomach then the combination 
with FAM could virtually negate any effect of NAC as very little might be absorbed.  
However, it was demonstrated in a study of radiolabeled NAC delivered orally to rats that 
NAC was incorporated into the intestinal and liver glutathione stores as early as 30 minutes 
after ingestion.153  Therefore, since NAC exists predominately in its monoanionic form, 
NACH-, in a pH range from 4 to 9,152 this study153 would suggest that NAC can be absorbed 
effectively within the intestines and would likely be transported by some form of an 
anionic transporter, with the Organic Anion Transporting Polypeptide (OATP) B-21 a 


page 25 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
potential candidate.  If a significant amounts of NAC are transported in the intestines as it 
appears, then raising the gastric pH may have little effect since oral NAC is ingested in its 
functional form and doesn’t depend on digestion by gastric enzymes that might be less 
efficient at a higher gastric pH. 
12. Possible Synergistic Effect between FAM and NAC via enhancement of Lymphocytes 
and IL-2 Production 
Famotidine use in a retrospective non-peer-reviewed report has observed to be to be 
associated with a significantly lower risk of death or intubation (10% versus 22%, p <0.01) if 
it was given in the first 24 hours of a patient’s admission to the hospital for a SARS-CoV-2 
infection.154   In this report the dose of famotidine was relatively low as famotidine users 
received a median of 5.8 days of drug for a total median dose of 136 mg (63 to 233 mg). 
 
As was previously discussed IELs are a critical 1st line of defense in coronavirus infections, 
increased levels of IL-2 have been demonstrated to enhance the activity of IELs bovine 
coronavirus infection, and famotidine has been demonstrated to suppress histamine-
inhibition of IL-2 production by IELs.  NAC has the ability to be synergistic with FAM as it 
has also been demonstrated to increase significantly increase T-cell secretion of IL-2 and 
significantly stimulate growth of T-cells.155  Therefore, the combination of NAC and FAM 
have the potential to synergistically create a positive feedback loop to enhance IELs 
defense against coronavirus infection with the potential to dramatically reduce the severity 
of the infection if given early enough in the course of infection. 
  
13. Possible Synergistic Effect between FAM and NAC to counteract effect of IL-6 in 
Prolongation of the QT Interval 
Increased pro-inflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-
syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-
threatening polymorphic ventricular tachycardia such as Torsades de Pointes. Inhibition of 
hERG by Interleukin-6 was demonstrated to underlie the risk for an acquired Long QT in 
Cardiac and Systemic Inflammation.156 
In January of 2020, it was demonstrated that Thioridazine also induces cardiotoxicity vis 
ROS-mediated hERG channel deficiency which was felt might be the ionic mechanism for 
QT prolongation.157  The authors further demonstrated that NAC significantly attenuated 
the hERG reduction induced by THIO and abolished the upregulation of ER stress marker 
proteins. 
While there is some data that famotidine may prolong the QT interval,158 the mechanism 
appears unrelated to hERG inhibition as there are several studies demonstrating that 
famotidine does not inhibit the hERG channel.158–160 Not only may FAM have the ability to 
modulate the Mast Cell expression of IL-6 as a potential mechanism to reduce the risk of 
QT interval prolongation but the ability to modulate the release of histamine and block the 
H2 rector activation is likely to further reduce the risk of QT interval prolongation.   It has 
been demonstrated that activation of the histamine H2 receptor exacerbates myocardial 


page 26 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
ischemia/reperfusion injury by disturbing mitochondrial and endothelial function.161  In fact 
famotidine was demonstrated to abolish the effect of H2R agonists on rat cardiomyocytes 
to induce apoptosis, increase mitochondrial permeability and increase caspase 3 
expression.  
A 2016 study demonstrates that macrolides induced ROS and increased the mitochondrial 
membrane permeability in rat cardiac myocytes.162  The authors make the case based on 
these results and a body of literature about the relationship between MMP and QT interval 
prolongation that, this may be the mechanism in which macrolides can lead to QT interval 
prolongation.  What is most fascinating about this study is that the authors demonstrated 
that NAC reversed the effect on the mitochondria from the macrolides.  
In addition to this data in macrolides, there is also data in mice with a knockout NOS1Ap 
(neuronal nitric oxide synthase-1 adaptor protein), which is associated with QT interval 
prolongation and sudden death, in which oxidative stress was induced by an injection of 
doxorubicin.  The knockout mice compared to WT mice not surprisingly had significant 
prolongation of QT interval, higher rates of ventricular arrhythmias, higher rates of death, 
and higher measured levels of H2O2. Administration of NAC to the knockout mice, 
significantly reduced mortality by doxorubicin injection, accompanied by prevention of QT 
interval prolongation.160  
There is also data in rats which were irradiated while heart monitoring was performed.  
The rats were found to have cardiac injury as observed on the EKG along with significant 
increases in cytokine levels and oxidative stress.  Pretreatment with NAC ameliorated the 
cardiac injury induced by irradiation.163   
Thus, there are at least two potential mechanisms by which NAC and FAM may 
independently reduce a risk of QT interval prolongation that a SARS-CoV-2 infection may 
precipitate by dramatically increasing the level of IL-6. 
In addition to the protection that NAC may provide from IL-6 and perhaps more 
importantly, NAC has been demonstrated to significantly reduce IL-6 levels in viral 
infections.  NAC’s ability to reduce IL-6 levels has been demonstrated in the H5N1 influenza 
A virus,72 H92N2 swine flu virus,140 RSV,70 and HIV.164  
 
14. Depletion of LC3-I is rate limiting in Coronavirus infection and NAC’s demonstrated 
ability to dramatically increase LC3-II to LC3-I ratio  
In addition to the mechanisms of actions previously described, the effect NAC exerts on 
autophagy could prove synergistic in the potential to reduce the severity of a SARS-CoV-2 
infection.  There is a body of literature since 2004 in coronaviruses to include mice 
(MHV),165 pig (PEDV and TGEV)166,167 and most notably the human coronavirus, SARS-
CoV,168 that demonstrates that coronaviruses create Double-Membrane Vesicles (DMV) 
from endoplasmic reticulum under oxidative stress.  It seems that the coronavirus 
components are shuttled around in these DMVs.  It has been demonstrated that depletion 


page 27 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
of LC3-I can be rate limiting in viral replication.169  It seems LC3-II normally decorates 
autophagosomes  and LC3-I normally decorates lysosomes.  It turns out that the 
coronaviruses DMVs are also decorated with LC3-I.  In a 2018 in-vitro study of 
cardiomyocytes and in-vivo in rats, NAC increased the ratio of LC3II/I and reduced LC3-II 
autophagic flux.59  These findings suggest that NAC triggers the accumulation of 
autophagosomes, which is the result either of increased synthesis or decreased 
degradation and that the availability of LC3-I for the formation of DMVs may be 
significantly decreased by NAC.   Therefore, by reducing ROS, inhibiting autophagy, 
inhibiting apoptosis, and potentially limiting LC3-I, these effects would potentially result 
in synergy between FAM and NAC to reduce the severity of a SARS-CoV-2 infection. 
Finally, because the dose limiting toxicity of NAC appears to be an anaphylactoid reaction, 
the combination has the potential to be synergistic if for no other reason than to allow 
higher doses of NAC to be tolerated orally through the action of FAM as an antagonist of 
the histamine-2 receptor.  
    ii) Clinical Significance 
Rationale for a clinical trial 
Given the existing biochemical data to suggest FAM inhibits suppression of intraepithelial 
lymphocytes by histamine and Mast Cell release of histamine; the correlation of severity of 
tissue fibrosis and thrombosis with ACE2 depletion; the ability of NAC to reduce oxidative 
stress, which appears related to severity of the SARS-CoV-2 infection; the ability of NAC to 
prevent tissue fibrosis, thrombosis and reduce viral replication;  the favorable side effect 
profiles of FAM and NAC; the wide prevalence of SARS-CoV-2 infection and its substantial 
mortality rate; and, the lack of vaccine or proven therapies for non-hospitalized patients 
who have tested positive for a SARS-CoV-2 infection; a clinical trial of the safety and 
efficacy of the combination of NAC and FAM is justified. These medications are readily 
available and their combination does have the possibility of reducing the severity of 
infection and mortality for these patients (see figure 9).170 


page 28 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
 
 
 
 
Figure 9: A cartoon drawing170 of the putative effect of FAM to reduce inhibition of Intra-Epithelial 
Lymphocytes and of NAC to reduce severity of infection through reduction of oxidative stress and 
reduction of viral replication 


page 29 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
III) RESEARCH DESIGN AND METHODS (including 
data analysis) 
      i) Study Design - Parallel Phase I/II Clinical Trial 
The proposed parallel phase I/II design allows for simultaneously evaluating the safety and 
efficacy of combination dose levels and to select the optimal combination dose. The trial is 
started with an initial period of dose escalation, and then patients are randomly assigned to 
permissible dose levels.  Bayesian posterior probabilities are used in the randomization to 
adaptively assign more patients to doses with higher efficacy levels.  Combination doses with 
lower efficacy are temporarily closed and those with intolerable toxicity are eliminated.  The 
trial is stopped if the posterior probability for safety, efficacy or futility crosses our pre-specified 
boundaries.   This design has been shown in simulations to save sample size, to have better 
power and efficiently assigns more patients to doses with higher efficacy levels.171   
Phase I Portion (Dose Escalation Phase) 
The doses to be tested for 
famotidine are 20 mg thrice daily, 
40 mg thrice daily, 80 mg thrice 
daily and no famotidine.  The 
doses to be tested for n-acetyl 
cysteine are 600 mg thrice daily, 
1200 mg thrice daily and 1800 mg 
thrice daily.  The dose 
combinations are labelled 1 
through 12 and are zoned as 
illustrated in Figure 10.  The first 
zone has the combination of the 
lowest dose of each drug.  The 
second zone has the combination 
of the lowest dose of each drug 
with the middle dose of each drug.  
The dose escalation starts with the 
first zone and follows with the 
second zone and then each combination of doses in the zone next closest to the coordinate 


page 30 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
origin shown in figure 10.  Combination doses in the same zone are tested simultaneously using 
block randomization to control the number of patients for each open dose.  Some combinations 
doses may close, in which case blocked randomization is applied to the remaining open 
combination doses in the same zone.  A modified “3+3” design172 will be used for the initial 
dose escalation.    
To find acceptable dose levels any grade 3 or higher toxicity will be considered a dose-limiting 
toxicity (DLT).  The modified “3+3” design proceeds as described below.  Three patients receive 
dose level 1.  Their responses determine the subsequent steps as described in the following 
decision rules. 
(1) If two patients (2/3) experience DLT, then we close dose level 1 and all larger doses to 
testing. 
(2) If no patient experiences DLT, then we designate dose level 1 as an admissible dose, and 
open doses in zone 2 for testing. 
(3) If only one of the first three patients (1/3) experiences DLT, then we assign three more 
patients to dose level 1. In this case, we assign up to six patients to this dose, and the 
following decision rules apply: 
a. If only one of the six patients (1/6) experiences DLT, then we designate dose 
level 1 as an admissible dose, and open doses in zone 2 for testing. 
b. If two of the six patients (2/6) experience DLT, then we designate dose level 1 as 
an admissible dose, and doses in zone 2 and higher are closed to testing. 
c. If more than two of the six patients (>2/6) experience DLT, then we close dose 
level 1 to testing, and we also close doses in zone 2 and higher. 
    ii) Study Procedure 
Subjects will be recruited from among patients at a Prisma Health-Upstate Emergency 
Department (ED) at either Greenville Memorial Hospital, Greer Memorial Hospital or Baptist 
Easley Hospital if testing for a SARS-CoV-2 infection is performed and the potential subject 
will be discharged to home from the ED.  Potential subjects who express a desire to be 
evaluated for possible enrollment on trial will have their chart screened by one of the ED 
Investigators to ensure they meet all inclusion criteria without any exclusion criteria.  If they 
have not had an eGFR measured within a year of enrollment, a blood draw will be performed 
to measure their eGFR.  Female participants who are of childbearing potential, i.e., 15 to 55 
years old and have not had their uterus surgically removed (i.e., hysterectomy) or both 
ovaries removed surgically, will have a urine pregnancy test performed.  A pregnancy test will 


page 31 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
not be performed if they would otherwise fit the category of childbearing potential described 
above but are of a confirmed postmenopausal state.  After enrollment and while still in the 
ED subjects will have a blood draw for research labs that will be collected into two tubes.  
One tube will be sent to the main lab where it will be held.  If the subject tests positive for a 
SARS-CoV-2 infection, they will be randomized within 24 hours of a positive test.  A CURB-65 
Assessment Form will be completed by the ED Investigator research staff member and a CAP-
SYM 18 survey will be administered the ED Investigator.  For male subjects an IPSS survey will 
also be completed by the ED Investigator.  All subjects who have been enrolled will be 
provided with a signed copy of their Informed Consent Form, a copy of their signed Research 
HIPPA Authorization form, 30 copies of the daily diary CRF, 4 copies of the medication log 
CRF, an instruction sheet for the Roth Score and 40 Step Test and 4 sterile urine specimen 
containers. 
The randomization process will be performed using the Randomization module within 
REDCAP®.  This will be performed through use of the data entry form entitled,  “COVID-19 
Test Result and Drug Randomization Case Report Form.”  If the subject has a Rapid Test 
Performed in the ED and a positive result is obtained prior to discharge, the Co-Investigator 
who enrolled the subject will be able to access this form an perform the randomization.  
Otherwise, the randomization will be performed by the PI.  Due to the trial design as a Phase I 
trial, the number of subjects on any arm can vary from zero to six depending on any dose 
limiting toxicities that may occur.  Also, a new zone in the trial will not be able to open until 
all subjects in the previous zone have completed the trial.  Therefore, the randomization 
process will be dynamic which REDCap® is incapable of handling directly but is capable of 
handling indirectly in a two-step process as described below.  Prior to the start up the trial, a 
randomization lookup table will be uploaded into REDCap®, which will be nothing more than 
an ordered table from one to one hundred.  While this may seem trivial, it is utterly essential 
in order to harness the power of REDCap® for a dynamic randomization process.  After an 
investigator has performed the randomization task in REDCap®, the randomization number 
will be returned from this table.  The investigator will then be required to lookup manually 
the arm to which the subject has been randomized in a file called “Dynamic Randomization 
Lookup Table” which they will only find within the “File Repository” in REDCap®.  An example 
of this file can be found in the Appendix below.  This file will be created prior to the trial 
initiation by the Lead Statistical Investigator initially assuming three subjects for each trial 
arm.   Anytime, a change is needed to the “Dynamic Randomization Lookup Table” due to a 
DLT, the PI will suspend the ability for anyone to enroll or randomize a subject through the 
“User Rights” feature of REDCap® which can be used to restrict access by role to data entry 
forms.  Once a decision has been made about either expanding or closing a trial arm due to a 


page 32 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
DLT based on the trial rules and assuming the IRB and DSMB which will have also been 
notified of the DLT, have not imposed further restrictions, the PI will obtain from the 
Statistical Lead Investigator a new “Dynamic Randomization Lookup Table.”  The old 
“Dynamic Randomization Lookup Table” will be removed from the REDCap® “File Repository” 
but an electronic copy will otherwise be maintained by the Lead Statistical Investigator.  The 
new “Dynamic Randomization Lookup Table” will be uploaded into the file repository and the 
User Rights to the enrollment and randomization data entry forms in REDCap® will be 
restored.   
After the investigator has determined the trial arm to which the subject has been randomized 
through the two-step process as described above,  the investigator will verify that they 
correctly accessed the “Dynamic Randomization Lookup Table” in the form entitled,  “COVID-
19 Test Result and Drug Randomization Case Report Form.”  The remainder of the form will 
be completed to include entry of the trial arm and verification that the correct prescription 
has been entered.  The subject will be notified of the randomization and prescription entry.  
Whenever, a Randomization CRF is saved, the PI will receive an immediate electronic 
notification via REDCap® and the PI will then complete the Investigator Assignment Form in 
REDCap®, a copy of which can be found in the Appendix.  It is through this form that the 
subject will be assigned to an individual Investigator and an individual Research Assistant for 
the remainder of their trial participation.  The assigned Investigator and Research Assistant 
will be immediately notified electronically via REDCap®.  The subject will be notified by the PI 
to which Investigator and Research Assistant they have been assigned.  Unless the subject has 
declined a Vivify® electronic device, such device, the trial medication and paper copies of the 
medication log and daily diaries will be delivered to the subject’s home within 24 hours of 
randomization by a courier who will have the appropriate training and PPE.  If the subject has 
declined a Vivify® electronic device, they will be required to pick-up their study drugs and 
paper copies of their forms at an Upstate Pharmacy.     
After a subject has been randomized to a combination of trial drugs the Prisma-Health lab will 
be notified to process the first tube of blood for a determination of the subject’s blood type 
and Rh factor.  The second tube will be sent to Kiyatec® to determine their Glutathione level, 
a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα and GM-CSF), and their tryptase level. 
The collected urine sample will also then be sent to Kiyatec® to measure the subject’s F2-
Isoprostane level,  creatinine level, a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα 
and GM-CSF), n-methylhistamine level and TMPRSS2 levels.  The research labs will be held, 
and the tests will only be performed if the subject is randomized to take an investigational 


page 33 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
drug.  Otherwise the specimens will be discarded.  The lab evaluations to be performed by 
Kiyatec® will be kept frozen and typically run in batches of 40.           
If the SARS-CoV-2 test results are negative after enrollment, the subject’s participation in the 
trial will be completed and randomization to an investigational drug will not occur.  An alert 
will be triggered within REDCap® with an immediate electronic notification to the PI both 
when a subject has been enrolled and when they have been randomized.  When a zone has 
completed accrual, a text message will be sent by the PI to all investigators that the trial is 
temporarily closed to accrual, and the enrollment and randomization forms in REDCap® will 
be taken offline.  When all subjects within the current zone have completed the trial, and the 
trial is not closed due to toxicity, the next zone will be opened.  All Investigators will be 
notified by text message from the PI when a new zone is open and the enrollment and 
randomization forms in REDCap® will be placed back online. 
Subjects will be expected to take the dose combination to which they are as assigned and as 
prescribed.  Subjects will record dates and times each medication dose was taken on their log 
forms which will be collected weekly.  Subjects will be contact at least weekly by a Research 
Assistant to monitor symptoms, verify compliance with study drugs and compliance with 
completing medication logs and daily diary.  The Research Assistant will also administer a 
CAP-SYM 18 during this call.  The Research Assistant will communicate any concerns and all 
findings to a study Investigator who will later call the subject to assess how the subject is 
doing, discuss any concerns and will monitor the subject in the performance of a 40 Step Test 
for those subjects provided with an electronic device capable of measuring an Oxygen 
Saturation level unless the Investigator is concerned about the safety of doing so.   Subjects 
will collect a urine sample weekly.  The urine samples and the daily diary and medication log 
CRFs completed by the subject will be delivered by the subject or a family member within 4 
hours of collection by means of the COVID-19 testing car line at Greenville Memorial Hospital.  
The urine specimens will be sent to Kiyatec® to measure the subject’s F2-Isoprostane level,  
creatinine level, a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα and GM-CSF), n-
methylhistamine level and TMPRSS2 levels.  Subjects will self-isolate per current CDC 
recommendations.  Subjects will remain on medication for a minimum of 7 days and unless 
hospitalized will continue on the medications until it has been more than 10 days beyond the 
start of symptoms, symptoms have improved and the subject has been without a fever for at 
least 24 hours without the use of a fever reducing medication.  If subjects are hospitalized, 
then the will instructed to discontinue taking the study medications.  After discontinuing 
study drugs for any reason, the subject will have their blood will be drawn to measure 
Glutathione level, a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα and GM-CSF), and 


page 34 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
their tryptase level; and a urine sample will be collected to measure the subject’s F2-
Isoprostane level,  creatinine level, a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα 
and GM-CSF), n-methylhistamine level and TMPRSS2 levels.    
Responsibilities and those tasks and responsibilities delegated to co-investigators and all 
others participating in the conduct of this trial are specified in the Appendix in the Table with 
the heading, “Responsibilities and Delegated Tasks and Responsibilities” 
  iii) Inclusion / Exclusion Criteria 
Inclusion criteria: 
(1) Age > 18 
(2) performance of a SARS-CoV-2 test within 1 day of enrollment 
Exclusion criteria:  
(1) 
All patients under 18 
(2) 
Known allergy to N-Acetyl Cysteine 
(3) 
Known allergy to famotidine or other H2-receptor antagonists 
(4) 
Pregnant or Nursing Mothers 
(5) 
Laboratory Evidence or History of Renal Impairment (eGFR < 30 
mL/min/1.73 m2)  
(6) 
Taking H2-receptor antagonists, hydroxychloroquine or chloroquine. 
(7) 
Patient has been admitted to the hospital prior to study enrollment 
   iv) Data Collection Methods 
 
Please note that for ease of reference a figure is included in the Appendix of the mapping of 
the Data Collection Instruments to be used in REDCap® with the corresponding events as 
described in outline form below.  
 
a. Enrollment Data Collection Process 
Data will be collected in the ED by a study Investigator by taking a patient history, 
performing a physical exam and performing a chart review to ensure all inclusion criteria 
are meet and that no exclusion criteria exist.  The Investigator will complete the Eligibility 
Assessment CRF, Demographics CRF, IPSS Questionnaire, CAP-SYM 18 CRF and the Post 
Enrollment Checklist directly into REDCap®.  Adobe Acrobat pdf copies of these forms are 
included in the Appendix.  It should be noted that these forms include branching logic 
that will indicate the subject is not eligible for enrollment if they do not meet the 
eligibility criteria, have any excluded conditions or have not had a pregnancy test if 


page 35 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
required.  Additionally, the Post Enrollment Checklist has branching logic to ensure that 
the subject has meet all eligibility criteria without any exclusion criteria being met and 
that all the forms mentioned above have been saved and marked with a status of 
“Complete.”   After the Post Enrollment Checklist has been marked complete, the PI will 
immediately be sent an email via a REDCap® alert which will indicate the Subject’s study 
identification number and the name of the enrolling Investigator. 
b. Post-Enrollment Data Collection Process 
Within 3 days of a positive SARS-CoV-2 test for an enrolled subject, a research assistant 
will complete the Baseline Data form in REDCap®.  The CBC, BMP, Coag, Crp, Liver Panel, 
Pregnancy Test, EKG, Blood Gas and PSA Forms will also be completed in REDCap® if any 
of the corresponding studies were completed within a year prior to enrollment and if so 
only the most recent value will be recorded.  A Starting Medication Form will also be 
completed in REDCap® for every medication the subject is taking at the time of 
randomization.  These Forms can all be found in the Appendix. 
c. Randomization Data Collection Process 
Within 1 day of a positive SARS-CoV-2 test, a subject previously enrolled will be 
randomized to combination of drugs by completing the COVID-19 Test Result and Drug 
Randomization Case Report Form in REDCap®.  If the result is known before discharge 
from the ED this form will be completed by the Investigator in the ED and the PI will be 
immediately sent an email via a REDCap® alert which will indicate the Subject’s study 
identification number and dose combination to which they were randomized.  If the 
SARS-CoV-2 test result is returned after discharge home from the hospital, this form will 
be completed by the PI.  This form also contains a checklist to document, the date of the 
positive result, that the prescription was sent to an Upstate Pharmacy, that the subject 
was contacted to pickup the prescription, that the subject was reminded to complete the 
medication log and daily diary forms.  Within 24 hours of randomization, the PI will 
assign the subject to a non-ER study investigator and research assistant.  The PI will 
notify the subject, investigator and research assistant of these assignments and 
document such in REDCap® using the Investigator Assignment Form. 
 
d. Research Lab Data Collection Process 
The subject’s Blood Type and Rh factor will be entered by the assigned Research 
Assistant directly into REDCap® using the Blood Type Form.  The Cytokine Panel results, 
tryptase level, glutathione level, TMPRSS2 level and n-methyl histamine level will all be 
provided by Kiyatec® in an Microsoft Excel file with fields to identify the Subject ID  
number, days since enrollment for which the specimen was collected and the specimen 
source (i.e., blood or urine).   These files will be converted into a comma-separated 
values format and uploaded into REDCap® by the PI after verification that the field 
names correctly correspond to the field names in the form Cytokine Panel. 
e. Outpatient Follow-up Data Collection Process 


page 36 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
Subjects will be contacted weekly at minimum by the assigned Research Assistant and 
the assigned Investigator.  It will be the responsibility of the assigned Investigator to 
ensure this happens correctly.  Depending how a subject is doing clinically, an 
Investigator will have the discretion to perform more frequent contacts.  These contacts 
will preferably be done with both a video and audio connection for which the Vivify® 
devices are capable.  A telephonic contact will be discouraged but will be permissible for 
those who do not have a Vivify® device or for whom an acceptable audio-video 
connection cannot otherwise be established.   Data will be collected and recorded for 
these contacts on the appropriate REDCap® form, i.e., Research Assistant Weekly 
Assessment, or Investigator Weekly Assessment.  It will be the responsibility of the 
assigned Research Assistant to enter weekly data from the patient’s medication log and 
daily diaries into the REDCap® forms, Daily Medication Log and Daily Diary.  If any new 
medications are started or any non-trial medications are changed by either the 
Investigator or any other provider involved in the subject’s care as documented in EPIC, 
the Research Investigator will document such changes using the REDCap® form, New 
Medications.  At the end of every evaluation by the assigned Investigator, the 
Investigator will document in the REDCap® form their assessment which must be one of 
the following: 1, Continue on Study Without Change; 2, Have made arrangements for 
short interval follow-up with myself; 3, Discontinue Study; 4, Recommend Evaluation in 
ER; 5, Recommend Evaluation by Primary Provider; 6, Recommend Dose Reduction in one 
or both Trial Medications.  If the Investigator Documents any assessment other then 
“Continue on Study Without Change”, an electronic notification will immediately be sent 
to the PI notifying the PI of the Investigator’s Assessment.  If the Investigator’s 
assessment is to recommend a dose reduction, they will be directed to document such on 
the REDCap® form, Trial Drug Adjustment.    Within this form, the new dosages will be 
documented, to include the possibility of discontinuing either or both medications.  
Additionally, the Investigator will be required to identify whether the adjustment is being 
made due to a drug toxicity.  If the Investigator documents that the adjustment is made 
due to a drug toxicity upon saving the form an immediate electronic notification will be 
made to the PI and Chair of the DSMB.  The PI will then complete the REDCap form “NCI 
Adverse Event Serious Adverse Event CTCAE v5.”  This is an extensive form for which the 
PI will complete for any AE or SAE.  It is comprehensive as it includes the entirety of the 
CTCAE v5 to include every possible grade of toxicity.  Through branching logic, it 
minimizes the task of data entry only to the particular organ systems or laboratory values 
involved, an allows the PI to easily document all the data necessary for AE and SAE 
determination so that the IRB, DSMB and FDA can all be notified as necessary and within 
the required timelines as described more fully in the “Protection Against Risk” section 
below.  
f. Hospital Follow-up Data Collection Process 
If a subject becomes hospitalized, the subject’s in-patient provider will be notified that 
the subject was on a clinical trial and of the trial medications the subject was on and any 


page 37 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
other pertinent events that occurred while on trial.  Also the in-patient provider will be 
notified of the trial requirement for a final blood draw to measure Glutathione level, a 
cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα and GM-CSF), and their tryptase 
level; and a urine collection to measure the subject’s F2-Isoprostane level,  creatinine 
level, a cytokine panel (IL-1β, IL-2, IL-6, IL-8, IL-10, IFNγ, TNFα and GM-CSF), n-
methylhistamine level and TMPRSS2 levels.  These labs will be ordered in EPIC® by a 
study investigator.  On a weekly basis the assigned Research Assistant will review the 
subject’s chart in EPIC to review for any of the following: C Reactive Protein blood draw; 
EKG, Blood Gas; new medications; COVID19 NP swab; supplemental oxygen start or 
change; intubation; extubation;  supplemental oxygen decreased or stopped; ICU 
admission; ICU discharge; SARS-CoV-2 serum antibody test; and, hospital discharge.  A 
corresponding form for any such event will be completed in REDCap®. 
g. Study Completion Data Collection Process 
 Upon completion of Study, the REDCap® form, Completion Data will be completed.  
     v) Data Analysis Methods 
Data will be exported from REDCap® using the Data Export Tool into a format that can be 
analyzed using R, JMP and/or SAS (SAS, Cary, NC).  The User Rights in REDCap® will restrict 
the use of the REDCap® “Data Export Tool” to only the PI, Epidemiologist and the Statistical 
Co-Investigators.  The rights will be further restricted within REDCap® such that only De-
Identified data can be exported from Data Export Tool.  Therefore, because no date or time 
fields can be extracted from REDCap® as described above, any Data Entry Form within 
REDCap® that collects a date has been created to include a hidden calculation field to 
calculate and store the number of days between such a date and either the enrollment date 
or the medication start date.  Some dates are calculated based on the medication start date 
to make data collection easier on certain forms; however, the number of days between 
enrollment and medication start is also calculated and stored so that any number of elapsed 
days can easily be determined from either.  After the data has been exported from REDCap 
into an aforementioned statistical package and descriptive statistics have been generated 
and analyzed by the Statistical Investigators.  These results will be shared with the 
Epidemiologist and all Investigators so that appropriate conclusions can be reached and 
ultimately disseminated. 
   vi) Limitations of the Proposed Study Design 
This is a phase I trial and may be limited by unmeasured confounders such as clinical practice 
patterns of the providers ordering initial SARS-CoV-2 testing.  It also may be limited as 
subjects are being recruited directly from the ED and thus may be more symptomatic or have 
other unmeasured cofounders as compared to the general population who may become 
infected with SARS-CoV-2.   
 
 


page 38 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
IV) PROTECTION OF HUMAN SUBJECTS 
      i) Risks To The Subjects 
The main risks to Famotidine which have been occurred in greater than or equal to 1% of 
subjects in clinical trials are headache; dizziness and constipation.   
Other adverse reactions that were reported in less than 1 % of subjects in clinical trials 
include: fever, abnormal weakness or lack of energy; fatigue; heart palpitations; elevated 
liver enzymes; vomiting; nausea; abdominal discomfort; decreased appetite; dry mouth; 
decreased platelet counts in your blood; swelling of the tissue around your eyes; rash; eye 
redness and irritation; difficulty breathing; muscle pain; joint pain; seizure; hallucinations; 
depression; anxiety; decreased interest in sexual intercourse; difficulty falling asleep; 
prolonged sleeping; dry skin; flushing; ringing in your ears; altered sense of taste; and 
difficulty in men with achieving erections capable of intercourse.  The following have also 
been reported during post-approval use of famotidine: changes to your heart by effecting the 
rhythm in which it beats; jaundice; inflammation and possible damage to your liver; 
decreased levels of white blood cells, red blood cells or platelets which could be life 
threatening; allergic reaction which could be life-threatening; rapid swelling of soft tissues 
often involving tissue around the face, limbs or genitals; hives; muscle damage; muscle 
cramps; confusion; agitation; tingling, numbness, or burning sensation in the skin often 
involving hands, feet, arms, or legs; pneumonia; and rash and blistering which could be life 
threatening. 
The main risks to N-Acetyl Cysteine include but are not limited to the following: allergic 
reaction which could be life threatening; rash; itching; nausea or vomiting. 
    ii) Total Planned Enrollment 
Estimated Number of Subjects: 42 
We estimate a sample size of around 42 subjects for a 3+3 dose escalation period of our 
parallel phase I/II trial design.  Based on our simulation of the phase I period of the trial 
and an assumption that a drug limiting toxicity ranges between 5% and 8%, we found an 
83% chance that between 27 and 33 subjects would be required.  During the adaptive 
phase of our trial with predicted rates of hospitalization ranging from 20 to 5% as shown in  
  iii) Does this study involve any of the following: prisoners, 
pregnant women, children, institutionalized individuals, or other 
populations that may be considered vulnerable? 


page 39 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
No 
   iv) Does this study seek to exclude a specific racial, ethnic, or 
gender group? Include a compelling rationale if so. 
No 
     v) Sources of Materials 
Data will primarily be abstracted via chart review and patient’s history and physical exam and 
by patient completed medication logs and daily diary of temperature and symptoms.  Data of 
Oxygen saturation level and vital signs will also be obtained directly from the subjects Vivify® 
device. 
 
 


page 40 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
V) ADEQUACY OF PROTECTION AGAINST RISKS 
      i) Recruitment and Informed Consent 
See attached Informed Consent Form. 
    ii) Protection against Risk 
Prerana Roth, M.D., will serve as the medical monitor and will chair an internal Data and 
Safety Monitoring Board to ensure the safety of all subjects and their data. 
It is essential that all AEs, including serious adverse events (SAEs), which occur during the 
course of research subjects' involvement in a study are appropriately identified, documented, 
reported, and managed in order to ensure the subjects' continuing safety. This is the 
responsibility of the investigative site. 
The PI will Complete in REDCap® an NCI Adverse Event Serious Adverse Evet CTCAE v5 form 
within 24 hours of notification of an adverse event by a subject, research assistant, co-
investigator, outside provider or by any other means in which this information may be 
obtained.  If the event is life-threatening or fatal, this form will be completed immediately, 
and the event will be reported immediately to Dr. Roth and the IRB.  Whenever this form is 
completed by the PI, an email will be immediately sent Dr. Roth and any other individuals 
specified by Dr. Roth.  Whenever this form is completed by the PI and a Serious Adverse 
Event has occurred, an email will be immediately sent via the REDCap® alert mechanism to 
the IRB Chair and any other individuals specified by the IRB.   This copy of this form can be 
found in the Appendix and includes all the elements described below.  
Adverse Event (AE) 
An AE in this clinical trial is defined as any unfavorable change in a research subject that 
may occur during or after administration of the investigational drugs.  There need be no 
causal relationship to the investigational drugs and may be due to the SARS-CoV-2 
infection or for any other reason. This change does not have to be caused by the 
investigational product or study procedures to be described as an AE. 
 AEs may include: 
• Physical signs or symptoms 
• Abnormal laboratory values 


page 41 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
• Changes in vital signs, physical examinations or an electrocardiogram 
(ECG) 
• An increase in the frequency or intensity (worsening) of symptoms that 
were present before study enrolment 
• Complications from procedures or a surgery 
• Psychological, economic, or social harm 
Causality Determination 
All AEs will be assessed by either the sponsor-investigator and a determination of causality 
will be made as described below.   Causality refers to the likelihood and extent that the 
investigational drugs being studied contributed to the development of an AE. Because the 
determination of causality involves medical decision making, only investigators as 
described above who have medical expertise will be making the causality or relationship 
determination.  Any determination of causality will be reviewed by the Sponsor-
Investigator and the Data and Safety Monitoring Board. If it is determined that an AE is 
related to the investigational drugs, required reporting to the IRB and FDA will be made in 
accordance with the required regulations. 
When determining causality, the investigator will consider: 
• 
Elimination of other causes 
• 
Effect of the drug or drug class 
• 
Temporal sequence 
• 
Chronic effects 
• 
Cumulative effects 
• 
Late effects 
• 
Re-challenge 
Causality categories will include the following: 
• 
Definitely related: There is a certainty that the event is related to the 
investigational product. 
• 
Probably related: There is high likelihood that the event is related to the 
investigational product. 
• 
Possibly related: There is a likelihood that the investigational product is the 
cause of the event, but other causes cannot be ruled out. 
• 
Unlikely to be related: It is not likely that the event is related to the 
investigational product, and other more likely causes are present. 
• 
Unrelated: Evidence exists that the event is related to something other than 
the investigational product. 
Criteria for determining the causality category will be made as described in the below 
table. 
 


page 42 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
Determination of Causality Category of AEs as Related to the 
Investigational Drugs 
Definite 
(must 
have all 
four [4]) 
1. Has a reasonable temporal relationship to the 
investigational drugs 
2. Could not have readily been produced by the 
subject's clinical state or have been due to 
environmental or other interventions 
3. Follows a known pattern of response to the 
investigational drugs 
4. Disappears or decreases with reduction in dose or 
cessation of study drugs and recurs with re-
exposure 
Probable 
(must 
have 
three [3]) 
1. Has a reasonable temporal relationship to the 
investigational drugs 
2. Could not have readily been produced by the 
subject's clinical state or have been due to 
environmental or other interventions 
3. Follows a known pattern of response to the 
investigational drugs 
4. Disappears or decreases with reduction in dose or 
cessation of study drugs and recurs with re-
exposure 
Possible 
(must 
have two 
[2]) 
1. Has a reasonable temporal relationship to the 
investigational drugs 
2. Could not have readily been produced by the 
subject's clinical state or have been due to 
environmental or other interventions 
3. Follows a known pattern of response to the 
investigational drugs 
4. Disappears or decreases with reduction in dose or 
cessation of study drugs and recurs with re-
exposure 
Unlikely 
(must 
1. Does not have a temporal relationship to the 
investigational drugs 


page 43 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
have two 
[2]) 
2. Could readily have been produced by the subject's 
clinical state 
3. Could have been due to environmental or other 
interventions 
4. Does not follow a known pattern of response to the 
investigational drugs 
5. Does not reappear or worsen with reintroduction of 
investigational drugs 
 
Duration of AEs 
 
Another important element for evaluation of an AE is the duration of the event. Onset of 
the event will be measured from the onset of signs and symptoms. Resolution of the event 
will be recorded as well, which we will define as the point when all signs and symptoms 
have subsided. 
Some events continue or change in severity over time. Capturing this information is also 
important. Changes in severity such as when an event improves from severe to mild will be 
recorded as separate events, with separate intensities and durations collected. The 
ongoing nature of the event will be noted in the subject's research record. 
 
Determining Severity 
An important component in evaluating AEs is their severity. Severity refers to the intensity 
of the event and will be indicated as mild, moderate, or severe, as shown in the table 
below. 
 
Grading of Severity of AEs Based on Signs and Symptoms 
None 
No signs/symptoms or within normal limits 
Mild 
Minor signs/symptoms; no specific medical intervention 
required; asymptomatic laboratory findings only, 
radiographic findings only; marginal clinical relevance 


page 44 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
Moderate 
Requiring minimal, local, or non-invasive intervention only 
Severe 
Significant symptoms requiring hospitalization or invasive 
intervention 
Life-
threatening 
or 
disabling 
Complicated by acute, life-threatening metabolic, or 
cardiovascular complications (such as circulatory failure, 
hemorrhage, sepsis); life-threatening physiological 
consequences; or need for intensive care or emergent 
invasive procedure 
Fatal 
Causing death 
 
Serious Adverse Event (SAE) 
A grade of severe is not the same as serious. Serious is a specific term used in determining 
whether AEs must be reported to sponsors and regulatory agencies. SAEs, regardless of 
severity, demand immediate action and attention. A serious adverse event (experience) or 
reaction is any untoward medical occurrence that at any dose: 
• 
Results in death; 
• 
Is life-threatening (and puts subject at immediate risk of death); 
N.B., The term "life-threatening" in the definition of "serious" refers to an 
event in which the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity; or 
• 
Is a congenital anomaly/birth defect. 
 
Medical and scientific judgement will be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These will also usually be considered serious. 


page 45 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Reporting Requirements for AEs/SAEs 
Clinical Co-Investigators and Sponsor-Investigator’s Responsibilities: 
All SAEs will be reported to the IRB within twenty-four (24) hours of their identification. 
If the event is life-threatening or fatal, the event will be reported immediately. 
Expedited reporting to regulatory agencies is generally not required for events that are 
either: 
• 
Serious but expected 
• 
Not reasonably related to the investigational drugs 
These latter events, if serious, will still be reported to the IRB.  Because all SAEs are still 
adverse events, they will be recorded on a Form FDA 3500A, which is the MedWatch 
Mandatory Reporting form.  
Sponsor-Investigator's Responsibilities: 
The Sponsor-Investigator will report SAEs that are unexpected and associated with the 
use of the investigational drugs to the US FDA within specific time periods. This report is 
an Investigational New Drug (IND) Safety Report. The objective of rapid notification is to 
protect subjects participating in this trial of the investigational drugs. 
Unexpected adverse event or suspected adverse reaction refers to an event or reaction 
that is not listed in the investigator’s brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator’s brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan or 
elsewhere in the current IND application. 
• Initial reporting: The sponsor-investigator will report any suspected adverse 
reaction or adverse reaction to study treatment that is both serious and 
unexpected.  
Unexpected fatal or life-threatening suspected adverse reactions represent 
especially important safety information and will be reported to FDA as soon as 
possible but no later than 7 calendar days following the sponsor-investigator’s 
initial receipt of the information. 
• Follow-up reporting: Any relevant additional information obtained by the sponsor-
investigator that pertains to a previously submitted IND safety report will be 
submitted as a Follow-up IND Safety Report. Such report will be submitted without 
delay, as soon as the information is available but no later than 15 calendar days 
after the sponsor-investigator receives the information.   


page 46 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
All IND safety reports will be submitted on Form FDA 3500A and will be accompanied by 
Form FDA 1571. The type of report (initial or follow-up) will be checked in the respective 
boxes on Forms 3500A and 1571. 
The submission will be identified as: 
• “IND safety report” for 15-day reports, or 
• “7-day IND safety report” for unexpected fatal or life-threatening suspected 
adverse reaction reports, or 
• “Follow-up IND safety report” for follow-up information. 
The report will be submitted to the appropriate Review division that has the 
responsibility to review the IND application under which the safety report is submitted. 
The sponsor-investigator will submit all safety reports electronically.  
Once an IND Safety Report is filed with the FDA, the sponsor-investigator will notify the 
IRB, the Chair of the Data and Safety Monitoring Board and all the clinical co-
investigators participating in this clinical trial.    
Data and Safety Monitoring Board Responsibilities 
The Data and Safety Monitoring Board in consultation with the IRB a will determine if the 
trial or trial arm needs to be temporarily or permanently closed or if any required 
modifications to the informed consent form and notification to research subjects are 
required. 
  iii) Potential benefits of this research to the subjects 
The combination of famotidine and n-acetyl cysteine may be of potential benefit to the 
enrolled subjects as it may reduce the severity of their SARS-CoV-2 infection and potentially 
reduce the risk of hospitalization. 
   iv) Potential benefits of this research to society 
Potential benefits to society include determination if the combination of famotidine and n-
acetyl cysteine is safe and may improve clinical outcomes in patients suffering from SARS-
CoV-2 infection. 
 
 


page 47 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
    VI) SUBJECT SAFETY AND MINIMIZING RISKS 
(Data and Safety Monitoring Plan) 
  i) Is this study a clinical trial? 
Yes 
    ii) What is the Data Safety plan for this study? If this study is a 
clinical trial, please include a detailed description of the Data and 
Safety Monitoring Plan. 
At the time of consent the Data Safety Plan will be discussed with the subject and the subject 
will be required to sign a CIRB Research HIPAA Authorization Form in addition the trial 
informed consent form.  The trial consent form and the CIRB Research HIPPA Authorization 
Form will be kept together with all Paper CRFs in a locked room when not occupied by 
qualified research staff or in a locked cabinet.  No PHI will be recorded on paper CRFs.   All 
electronic data will be kept on the REDCap® server within the forms as described previously.  
A copy of the REDCap® Codebook can be found in the Appendix.  Access to the REDCap® 
project for this trial will be restricted to study personnel.  The ability to export data from 
REDCap® will be restricted to the Statistician Co-Investigators, the Epidemiologist and the PI.  
All patient identifier fields are identified in REDCap®, and data will only De-Identified Data 
can be exported.  A figure depicting the assigned rights as organized by role with REDCap® 
can be found in the Appendix.   No paper copies of an identification key will be created or 
maintained.  It is anticipated that within 30 days of trial completion all database records 
containing any PHI will be de-identified. 
 
 


page 48 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
VII) CONSULTANTS 
      i) Academic Partner Institutions 
Clemson University, School of Mathematical and Statistical Sciences 
Deborah Kunkel, PhD, (effort in-kind): Dr. Kunkel is a statistician with expertise in 
Bayesian statistical methodology. Dr. Kunkel will perform the mathematical derivations 
required for the design of the proposed parallel phase I/II trial.  She and Dr. Rennert 
will oversee power calculations and all subsequent data analysis. 
Clemson University, College of Behavioral, Social and Health Sciences 
Lior Rennert, PhD, (effort in-kind): Dr. Rennert is an expert biostatistician with expertise 
in collaborative health research. Dr. Rennert has 10 years of experience with power 
calculations and application of statistical models for clinical trial data.  
Corey Kalbaugh, PhD, (effort in-kind): Dr. Kalbaugh is an Assistant Professor at Clemson 
University and an expert epidemiologist.  He will be instrumental in the writing, study 
design and execution of this research especially as it pertains to the phases following 
this trial and subsequent research trials as appropriate.  Additionally, he will have a 
leading role in overseeing the analysis of the data. 
University of South Carolina School of Medicine Greenville 
David Pritchett: Mr. Pritchett is a second-year medical student at the University of South 
Carolina School of Medicine Greenville and has an undergraduate degree in Chemistry 
from Furman University.  He will assist primarily with data collection. 
Benjamin Hutto: Mr. Hutto is a second-year medical student at the University of South 
Carolina School of Medicine Greenville and has an undergraduate degree in from USC-
Aiken.  He will assist primarily with data collection. 
Josiah McDonald: Mr. McDonald is a second-year medical student at the University of 
South Carolina School of Medicine Greenville.  He will assist primarily with data 
collection. 
Halee Bryant Vaughn: Ms. Vaughn is a fourth-year medical student at the University of 
South Carolina School of Medicine Greenville. She will assist primarily with data 
collection. 
    ii) Non-academic Partner Institutions 
Timothy F. McTigue, M.D., (effort in-kind): Dr. McTigue is an ER Physician who is Board 
Certified in Internal Medicine and Pediatrics and is an independent contractor serving 
as a consultant in the intellectual development and writing of the trial.  He also will 
assist in the data analysis. 


page 49 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
VIII) FACILITIES AVAILABLE 
Facilities include Greenville Memorial Hospital, Greer Memorial Hospital, Baptist Easley 
Hospital. 
 
 


page 50 
O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
Hutto, McDonald, Orsky, McTigue and Edenfield.  A Phase I Clinical Trial for the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine 
(NAC) Open Label for Outpatient Treatment of Subjects with Newly Diagnosed SARS-CoV-2 Infection 
IX) APPENDICES 
 
List of Separate Attachments  
Schedule of Assessments 
 
Medication Log Form (N.B., Provided to Subject) 
 
Daily Diary (N.B., Provided to Subject) 
 
Instruction Sheet for Roth Score and 40 Step Test (N.B., Provided to Subject) 
Figure of REDCap® Data Entry Forms Mapped by Event 
 
Table of Contents of REDCap® Data Entry Form Attachment 
 
Responsibilities and Delegated Tasks and Responsibilities 
Study Personnel and Roles 
Figure of REDCap® User Rights 
 
Prisma-Health Clinical Guidance 
 
 
 
 
 


List of Separate Attachments 
1. Prisma Health Upstate Informed Consent Form 
2. CIRB Research HIPPA Authorization Form 
3. REDCap® Data Entry Forms (See following Table of Contents) 
4. Randomization Allocation Table Dev (Sample Used in Development Status) 
5. Sample Dynamic Randomization Table (Sample Used in Development Status) 
6. REDCap® Codebook 
7. Sample NCI AE/SAE CTCAE v5 REDCap® form (with saved data) 
8. NCI AE/SAE CTCAE v5 REDCAP® form (comprehensive with branching logic) 
 
 


 
Schedule of Assessments 
 
Schedule of Assessments:  Trial of  FAM and NAC for SARS-CoV-2 
Assessment 
Enrollment 
(within 24 
hours of a 
SARS CoV-
2 Test) 
Weekly after 
Randomization 
Until Hospital 
Admission or 
Study 
Completion 
Upon Study 
Completion (If 
SARS CoV-2 
Positive) 
If Hospitalized and 
Until Discharge 
Informed Consent  
X 
 
Urine Pregnancy Test  
(If appropriate) 
X 
Blood Type and Rh 
X 
 
(Serum) 
Cytokines 
(IL-1β, IL-2, IL-6, IL-8, 
IL-10, IFNγ, TNFα and 
GM-CSF), Tryptase and 
Glutathione Level  
X 
 
X  
 
X  
(once upon 
hospitalization) 
(Urine) 
F2-Isoprostane/Creatinine 
Ratio, TMPRSS2 
Cytokines (IL-1β, IL-2, 
IL-6, IL-8, IL-10, IFNγ, 
TNFα and GM-CSF) and 
N-methylhistamine  
X 
X 
X 
 
X  
(once upon 
hospitalization) 
CURB-65 Score 
X 
 
CAP-Sym 18 
X 
X 
X 
 
IPSS (men only) 
X 
 
X 
 
Weekly Review of Daily 
Medication Logs and 
Daily Diary 
 
X 
 
 
Weekly Assessment CRFs 
 
X 
 
 
Completion Data CRF 
 
 
X 
 
Hospital Tracking CRFs 
 
X 
 
 


 
Medication Log Form 
Medication Log Form: Trial of FAM and NAC for SARS-CoV-2 
Subject Study Number: _______________________    Week #: _____________ 
Day of Week Trial Started: ____________(fill this in by hand under Day 1 below) 
Dose of Famotidine 20 mg tablets Assigned to Taken Thrice Daily:         0   1   2   3  
(Research Staff to Circle) 
 
Number of N-Acetyl Cysteine Capsules Assigned to Take Thrice Daily:   1   2   3       
                   (Research Staff to Circle)    
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day of Week 
 
 
 
 
 
 
 
Date (MM/DD) 
 
 
 
 
 
 
 
Famotidine (20 mg tablet) 
1st   Dose  
 
 
 
 
 
 
 
2nd  Dose  
 
 
 
 
 
 
 
3rd   Dose  
 
 
 
 
 
 
 
N-Acetyl Cysteine (600 mg capsule) 
1st    Dose 
 
 
 
 
 
 
 
2nd  Dose 
 
 
 
 
 
 
 
3rd   Dose 
 
 
 
 
 
 
 
Instructions for Research Staff: 
1. Print a minimum of 4 Sheets and enter Subject Study Number on each.  Write in week numbers 
1 to 4 on each sheet. 
2. Enter Day of Week Subject is to start taking medicine.  This should be the same for each sheet. 
3. Under Day 1 enter the day of the week that subject is to start taking medicine.  Under each 
subsequent Day enter the next day of the week. 
4. Circle the assigned number of Famotidine tablets to take thrice daily. 
5. Circle the assigned number of N-Acetyl Cysteine capsules to take thrice daily. 
 
Instructions for Research Subject: 
1. You will be assigned to take one, two or three Famotidine tablets three times a day.  Please 
enter the time of day for the correct day for each dose you take.   
2. You will take the N-Acetyl Cysteine capsules thrice a day.  You will be assigned to take one, two 
or three capsules each time.  Please enter the time of day for the correct day for each dose you 
take. 
3. Please note that the days of each new week should correspond to the same day of the week you 
started on the trial which won’t necessarily be a Monday or Sunday. 
4. Please call the study coordinator if you have any questions.  If you cannot get a hold of the study 
coordinator, then please call the Principal Investigator, John Joseph O’Connell, M.D., at any time 
day or night at (864)679-3900. 
 


 
Daily Diary 
Daily Diary: Trial of FAM and NAC for SARS-CoV-2 
Subject Study Number : __________________________________    Week #: __________________________ 
Day of Week Trial Started: __________________________________(fill this in by hand under Day 1 below)__ 
 
DAY 1 
DAY 2 
DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Day of Week 
 
 
 
 
 
 
 
Date (MM/DD) 
/ 
/ 
/ 
/ 
/ 
/ 
/ 
 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Time 
___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ ___:___ 
Temperature 
___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F ___._°F 
O2 Sat  
Pulse 
Blood Pressure 
Roth Score 
 
Symptoms 
0 indicates absence of symptom; 1 is mild; 3 is moderate; and 5 is severe  
Felt Feverish (0 to 5)        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cough (0 to 5)               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shortness of Breath/Difficulty 
Breathing (0 to 5)        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest Pain (0 to 5)       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chills (0 to 5)                
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Muscle Pain (0 to 5)    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sore Throat (0 to 5)     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (Y/N) Specify Below 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Notes 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
_______________________________________________________________________________________________________________________ 
Instructions for Research Subject: 
1. Please take your temperature twice daily, once in the morning and once after noon.  Please record your temperature in Fahrenheit to a 
single decimal point.  If you take your temperature more than once during a time period, please record only the highest temperature 
during that time period.  Please record the time you took your temperature.  
2. Please record a value for every listed symptom twice a day on a scale of 0 to 5.  0 should indicate the absence of the symptom with 1 
indicating mild, 3 moderate and 5 severe. 
3. If you are experiencing any other symptoms, please indicate with a Y and describe below.  
4. Please call the study coordinator if you have any questions.  If you cannot get a hold of the study coordinator, then please call the 
Principal Investigator, John Joseph O’Connell, M.D., at any time day or night at (864)679-3900. 


Instruction Sheet for Roth Score and 40 Step Test 
Roth Score 
The Roth Score has not been proven to be an effect measure of one’s respiratory status and may lead 
to a false reassurance.  It has not been previously studied in patients with a SARS-CoV-2 infection.  If 
you feel your ability to breathe is worsening, you should seek medical attention immediately.  We are 
asking you to perform this test daily for research purposes so that we can better understand the 
severity of a SARS-CoV-2 infection.  It is possible that we may learn that changes in the Roth Score 
together with other objective measures may allow us to understand earlier predictors for severity of a 
SARS-CoV-2 infection. 
To perform this test correctly you will need to take a deep breath followed by counting out loud from 
1 to 30 in your native language, in a single breath, as rapidly as possible.  You should stop your count 
when you reach 30 or take another breath whichever comes first.  You will also need to use a 
physical or electronic stopwatch with a second hand and measure in seconds the time it takes 
between your count of 1 and the highest number you achieve.  The result of the Roth score includes 
2 measurements: (1) the duration of time elapsed between counting from 1 to 30 in 1 breath, or until 
the you take another breath; and (2) the highest number you reach in 1 breath.  The first 
measurement is known as the “counting time” and this should be entered your Daily Diary in the row 
labelled “Roth Score” under the AM column.  The second measurement is known as the “maximal 
count” and should be entered under the PM column.  You only need perform this test once daily and 
ideally around the same time of day. 
 
40 Step Test 
The 40 Step Test should only be performed under the direct supervision of a health care provider and 
for the purposes of this trial will be done during your weekly virtual visit with one of the trial 
investigators.  There is no evidence that this test is harmful; however, its safety has also not been 
conclusively proven.  This test has not been studied previously in patients with a SARS-CoV-2 infection.  
This test is an exertional desaturation test and a determination will be made by the study investigator 
at the time of your weekly virtual visit.  You will not have to perform this test if you are uncomfortable 
or unable to do so. 
This test will only be administered if you were provided a pulse oximetry device.  You will be asked to 
measure oxygen saturation prior to beginning this test.  You will then be asked to walk 40 steps on a 
level surface, and you will then measure your oxygen saturation after completing your 40 step walk.  
      
 
 
 
 
 
 
 
 


 
Figure of REDCap® Data Entry Forms Mapped by Event 
 
N.B. Not all forms are required and most have very few data fields but allow for multiple instances and 
thus were created as separate data entry forms 
 


 
Table of Contents of REDCap® Data Entry Form Attachment 
 
Eligibility Assessment CRF 
 
 
Page 
1 
 
Demographics CRF 
 
Page 
4 
 
CURB-65 CRF  
 
Page 
6 
 
IPSS CRF 
 
Page 
7 
 
CAP-SYM 18 CRF 
 
Page 
9 
 
Post Enrollment Checklist CRF 
 
Page 11 
 
Baseline Data CRF 
 
Page 13 
 
CBC CRF 
 
Page 19 
 
BMP CRF 
 
Page 21 
 
Coag CRF 
 
Page 22 
 
Liver Panel CRF 
 
Page 23 
 
C Reactive Protein CRF 
 
Page 24 
 
Pregnancy Test CRF 
 
Page 25 
 
EKG CRF 
 
Page 26 
 
Blood Gas CRF 
 
Page 28 
 
PSA CRF 
 
Page 29 
 
Starting Medications CRF 
 
Page 30 
 
COVID-19 Test Result and Drug Randomization CRF 
 
Page 31 
 
Investigator Assignment CRF 
 
Page 36 
 
Trial Drug Adjustment CRF 
 
Page 40 
 
Daily Medication Log CRF 
 
Page 42 
 
Daily Diary CRF 
 
Page 43 
 
New Medications CRF 
 
Page 46 
 
Research Assistant Weekly Assessment CRF 
 
Page 47 
 
Investigator Weekly Assessment CRF 
 
Page 48 
 
Blood Type CRF 
 
page 52 
 
Cytokine Panel CRF 
 
Page 53 
 
COVID 19 NP Swab Results CRF 
 
Page 54 
 
Hospital Admission CRF 
 
Page 55 
 
Supplemental Oxygen Started or Increased CRF 
 
Page 56 
 
Intubation CRF 
 
Page 57 
 
Extubation CRF 
 
Page 58 
 
Supplemental Oxygen Decreased or Stopped CRF 
 
Page 59 
 
ICU Admission CRF 
 
Page 60 
 
ICU Discharge CRF 
 
Page 61 
 
Hospital Discharge CRF 
 
Page 62 
 
Completion Data CRF 
 
Page 63 
 
Antibody Results CRF 
 
Page 64 
 
 
 
 
 
 
 
 


Responsibilities and Delegated Tasks and Responsibilities 
Responsibilities 
Investigator-
Sponsor 
Clinical Co-
Investigators 
Epidemiologic 
and Statistician 
Co-
Investigators 
Pharmacy Co-
Investigators 
Consultants/ 
Senior Medical 
Mentor 
Study 
Coordinator 
Research 
Assistants 
Data And 
Safety 
Monitoring 
Committee 
Study design and 
general 
coordination of 
research 
X 
 
 
 
 
 
 
 
Advise and Support 
in Study Design 
and Conduct of 
Research 
 
X 
X 
X 
X 
X 
X 
X 
Recruit eligible 
subjects 
X 
X 
 
 
X 
 
 
 
Screen eligible 
subjects  
X 
X 
 
 
X 
X 
X 
 
Obtain informed 
consent 
X 
X 
 
 
X 
 
 
 
Conduct research 
procedures 
involving direct 
interaction with 
subjects 
X 
X 
 
 
X 
 
 
 
Prescribe Study 
Drug 
X 
X 
 
 
X 
 
 
 
Weekly Calls with 
Individual Subjects 
to Review 
Compliance with 
taking Assigned 
Study Drugs, 
X 
X 
 
 
X 
X 
X 
 


 
Completing 
Medication Log 
and Daily Diary. 
Administer CAP 
SYM 18 Survey 
and Ensure Urine 
Specimen has been 
dropped off by 
Subject 
Weekly Review of 
Inpatients Records 
of Subjects who 
have been 
Hospitalized 
X 
X 
 
 
X 
X 
X 
 
Coordinate clinical 
laboratory tests or 
support 
X 
X 
 
 
X 
X 
X 
 
Coordinate research 
laboratory assays, 
tests, or support 
X 
X 
 
 
X 
X 
X 
 
Coordinate 
Pharmacy support 
(i.e. storage, 
inventory, and 
dispensing of all 
investigational 
drugs used in the 
research) 
X 
 
 
X 
 
X 
X 
 
Data entry 
X 
X 
X 
 
X 
X 
X 
 
Data analysis 
X 
X 
X 
X 
X 
X 
X 
X 
Storing/sharing 
research data  
X 
X 
X 
 
X 
X 
X 
 


 
Storing research 
protocol documents 
(including 
consent/information 
sheets) 
X 
X 
 
 
X 
X 
X 
 
Storing/sharing 
specimens for 
current research 
X 
X 
 
 
X 
X 
X 
 
Reporting to IRB, 
institutional 
officials, and /or 
sponsor - 
unanticipated 
problems involving 
risks to subjects or 
others, adverse 
events, and serious 
or continuing non-
compliance  
X 
X 
 
 
X 
X 
 
X 
Establishing 
procedures to 
ensure subject 
privacy and 
confidentiality of 
research data  
X 
 
 
 
 
X 
 
 
Continuing Review 
by the IRB 
X 
 
 
 
 
X 
 
 
Post-approval 
monitoring of the 
conduct of the 
research 
X 
X 
 
 
X 
X 
 
X 


 
Data monitoring 
plan – coordination 
and communication 
X 
X 
 
 
X 
X 
 
 
Clearance of 
research-related 
publications or 
presentations 
X 
 
 
 
 
 
 
 
Review of All 
Adverse Events 
X 
X 
 
 
X 
 
 
X 
Authority to 
Temporarily Halt 
Conduct of 
Research 
X 
X 
X 
X 
X 
 
 
X 
Weekly 
Calculations of 
Posterior 
Probabilities and 
Decision to 
Temporarily Close 
Treatment Arms 
due to Relative 
Ineffectiveness In 
Accordance with 
Trial Design and 
Pre-Determined 
Temporary 
Stopping Rules 
 
 
X 
 
 
 
 
 
Permanent Closure 
of Treatment Arms 
or Trial Due to 
Futility or Dose 
Limiting Toxicities 
In Accordance with 
 
 
X 
 
 
 
 
 


 
 
 
 
Trial Design and 
Pre-determined 
Stopping Rules 
Randomization to 
Assigned 
Treatment Arm at 
Time of Enrollment 
 
 
X 
 
 
 
 
 
Sponsor Reporting 
Requirements to the 
U.S. FDA 
X 
 
 
 
 
 
 
 


 
Study Personnel and Roles: 
1. Sponsor-Investigator 
John Joseph O’Connell, M.D. 
Prisma Health-Upstate 
Department of Medicine 
Phone: 
(864) 679-3900 (office) 
Email: 
John.O’Connell@PrismaHealth.org 
2. Clinical Co-Investigators 
Larisa D Coldebella Perino, M.D. 
Angelo Perino, M.D. 
Prisma Health-Upstate 
Prisma Health-Upstate 
Department of Emergency Medicine 
Department of Emergency Medicine 
Phone:   
(864) 313-9576 (office) 
Phone:   
(864) 313-9493 (office) 
Email: Larisa.Coldebella@PrismaHealth.org 
Email: Angelo.Perino@PrismaHealth.org  
 
 
Amanda Schnee, M.D. 
W. Jeffery Edenfield, M.D. 
Prisma Health-Upstate 
Prisma Health-Upstate 
Department of Medicine 
Cancer Institute 
Phone:  
(864) 455-9033(office) 
Phone:  
(864) 679-3900 (office) 
Email: Amand.Schnee@PrismaHealth.org  
Email: Jeffery.Edenfield@PrismaHealth.org 
 
 
Phillip Moschella, M.D., Ph.D. 
Jennica Siddle, M.D. 
Prisma Health-Upstate 
Prisma Health-Upstate 
Department of Emergency Medicine 
Department of Emergency Medicine 
Phone  
(864) 455-9033(office) 
Phone  
(864) 455-9033 (office) 
Email: Phillip.Moschella@prismahealth.org  
Email: Jennica.Siddle@PrismaHealth.org  
3. Epidemiologic Co-Investigator 
Corey Andrew Kalbaugh, Ph.D. 
 
Clemson University 
 
College of Behavioral, Social and Health Sciences 
 
Phone:  
(864) 656-6694 (office) 
 
Email: coreyk@clemson.edu  
 
4. Statistician Co-Investigators 
Deborah Kunkel, Ph.D. (Lead) 
Lior Rennert, Ph.D. 
Clemson University 
Clemson University 
School of Mathematical and Statistical Sciences 
College of Behavioral, Social and Health Sciences 
Phone:   
(864) 656-1656 (office) 
Phone:   
(864) 656-7640 (office) 
Email: dekunke@clemson.edu  
Email: liorr@clemson.edu  
 
 
Alex Ewing, Ph.D. 
 
Prisma Health-Upstate 
 
Division of Research and Scholarship 
 
Phone:  
(864) 455-1130 (office) 
 
Email: Alex.Ewing@PrismaHealth.org 
 
 
 


 
5. Pharmacy Co-Investigators 
Michael Cohen, PharmD 
 
Prisma Health-Upstate 
 
Department of Pharmacy 
 
Phone:   
(864) 455-7000 (office) 
 
Email: Michael.Cohen@prismahealth.org  
 
6. Senior Medical Mentor 
W. Jeffery Edenfield, M.D. 
 
Prisma Health-Upstate 
 
Cancer Institute 
 
Phone:   
(864) 679-3900 (office) 
 
Email: Jeffery.Edenfield@PrismaHealth.org  
 
7. Consultants 
Arwen BL Declan, M.D., Ph.D. 
Timothy F McTigue, M.D. 
Prisma Health-Upstate 
Independent Contractor (in-kind effort) 
Department of Emergency Medicine 
 
Phone:   
(864) 455-7000 (office) 
Phone:   
(863) 221-8195 (office) 
Email: Arwen.Declan@PrismaHealth.org  
Email: tfmctigue@aol.com  
 
 
Angela Orsky, DNP 
 
Prisma Health-Upstate 
 
Post-Acute Services 
 
Phone:   
(864) 797-7784 (office) 
 
Email: Angela.Orsky@PrismaHealth.org  
 
8. Study Coordinator 
TBD 
 
Prisma Health-Upstate 
 
 
 
Phone:   
(office) 
 
Email 
 
9. Research Assistants 
Halee Bryant Vaughn 
Benjamin R. Hutto 
University of South Carolina 
School of Medicine Greenville 
University of South Carolina  
School of Medicine Greenville 
Phone:   
(864) 455-7992 (office) 
Phone:   
(864) 455-7992 (office) 
Email: habryant@email.sc.edu  
Email: brhutto@email.sc.edu 
 
 
David Y. Pritchett 
Josiah N. McDonald 
University of South Carolina  
School of Medicine Greenville 
University of South Carolina 
School of Medicine Greenville 
Phone:   
(864) 455-7992 (office) 
Phone:  
(864) 455-7992 (office) 
Email: DavidYP@email.sc.edu  
Email: josiahm@email.sc.edu  
 
 


 
10. Data and Safety Monitoring Committee 
Prerana Roth, M.D. (Chair) 
 
Prisma Health-Upstate 
 
Department of Medicine 
 
Phone:   
(864) 455-9033 (office) 
 
Email: Prerana.Roth2@prismahealth.org  
 
 
 


 
Figure of REDCap® User Rights by Role 
 
 
 


 
Prisma Health-Upstate Clinical Guidelines
 


 
 


 


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O’Connell, Coldebella Perino, Siddle, Moschella, Declan, Perino, Schnee, Kunkel, Kalbaugh, Rennert, Ewing, Roth, Cohen, Vaughn, Pritchett, 
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