Intranasal Heparin Tolerability Study
Phase: EARLY_PHASE1
Conditions: Covid19
Sponsor: Joshua Sharp

1 
V20 9.1.2020 
 
Intranasal Heparin Tolerability Study  
IND 152357 
 
 
Principal Investigator:  
 
Bill Gurley, PhD 
 
 
 
 
 
Principal Scientist 
 
 
 
 
 
NCNPR 
 
 
 
 
 
University of Mississippi 
 
 
 
 
 
University, MS 38677 
 
 
 
 
 
Phone: 662-915-7130 
 
 
 
 
 
e-mail: bjgurley@olemiss.edu  
 
 
 
Co- Investigator 
 
 
Joshua Sharp, PhD 
Associate Professor 
Dept. of BioMolecular Sciences 
School of Pharmacy 
University of Mississippi 
University, MS 38677 
 
 
 
 
 
 
Ryan Yates, PharmD, PhD 
 
 
 
 
 
Principal Scientist 
 
 
 
 
 
NCNPR 
 
 
 
 
 
University of Mississippi 
 
 
 
 
 
University, MS 38677 
 
 
 
 
 
Phone: 662-915-6994 
 
 
 
 
 
e-mail: cryates2@olemiss.edu 
 
 
 
Test Article:  
Tolerability of topically applied intranasal heparin  
 
 
Drug supplier:  
 
 
National Center for Natural Products Research 
 
 
Clinical Phase:  
 
 
Phase 0 - exploratory 
 
 
 
 
 
 
 
 
 

2 
V20 9.1.2020 
 
 
Table of Contents 
1.0  
General Information ............................................................................................................................................ 3 
1.1  
Contact Information ........................................................................................................................................ 3 
2.0  
Background Information ...................................................................................................................................... 4 
2.1  
Introduction and Background .......................................................................................................................... 4 
2.2  
Preliminary Studies ......................................................................................................................................... 5 
3.0  
Study Objectives .................................................................................................................................................. 6 
4.0  
Study Overview .................................................................................................................................................... 6 
5.0 
Test Article .......................................................................................................................................................... 6 
6.0  
Study Population ................................................................................................................................................. 9 
7.0  
Administration of Investigational Product .......................................................................................................... 10 
8.0  
Study Conduct ................................................................................................................................................... 11 
8.1 
 Procedures ....................................................................................................................................................11 
8.1.1  
Subject Enrollment and Screening ..........................................................................................................11 
8.1.2  
Initiation of Investigational Product: Initial Dose/Day 0 (Acute Phase) ....................................................12 
8.2 Initiation of Multi-day Dose (Chronic Phase) ............................................................................................................ 14 
9.0  
Safety Assessments ............................................................................................................................................ 16 
9.1 
Vital Signs ......................................................................................................................................................16 
9.2 
Physical Examination ......................................................................................................................................16 
9.3 
Laboratory Parameters ..................................................................................................................................16 
10.0 
 Blood Sample Processing .................................................................................................................................. 17 
11.0  Adverse/Serious Adverse Events ........................................................................................................................ 17 
12.0  Discontinuation and Replacement of Subjects.................................................................................................... 18 
13.0  Data Handling and Record Keeping .................................................................................................................... 18 
14.0  Institutional Review Board (IRB)/Ethics .............................................................................................................. 19 
15.0  Reference List .................................................................................................................................................... 19 
 
 
 
 
 
 
 
 
 

3 
V20 9.1.2020 
 
 
 
 
1.0  
General Information 
 
1.1  
Contact Information 
PRINCIPAL INVESTIGATOR 
Bill Gurley, PhD 
Principal Scientist 
 
NCNPR 
University of Mississippi 
University, MS 38677 
Phone: 662-915-6994 
e-mail: bjgurley@olemiss.edu 
 
Co-Investigators 
Joshua Sharp, PhD 
Associate Professor 
Dept. of BioMolecular Sciences 
School of Pharmacy 
University of Mississippi 
University, MS 38677 
 
Ryan Yates, PharmD, PhD 
Principal Scientist 
NCNPR 
University of Mississippi 
 
University, MS 38677 
 
Phone: 662-915-6994 
 
e-mail: cryates2@olemiss.edu 
 
 
Study Physicians/Nurses: 
Eric Dahl, DO 
 
606 Wildwood Lane 
 
Oxford, MS 38655 
 
Phone:662-202-5038 
 
 
Brett Lampton, MD 
 
209 Windsor Ridge 
 
Oxford, MS 38655 
 
662-832-4003 
 
 
 
Kerri A. Harrison R.N. 
 
        
University of Mississippi 
 
 
University, MS 38677 
 
            Phone:662-915-2103 
 
 
kaharri6@olemiss.edu 
 
 
 
 
 

4 
V20 9.1.2020 
 
 
2.0  
Background Information 
 
2.1  
Introduction and Background 
 
The recent emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in 
Wuhan,China in late 2019 and its subsequent spread to the rest of the world has created a pandemic 
situation unprecedented in modern history 1-4. SARS-CoV-2 is a betacoronavirus closely related to 
SARS-CoV; however, significant differences in the Spike glycoprotein (SGP) are present in SARS-
CoV-2 that may drive differences in the attachment and entry process. In SARS-CoV, the SGP binds 
to its cognate receptor, human angiotensin converting enzyme 2 (hACE2). The bound virus is then 
endocytosed into the cell, where SGP is acted upon by the endosomal protease TMPRSS2 to allow 
envelope fusion and viral entry. 
While ACE2 has been confidently identified as the viral receptor, many viruses (including some 
betacoronaviruses) will use cellular polysaccharides as cellular attachment coreceptors, allowing the 
virus to adhere to the surface of the cell and increasing the local concentration of viral particles to 
increase effective infection rates. Sequence analysis of SGP of SARS-CoV-2 suggest that this virus 
has evolved to have additional potential glycosaminoglycan (GAG) binding domains compared to 
SARS-CoV. GAGs are a family of linear sulfated 
polysaccharides found on the surface of virtually all 
mammalian cells, and commonly includes 
chondroitin sulfate (CS) and heparan sulfate (HS). 
Previous studies using isolated SARS-CoV-2 SGP 
monomer or trimer and surface plasmon resonance 
(SPR) have shown that SARS-CoV-2 SGP has high 
affinity to heparin 5-6, a specialized member of the 
HS family that is highly sulfated and commonly used 
clinically as an anti-coagulant drug. It was also 
reported that heparin was capable of inhibiting 
infection of SARS-CoV-2 in Vero cell culture in a 
dose-dependent fashion 6. These results support a 
model of SARS-CoV-2 attachment and entry 
illustrated in Figure 1, where SARS-CoV-2 initially 
binds to HS in the nasal epithelium glycocalyx, 
where it then binds hACE2 and is endocytosed.  
Based on this model, disruption of the initial 
interaction between SARS-CoV-2 SGP and HS could be an effective method for preventing COVID-19 
or treating the disease, especially in its earliest stages. Heparin is an FDA-approved drug commonly 
used via intravenous infusion, intravenous injection or deep subcutaneous injection as an anti-
coagulant, where it acts in the blood to disrupt the coagulation cascade. Heparin has numerous side 
effects, including bleeding and heparin-induced thrombocytopenia, all of which also occur due to 
heparin activity in the blood. Moreover, heparin is used in COVID-19 treatment where evidence of 
microclotting (such as high D-dimer levels) is present. Because of this, use of heparin as an anti-viral 
through a route of administration that allows for significant distribution to the blood carries risks, 
especially for projected use outside of a closely-observed clinical setting. 
Figure 1: Model of SARS-CoV-2 
attachment and entry. Binding of virus to 
HS in the glycocalyx increases the local 
concentration of virus, improving binding to 
hACE2. 

5 
V20 9.1.2020 
Previous studies have examined large doses of heparin via an inhalation route in both humans 7-8 and 
rodents 9 indicate that even very large doses of heparin administered via inhalation has very poor 
serum bioavailability, and no reported toxicity. These results suggest that COVID-19 treatment by 
heparin via an intranasal or inhalation route could avoid dangerous side effects or complications with 
anti-coagulation treatments while potentially still providing a prophylactic or therapeutic benefit. 
Heparin’s inability to affect blood coagulation when administered intranasally is due to the molecule’s 
large molecular weight which precludes its active and passive transport across the epithelial barrier of 
the nasal passages.  Recent published reports indicate that the nasal epithelium is a probable major 
portal for initial infection and transmission based on viral loads in both symptomatic and asymptomatic 
patients 10-11, as well as expression patterns of both the hACE2 receptor and the TMPRSS2 protease 
12. This suggests that a self-administered nasal spray of heparin may be a simple, safe and effective 
prophylactic to lower the rates of SARS-CoV-2 transmission. A previously disclosed patent indicated 
that heparin formulated in 15% ethanol had only 0.02% systemic bioavailability 13; this small amount of 
bioavailability is likely due to the presence of the 15% ethanol. Single intranasal administration of 
saline heparin in a rat model resulted in no noted toxicity and very poor serum bioavailability 9. We are 
aware of no published studies of repeated dosing of intranasal heparin. 
2.2  
Preliminary Studies  
In vitro potency and efficacy.  In order to test the potency and efficacy of heparin, we developed an 
in vitro model. We created a pseudotyped third-generation lentiviral system that expresses the SARS-
CoV-2 SGP, which drives cell attachment and entry in SARS-CoV-2. Upon attachment and entry into 
target cells (in this case, HEK293T cells), the pseudotyped system will drive expression of green 
fluorescent protein (GFP). Therefore, the number of cells that have been infected by the pseudotyped 
virus can be determined by counting the number of cells that fluoresce. Using this assay, we tested 
the ability of various sulfated polysaccharides, including heparin, to block infection. The results of this 
assay for heparin (160 USP/mg) are shown in Figure 2. 
Heparin showed high potency, with an IC50 of 5.99 µg/L (95% CI: 2.90 – 11.96 µg/L), or 0.96 U/L. 
Based on the average molecular weight of heparin of 15,000 g/mol, this equals an IC50 of ~400 pM. 
This is 10x higher than the KD of heparin for SARS-CoV-2 SGP measured by surface plasmon 
resonance 5. 
A
B
C
Figure 2. SARS-CoV-2 SGP pseudotyped lentiviral assay for heparin inhibition of viral attachment 
and entry. A. Representative fluorescent microscopy of inhibition assay results from chemically N-
desulfated heparin, which removes the anti-viral activity. Each spot is an infected cell. B. Representative 
fluorescent microscopy of inhibition assay results from heparin. Almost all infection has been stopped. C. 
Dose response curve of heparin for doses from 500 mg/L to 5 µg/L. 

6 
V20 9.1.2020 
 
 
 
 
Mouse toxicology of intranasally administered heparin 
In order to test the toxicity of repeated intranasally administered doses of heparin, we carried out a 
two-week blinded toxicology study in C57BL/6 mice. Mice were administered 12 µL (6 µL/nostril) of a 
heparin sodium saline formulation identical to the FDA-approved formulation used for deep 
subcutaneous injection (5 mg/mL sodium chloride, 1% benzyl alcohol, pH 5.0 – 7.5, adjusted using 
sodium hydroxide and/or hydrochloric acid as needed). Four groups of six mice each, plus one control 
group of six mice, were used to test heparin. Each group was given 12 µL of heparin daily for two 
weeks at concentrations of 5000 mg/L, 500 mg/L, 50 mg/L or 5 mg/L, with the control group given the 
vehicle. Given the average mouse nasal cavity volume of 32 mm3, this results in a peak nasal cavity 
concentration of 1875 mg/L, well above the highest dose tested in the in vitro pseudotype study. Mice 
were monitored daily for bleeding, nasal discharge, nose irritation or discoloration, and weight loss. 
At the end of the two-week study, the samples were unblinded and the mice exposed to the highest 
dose were tested for anosmia. All mice were euthanized, and a necropsy was performed to identify 
any gross tissue abnormalities. Blood was used to perform an activated partial thromboplastin time 
(aPTT) test to look for anticoagulant activity, as well as look for decreases in platelet count to indicate 
heparin-induced thrombocytopenia (HIT). In no cases were any evidence of toxicity found at any dose 
tested.  
3.0  
Study Objectives 
 
This exploratory clinical trial is designed to assess tolerability of increasing doses of intranasally 
administered heparin sodium in saline solution. Baseline values for aPTT and complete blood count 
will be obtained from six subjects. Heparin will be administered in increasing concentrations using 
one 0.1 mL spray per nostril (0.2 ml total) on a daily basis. Major signs of toxicity will be clinically 
relevant changes in aPTT time, clinically relevant decrease in platelet count, signs of anosmia 30 
minutes after administration, or epistaxis. Dosing will start at 1000 units of heparin administered (500 
U in each nostril) and then escalated to 2000 units. Signs of toxicity include a clinically relevant aPTT 
time (> 90s) or decrease in platelet count (below clinical lab normal limit). Tolerance of each dose 
during the acute phase will be used to determine the dose tested for a 14-day self-administered 
chronic phase to determine any adverse effects of repeated dosing. 
4.0  
Study Overview 
4.1 Description of Design of Study 
This study is a single center, prospective, Phase 0 exploratory tolerability trial.  A total of 6 healthy 
subjects (3 M and 3 F) will be enrolled into the study. This study will evaluate the acute and multi-day 
(14 days) tolerability of intranasally administered heparin. 
5.0 
Test Article 
5.1 Investigational Product 
 
The study will assess the single and multi-dose tolerability of intranasal administration of an aliquot 
of an FDA-approved heparin sodium injection (5,000 USP units/mL or 10,000 USP units/mL) to 
deliver 1000U or 2000U of heparin sodium.  Doses will be prepared and administered as follows: 
1000 U = (2 x 0.1 mL of 5000U/mL or one spray of 500 U in each nostril) 
2000 U = (2 x 0.1 mL of 10000U/mL or one spray of 1000 U in each nostril)  
 
In order to minimize the need for formulation stability testing, we are limiting our studies to 
formulations of heparin currently FDA-approved for administration by injection. In order to maximize 
patient compliance for self-administration, we are testing formulations that require only a single 100 
µL spray per nostril. Heparin sodium injection is currently available in concentrations up to 10,000 
units/mL, or 1,000 units/spray. As the formulation is liquid, we decided that nasal cavity volume was 
the appropriate measure to determine tolerable concentration. Our initial mouse studies found that 

7 
V20 9.1.2020 
doses up to 337.5 U of heparin per cubic centimeter of nasal cavity volume each day were tolerated 
for the entire 14 days of the study, based on an average mouse nasal cavity volume of 32 mm3 14. In 
humans, this corresponds to a dose of up to 7,155 U/day based on an average human nasal cavity 
volume of 21.2 cm3 15, well above the maximum dose for a single spray per nostril at the highest 
available heparin concentration (2,000 U/day).  
Our pharmacokinetic goal was to maintain a concentration of heparin ≥ 0.267 U/cm3 nasal cavity 
volume for at least eight hours (preferably twelve hours). In vivo imaging studies in a mouse model 
indicate that between 1% and 4% of the applied 2.67 U dose remained in the nasal cavity after 
twelve hours. If this elimination model holds in humans, a 1000 U dose (the lower dose to be 
tested) would results in a concentration between 0.47 and 1.89 U/cm3 nasal cavity volume after 
twelve hours, meeting our pharmacokinetic goal. The next lower concentration of heparin currently 
commercially available (1000 U/mL, or a 200 U dose), would result in a lower range of retained 
concentration below our target concentration after twelve hours (0.094 to 0.378 U/cm3). Both the 
1000 U dose (47.2 U heparin per cm3 nasal cavity volume) and the 2000 U dose (94.3 U heparin 
per cm3 nasal cavity volume) are well below our highest tested and tolerated dose in mice of 337.5 
U heparin per cm3 nasal cavity volume, and represent the highest two doses that can be achieved 
from a single 100 µL spray per nostril of currently available FDA-approved heparin sodium 
formulations. 
 
5.3 Labeling of Investigational Product 
Heparin Sodium (Injection, USP) is a sterile preparation of heparin sodium derived from porcine 
intestinal mucosa in water for injection as an anticoagulant.  The drug preparation is available in 
various potencies.  Potency is determined by a biological assay using a USP reference standard 
based on units of heparin activity per milligram. 
 
5,000-Units Solution 
National Drug Code: 71288-402-10 (71288-402-11 unit of sale) 
 
Each mL contains: 5,000 USP Heparin Units (porcine); 7 mg sodium chloride (to render isotonic); 
0.01 mL benzyl alcohol. Hydrochloric acid and/or sodium hydroxide may have been added for pH 
adjustment (5.0-7.5).  Note that 50,000 USP units per 10 mL equals 5,000 per mL. 
 
 
5,000-Units Heparin Sodium, Injection Solution Label 
 
10,000-Units Solution 
National Drug Code: 00409-2721-30 
Each mL contains: 10,000 USP Heparin Units (porcine); 5 mg sodium chloride (to render isotonic); 0.01 mL 
benzyl alcohol. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). 

8 
V20 9.1.2020 
 
10,000-Units Heparin Sodium, Injection Solution Label 
Heparin single & daily dose Nasal Sprayers 
 
LOT: xxx-xxx 
HEPARIN SODIUM INTRANASAL SOLUTION 
Heparin Concentration: 5,000 USP units/mL 
 
CAUTION: New Drug—Limited by United States law to investigational use. 
Instill one (1)  spray into each nostril every day at ______________ 
 
For Questions or Concerns: Contact Kerri A. Harrison RN, CCRC 662-915-2103 
Please return empty container to the Research Clinic 
 
Store at room temperature. 
National Center for Natural Products Research 
University, MS 38677 
 
 
Date_____________________   Test Subject ID #__________________ 
5,000-units Label 
 
LOT: xxx-xxx 
HEPARIN SODIUM INTRANASAL SOLUTION 
Heparin Concentration: 10,000 USP units/mL 
 
CAUTION: New Drug—Limited by United States law to investigational use. 
 
Instill one (1)  spray into each nostril every day at ______________ 
 
For Questions or Concerns: Contact Kerri A. Harrison RN, CCRC 662-915-2103 
Please return empty container to the Research Clinic 
 
 
Store at room temperature. 
National Center for Natural Products Research 
University, MS 38677 
 
Date_____________________   Test Subject ID #__________________ 
10,000-units Label 
 
 
5.4 Supplier 
 
The test article (Heparin Sodium USP) will be obtained from UM Pharmacy Health Services.  
  
 
 
 
5.4.1 Preparation of Investigational Product 
NCNPR personnel will prepare the investigational product within a Class II Type A2 
biosafety cabinet in the clinical laboratory where the study will take place. 

9 
V20 9.1.2020 
 
The test article will be prepared by transferring (4 mL) of sterile heparin sodium injection 
(5,000 USP units/mL or 10,000 USP units/mL) at ambient room temperature into 
intranasal spray bottles, one bottle for each individual subject. The sprayer has been 
verified to dispense 100 ± 20 µL heparin per spray  before delivery of the test article to 
subjects. The ability of the sprayer to dispense the appropriate 100 µL of heparin per 
spray has been tested by weighing the bottle before and after dispensing and using the 
change in mass to determine the amount of heparin dispensed (92± 8 uL/spray). 
 
The test article will be administered within 4 weeks of preparation, and the remainder 
discarded after study completion. 
6.0  
Study Population 
This study will be conducted in healthy volunteers, that are not currently taking prescription anti-
coagulants or blood thinners, not currently taking any nasal medication, and that have no symptoms 
of COVID-19. 
 
An equal number of males and females will be included in this study.  Racial distribution within this 
protocol is expected to reflect the racial distribution of the campus of the University of Mississippi, 
residents of the city of Oxford, MS, Lafayette County, MS or the surrounding counties in northeast 
Mississippi.  The student body of the University of Mississippi, the population of Oxford, Lafayette 
County, and surrounding counties is predominately Caucasian (72%) with a large minority of African-
Americans (24%), Asians (2%) and Hispanics (2%).  Attempts will be made to recruit subjects of all 
ethnicities; however, actual racial distribution will be dependent upon personal choice of each subject. 
 
The University currently has more than 23,000 students (undergraduate and graduate) enrolled with 
faculty and staff totaling almost 1,600. Lafayette County has a population of approximately 50,000. 
Advertisements, both print and media (email, campus intranet, and social media), will be used to inform 
and recruit subjects about the study as well as criteria for qualification and enrollment. 
 
6.1 Inclusion criteria: 
6.1.1 Normal, healthy adults aged 18 to 65 years 
 
6.2  Exclusion criteria 
6.2.1 
Allergy to Heparin 
6.2.2 
Currently taking any prescription blood thinners or anti-coagulants, aspirin, 
Ibuprophen, or other Non steroidal Anti-Inflammatory medications (NSAIDS), or 
currently taking any intranasal medication 
6.2.3 
Subject is a regular/heavy consumer of alcohol (3 or more drinks in a day or >14 drinks 
in a week for males; 2 or more drinks in a day and >7 drinks/week for females) 
6.2.4 
Known history of anemia, thrombocytopenia, heparin-induced thrombocytopenia (HIT) 
or other blood disorder (epistaxis)  
6.2.5 
Autoimmune disorders  
6.2.6 
Known history of neurologic/psychiatric disorders 
6.2.7 
Report of an active infection 
6.2.8 
Subject is pregnant or breast-feeding, or is expecting to conceive during the study.   
 
6.2.7.1  
Subjects of child bearing potential will use (or is currently using)  
 
 
 
during the study, one of the following acceptable methods of  
 
 
 
contraception: 
• 
Male Sterilization (vasectomy) 
• 
Female Sterilization (tubal ligation, hysterectomy) 
• 
Intrauterine Device IUD or other Implant 
• 
Oral Contraceptive, Injectable Contraceptive 
• 
Contraceptive Patch/Ring 
• 
Diaphragm 

10 
V20 9.1.2020 
• 
Male Condom 
• 
Sponge/Spermicide 
 
 
 
 
 
 
 
 
 
7.0  
Administration of Investigational Product   
 
 
7.1 Administration Regimens 
This study is a single center, prospective Phase 0 tolerability proof-of-concept trial of topical 
intranasal heparin solution.  Six (3 females, 3 males), individuals will be enrolled into the study 
Each test subject (all 6 subjects) will adhere to the following procedures for both acute and 
chronic dosing 
 
Table 1: Test subject dosing schedule over 5 weeks 
 
 
 
Table 2 Dose Calculations base on aPTT results 
1.5HR
15MIN.
1.5HR
15MIN.
MONDAY
TUESDAY
WEDNESDAY
THURSDAY
FRIDAY
SATURDAY
SUNDAY
DAY 0
DAY 1
DAY 2
DAY 3
DAY 4
 DAY 5
DAY 6 
24 HOURS
48 HOURS
72 HOURS
96 HOURS
120 HOURS
144 HOURS
PRE-DOSE DRAW
VS
aPTT/VS
VS
                       aPTT/VS *******************************************************************WASHOUT*************************
DOSE
0.1mL/1000u(500u/nostril)
0.1mL/2000u(1000u/nostril)
POST DOSE
1HR OBS.
1HR OBS.
FOLLOW UP CALL
1.5HRS
MONDAY
TUESDAY
WEDNESDAY
THURSDAY
FRIDAY
SATURDAY
SUNDAY
Day 7
DAY 1
DAY 2
DAY 3
DAY 4
 DAY 5
DAY 6
168 HOURS
CHRONIC PHASE                
PRE-DOSE DRAW
VS
DOSE
*****WASHOUT*******
0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
POST DOSE
1HR OBS.
FOLLOW UP CALL
MONDAY
TUESDAY
WEDNESDAY
THURSDAY
FRIDAY
SATURDAY
SUNDAY
CHRONIC PHASE
DAY 7
DAY 8
DAY 9
DAY 10
DAY 11
 DAY 12
DAY 13
PRE-DOSE DRAW
DOSE
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
*0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
POST DOSE
FOLLOW UP CALL
FOLLOW UP CALL
FOLLOW UP CALL
1.5HRS
1HR
MONDAY
TUESDAY
WEDNESDAY
THURSDAY
FRIDAY
SATURDAY
SUNDAY
CHRONIC PHASE
DAY 14
DAY 15
DAY 30 
PRE-DOSE DRAW
aPTT/VS
aPTT,PT/INR,CBC/VS/MD EVAL
aPTT,PT/INR,CBC/VS/MD EVAL
DOSE
0.1mL/1000u(500u/nostril) OR 
0.1mL/2000u(1000u/nostril)
POST DOSE
1HR OBS.
Week 5
ACTIVITY
* DENOTES DOSING AT HOME
WEEK 1
PRESCREENING WORK UP 
TIME COMMITMENT
Week 3
ACUTE PHASE
ACUTE PHASE
Week 2
Week 4

11 
V20 9.1.2020 
 
 
7.2 Data Collection at Enrollment and Follow-up 
For this study, subject data will be collected by paper source documents and transferred to a 
secure electronic data system (e.g. Excel).   
 
The investigator will ensure the data are recorded on the eCRFs as specified in the study 
protocol. He will ensure the accuracy, completeness, and timeliness of the data recorded. 
8.0  
Study Conduct 
All recruitment and enrollment procedures will follow approved UM IRB Appendix G COVID-19 Procedures.  
Initial recruiting interviews will be conducted by phone, email or video.  Potential subjects will be asked about 
COVID-19 exposure before an in-person interview is scheduled. Those that report COVID-19 like or 
respiratory symptoms WILL NOT BE SCHEDULED or ENROLLED 
       
 
8.1 
 Procedures 
 
 
 
8.1.1  Subject Enrollment and Screening 
 
A.  Prior to enrollment, the research team will: 
1. Complete COVID screening (subjects will report to clinic with proper face mask, 
have their temperature take by clinic RN, complete the COVID-19 Related exposure 
questionnaire, and sign the COVID-19 Compliance, Liability Waiver, and 
Assumption of the Risk form, see Appendix G) 
 
 
2. Subjects that complete the above and are asymptomatic and afebrile, will be 
eligilble for enrollment, as long as they meet other inclusion/exclusion criteria 
 
3. Determine initial eligibility prior to performing any study-specific procedures. 
4. Obtain signed informed consent from the subject before any study-specific 
procedures are performed. 
 
5. Review subject eligibility. 

12 
V20 9.1.2020 
6. Assign the potential subject a unique enrollment number. If a subject withdraws from 
participation in the study, then his/her enrollment code cannot be reused. 
 
 
B. Once the consent form is signed and the subject is enrolled into the study, the 
 
research team will: 
 
1. Collect demographics, medical history and concomitant medications/supplements. 
 
2. Obtain vital signs & complete a physical examination (per study Physician).(see 
section 9.1) 
 
3. Obtain blood samples (18 mL hematology, aPTT and PT/INR and hCG (females only) 
for baseline and inclusion/exclusion assessments at least one week prior to dosing. 
(see section 9.3) aPTT results must be 60 seconds or less to be enrolled. 
 
4. Schedule the dosing day.  Test subjects will report to the Research Clinic each day 
at specified time to receive dose. 
 
5. Once eligibility is conformed, subjects will be instructed to avoid alcohol consumption 
during the study, as it can compromise study findings.  
 
6. The subject is also instructed to report to the research team having more than 2 drinks 
a day at any time during the study progress.  
 
 
 
 
 
8.1.2  Initiation of Investigational Product: Initial Dose/Day 0 (Acute Phase) 
      
Once the eligibility of the subject is confirmed, the research team will: 
 
1. COVID Assessments as outlined in 8.1.1 prior to entering clinic 
 
2. Prior to dosing, obtain a set of vital signs. (see section 9.1) Test subjects will remain 
in clinic for about an hour post dose for observation. 
 
3. Collect 7 mL of blood for aPTT assessments and platelet count, (at least one week 
prior to dosing). For those test subjects with an aPTT result of 60 seconds or above 
(normal range is 30-40 seconds), will not receive the initial single dose. 
 
4. Obtain a urine sample for hCG on female Test subjects 
 
5. Administer one 0.1 mL spray of heparin nasal solution in each nostril to deliver a 
total dose of 1000U (500U per nostril/0.1mL per nostril to equal total dose of 0.2mL) 
 
6. Observe test subject for 1-hour post dose for signs of adverse events (e.g. nose 
bleed) 
 
7. Dismiss test subject with instructions to call with concerns/questions (emergency 
number will be provided), and to return the following day at designated time for 
blood draw, assessments 
 
 
 
8.1.3 24-Hour Follow Up 
1. COVID Assessments as outlined in 8.1.1 prior to entering clinic 
 

13 
V20 9.1.2020 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse event or new concomitant medications 
 
4. Collect 7 mL of blood for aPTT assessment and platelet count 
 
5. Dismiss test subject with instructions to call with concerns/questions (emergency 
number will be provided), and to return the following day at designated time for dosing 
 
 
 
 
8.1.4 48-Hour Follow Up/Dose Escalation 
1. COVID Assessments as outlined in 8.1.1 prior to entering clinic 
 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse event or new concomitant medications 
 
4. Obtain a urine sample for hCG on female Test subjects 
 
5. If the test subject’s aPTT result is 90 seconds or less (result from 24 hour follow up), 
administer one 0.1 mL spray of heparin nasal solution in each nostril to deliver a 
total dose of 2000U (1000U/0.1mL per nostril to equal total dose of 0.2mL) 
 
6. For those test subjects with an aPTT value >90 seconds (normal range is 30-40 
seconds), they will not receive the second single dose. (see section 9.0).Those 
subject will be withdrawn from the study, and have follow up aPTT labs until result 
returns to baseline 
 
7.  Observe test subject for 1-hour post dose  
 
8. Dismiss test subject with instructions to call with concerns/questions (emergency 
number will be provided), and to return the following day at designated time for 
blood draw and assessments. 
 
 
 
8.1.5 72-Hour Follow Up 
1. COVID Assessments as outlined in 8.1.1 prior to entering clinic 
 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse event or new concomitant medications 
 
4. Collect 7 mL of blood for aPTT assessment and platelet count 
 
5. Dismiss test subject with instructions to call with concerns/questions (emergency 
number will be provided). The test subject will return at the designated date and time 
for initiation of Multi-day dosing , blood draw and assessments 
 
8.1.6  Five Day Wash-Out Period  

14 
V20 9.1.2020 
 
All subjects will undergo at least a 5 day wash-out period.  Washout starts at
 
Day 3/72 hour post dose through Day 7/168 hours post dose in acute phase. (see 
 
scheme 1, in section 7.0). Test subjects will return to the research center after 
 
that time-period (appointment schedule will be given at 72 hour follow up) .   
8.2 Initiation of Multi-day Dose (Chronic Phase) 
 
8.2.1 Dosing Schedule 
1. The highest acute dose that has no clinically relevant impact on aPTT 
(i.e., aPTT ≤90 seconds) will be used for the multi-day phase of this 
study 
 
2. The test subject will receive one spray of heparin nasal solution into 
each nostril to deliver a total dose of either 1000U, or 2000U daily for 14 
days.  The administered daily dose (and volume) will depend upon 
the results of the acute phase. The highest dose in which aPTT ≤ 90 
seconds is observed will be used. (Some subjects may only tolerate 
1000U, while others may easily tolerate 2000U. Still others may not 
tolerate 1000U and will be removed from the study.  See Table 2)  
Subjects will receive the dose at which no clinically relevant 
increase in aPTT (i.e., ≤90 seconds) is observed (see Section 9.0) 
 
3. The initial dose (Day 0) and last dose (Day 14) will be administered at 
the NCNPR Clinical Studies Facility. All other doses will be self-
administered by subjects at home.  
 
 
 
8.2.2 Initial Daily Dose/Day 0 
1. COVID Assessments (as outlined in 8.1.1) prior to entering clinic 
 
2. Prior to dosing, obtain a set of vital signs. (see section 9.1) Test subjects 
 
 
will remain in clinic for about an hour post dose for observation. 
 
3. Evaluate the test subjects for any adverse event or new concomitant 
 
 
medications since last dose 
 
4. Obtain a urine sample for hCG on female Test subjects 
 
5. 
If the test subject’s aPTT result is 90 seconds or less for at least one of 
the two acute doses (result from 72 hour follow up, section 8.1.5), 
administer heparin nasal solution into each nostril to deliver a total dose 
of either 1000U or 2000U, per study RN. The administered daily dose 
(and volume) will depend upon the results of the acute phase (i.e. 
dose yielding aPTT ≤90 seconds) as outlined in 8.2.1. 
 
6. Observe test subject for 1-hour post dose   
7. Schedule subject for 14 day clinic visit.  Test subjects will report  
 
to the Research Clinic at specified date/time for blood draw and  
 
assessments. 
 

15 
V20 9.1.2020 
8. Test subjects will be given a 14 day dose nasal sprayer, along with 
“dosing diary” to record time of administration and number of intranasal 
sprays, during self-administer at home. (instructions will be given to each 
Test Subject) 
 
9. Instruct subject on proper self-administration of intranasal dose.  Subject 
 
 
will administer the dose once daily at the same time each day 
 
10. Dismiss test subject with instructions to call with concerns/questions 
(emergency number will be provided), and to return in fourteen days 
(visit 2) at designated time for blood draw & assessments. 
 
11. Test subject will be called every three days for updates and  
 
 
subjective reports (adverse events) 
 
 8.2.3 Day 14 Follow Up/Dose 14 
1. COVID Assessments (as outlined in 8.1.1) prior to entering clinic 
 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse event or new concomitant 
 
 
medications 
 
4. Collect 7mL of blood for aPTT assessment and platelet count 
 
5. Administer one 0.1 mL spray of heparin nasal solution into each nostril to 
 
deliver a total dose of either 1000U or 2000U, per study RN.  The 
 
administered daily dose will depend upon the results of the acute 
 
phase (i.e., aPTT ≤ 90 seconds) as outlined in 8.2.1. 
 
6.  Observe test subject for 1-hour post dose  
 
7. Dismiss test subject with instructions to call with concerns/questions 
 
 
(emergency number will be provided), and to return in 24 hours (visit 3) 
 
 
at designated time for final blood draw & assessments. 
 
 
 
8.2.4 Day 15 Post study Follow up 
1. COVID Assessments (as outlined in 8.1.1) prior to entering clinic 
 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse events  
 
4. Collect 7mL of blood for aPTT and PT/INR assessment and platelet count. 
 
5. Dismiss subject.  Schedule for a 30 day safety assessment. 
 
 

16 
V20 9.1.2020 
8.2.5 30 Day Post study Follow up 
 
1. COVID Assessments (as outlined in 8.1.1) prior to entering clinic 
 
2. Obtain a set of vital signs (see section 9.1) 
 
3. Evaluate the test subjects for any adverse events  
 
4. Collect 7mL of blood for aPTT assessment,  platelet count, and  
 
 
PT/INR (pre and post study only for baseline evaluations) 
 
5. Dismiss subject.  Concludes study 
 
9.0  
Safety Assessments 
Safety assessments will be completed as part of this single and  multi-dose study.  Safety will be 
assessed prior to test article administration and at 24, 48 and 72 hours post dose, in the acute phase. 
For the chronic phase, safety asssessments will be assessed prior to test article administration and on 
days 14, 15, and 30. Each subject will be called every three (3) days for updates and subjective reports 
(adverse events).  Subject safety will be assessed by monitoring adverse events, clinical laboratory 
tests, vital signs, and physical examinations.  
 
Throughout the study laboratory values will be monitored closely by the Investigator and study Physician 
to detect changes induced by the test article. Subjects with an aPTT value of 60 seconds or greater 
(normal range is 30-40 seconds) will not recieve the initial daily dose (one 0.1 mL spray of heparin nasal 
solution in each nostril to deliver a total dose of 1000U [500U per nostril/0.1mL per nostril to equal total 
dose of 0.2mL]), OR  proceed to dose 2 (one 0.1 mL spray of heparin nasal solution in each nostril to 
deliver a total dose of 2000U [1000U/0.1mL per nostril to equal total dose of 0.2mL]), in the acute phase. 
 
 
In the multi-day, or chronic phase, each individual test subject’s dose will be based on the highest acute 
dose received that produced no clinically relevant impact on aPTT (i.e., aPTT ≤ 90 seconds). This 
dose (1000U or 2000U) will be used for the multi-day phase of this study. 
 
 
9.1 
Vital Signs 
 
Vital signs (temperature, respiratory rate, blood pressure, heart rate, SpO2) will 
be collected prior to the initiation of the test article and with the Safety 
assessment visits at 24, 48 and 72 hours post dose, in the acute phase. During 
the chronic phase, vital signs will be assessed prior to test article administration, 
and on days 14, 15, 30-post per study RN. 
 
9.2 
Physical Examination 
 
A physical examination will be performed during the screening period, prior to 
test article initiation, and post study visit, per Study RN & MD.   
 
 
9.3 
Laboratory Parameters 
 
Laboratory parameters will be evaluated during screening and daily, to include 
the following: 
 
Complete Blood Count (WBC, RBC, Hematocrit, Hemoglobin, MCV, Platelet 
Count) 
 
 
aPTT  
 

17 
V20 9.1.2020 
 
PT/INR (baseline and post study assessments) 
 
 
Serum hCG baseline assessment only 
 
 
Urine hCG prior to each in clinic dose 
10.0  Blood Sample Processing 
 
 
 
10.1 Activated Partial Thromboplastin Time (aPTT)  
 
Blood samples for aPTT will be collected at baseline, prior to single dose, 24, 48,  
 
and 72-hours post dose, and again pre multi-day dose, and days 14, 15 and 30  
 
 
  10.2 Collection and Processing of Blood Samples 
For aPTT assessment, 3mL of venous blood will be collected and will be determined 
per Lab Corp before and at 24, 48, and 72 hours after each heparin administration 
as well as pre multi-day dosing, and on days 14, 15, and 30. 
 
For Safety Assessments (CBC & Other studies-see section 9.3),4 mls of venous 
blood will be collected in appropriate vacutainer and stored as per Lab processing 
sight specifications.  These specimens will be sent off site for analysis.  
 
 
 
11.0  Adverse/Serious Adverse Events 
 
 
11.1  
Clinical Adverse Events 
Clinical Adverse Events will be monitored throughout the study. However, such events 
are not anticipated during this trial due to the low systemic exposure of the test article 
being administered.  However, local side effects of intranasal heparin, such as epistaxis 
or nasal congestion may result.  
   
For any abnormal lab values, test subjects will be evaluated for any sign and symptoms, 
and labs will be redrawn, until stabilized or returned to baseline. Subjects will be referred 
to the primary physician for any continued care required. 
 
In the event of an Emergency, there will be an onsite RN for the duration of the study, the 
study Physician will present on the day of dosing. The use of emergency equipment 
(defibrillator) and 911 would be used as necessary, deemed prudent by study physician 
and investigators. 
 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB.  AEs 
that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review. 
 
 
11.2  
Adverse Event Reporting 
AE’s will be monitored and recorded in the source document to include the description of 
the event, onset date, stop date, and outcome. The subjects will be instructed to inform 
the study personnel or clinical staff of any AEs experienced during the trial. In addition, 
subject safety will be assessed by monitoring clinical laboratory tests, vital signs and 
physical examinations. Any subject who has an AE will be evaluated by the investigator 
and will be treated accordingly. The designated study physician will review each event 
and assess its relationship to the drug treatment. 

18 
V20 9.1.2020 
 
 
 
11.2.1 Time-Frame for Reporting 
Under 21 CFR 312.32(c), the Principal Investigator will notify the FDA within 7 
calendar days an event that meets all three definitions of a suspected adverse 
reaction, serious adverse reaction and unexpected adverse reaction via a secure 
e-mail account with the FDA. The Principal Investigator will evaluate the available 
information and decide whether there is a reasonable possibility that the test 
article causes the adverse event, and therefore, that the event meets the 
definition of suspected adverse reaction. In addition, the investigator will identify 
in each IND safety report all IND safety reports previously submitted to the FDA 
concerning a similar suspected adverse reaction in light of previous, similar 
reports of any other relevant information. As per 21 CFR part 312, the 
investigator will conduct ongoing safety evaluations, including a periodic review 
and analyses of the entire safety database, not only for IND safety reporting 
purposes, but also to update investigator brochures, protocols, and consent 
forms with new safety information. 
 
 
 
 
11.2.2 Regulatory Reporting 
 Reporting of SAEs by the Investigator to the IRB will be done in accordance with 
the standard operating procedures and policies of the IRB. Adequate 
documentation will be maintained showing that the IRB was properly notified 
 
 
11.3 
 Follow-Up of Adverse Events 
Any SAE or AE assessed after the last dose of the test article will be followed until either 
resolution of the event or determination by the Investigator that the event has become 
stable or irreversible. Follow-up data concerning reported SAE must also be  
 reported to the FDA. 
12.0  Discontinuation and Replacement of Subjects 
  
  
12.1  Discontinuation 
Subject(s) may be discontinued from study at any time if the subject or the investigator is 
of the opinion that continuing participation in the study is not in the interest of the subject. 
Subjects on their own may withdraw from study with reason or without  
providing any 
reason. If reasons for subject withdrawal from study is known, such reasons shall be 
documented. 
 
Other reasons why subjects may be withdrawn from study include: 
1. Subject withdrawal of consent 
2. Subject not adhering to study plan  
3. University request for study termination 
4. Changes in subject’s condition that meets exclusion criteria, e.g. pregnancy 
5. If withdrawn from study due to adverse events, subject(s) will be treated by the  
 
 
investigators and monitored till adverse effects are resolved. 
 
 
12.2  Replacement  
Subjects who withdraw from the study may be replaced if so considered by the 
investigators, by another qualified subject.   
13.0  Data Handling and Record Keeping 
In compliance with ICH guidelines, the investigator will maintain copies of all source documents that 
support data collected from each patient and all study documents as specified in ICH Section 8, 
Essential Documents for the Conduct of a Clinical Trial. The investigator will take measures to prevent 
accidental or premature destruction of these documents.  
 

19 
V20 9.1.2020 
All data containing identifiable health information will be collected and stored in a locked cabinet located 
in the UM SOP Research Center. In addition, all electronic data in the form of Microsoft excel 
spreadsheet, word documents etc. will be stored in a password protected encrypted computer.  
14.0  Institutional Review Board (IRB)/Ethics 
The protocol complies with the principles of the Declaration of Helsinki, 1964. In addition, the protocol 
complies with the laws and regulations of the state of Mississippi.  
The collection and processing of personal data from subjects enrolled in this study will be limited to that 
data which is necessary to investigate the efficacy, safety, quality, and utility of the investigational test 
article used in this study.  
The data will be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations.  
Only approval by the Institutional Review Board (IRB), explicit consent for the enrollment in this research 
study, and processing of personal data will be obtained from the  participating 
subject 
before 
collection of data.  
The subject has the right to request through the investigator access to his/her personal  data and the 
right to request rectification of any data that is not correct or complete. Reasonable steps will be taken 
to respond to such a request, taking into consideration the nature of the request, the conditions of the 
study, and the applicable laws and regulations.  
Data will be kept confidential and if published in a scientific journal, will be done without identification of 
the individual patients. 
15.0  Reference List 
 
1. 
Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; 
Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W.; China Novel Coronavirus, I.; Research, T., A 
Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020, 382 (8), 727-733. 
2. 
Wu, F.; Zhao, S.; Yu, B.; Chen, Y. M.; Wang, W.; Song, Z. G.; Hu, Y.; Tao, Z. W.; Tian, J. H.; Pei, Y. 
Y.; Yuan, M. L.; Zhang, Y. L.; Dai, F. H.; Liu, Y.; Wang, Q. M.; Zheng, J. J.; Xu, L.; Holmes, E. C.; Zhang, Y. 
Z., A new coronavirus associated with human respiratory disease in China. Nature 2020, 579 (7798), 265-
269. 
3. 
Perlman, S., Another Decade, Another Coronavirus. N Engl J Med 2020, 382 (8), 760-762. 
4. 
Gates, B., Responding to Covid-19 - A Once-in-a-Century Pandemic? N Engl J Med 2020, 382 (18), 
1677-1679. 
5. 
Kim, S. Y.; Jin, W.; Sood, A.; Montgomery, D. W.; Grant, O. C.; Fuster, M. M.; Fu, L.; Dordick, J. S.; 
Woods, R. J.; Zhang, F.; Linhardt, R. J., Glycosaminoglycan binding motif at S1/S2 proteolytic cleavage site 
on spike glycoprotein may facilitate novel coronavirus (SARS-CoV-2) host cell entry. bioRxiv 2020, 
2020.04.14.041459. 
6. 
Mycroft-West, C. J.; Su, D.; Pagani, I.; Rudd, T. R.; Elli, S.; Guimond, S. E.; Miller, G.; Meneghetti, M. 
C. Z.; Nader, H. B.; Li, Y.; Nunes, Q. M.; Procter, P.; Mancini, N.; Clementi, M.; Bisio, A.; Forsyth, N. R.; 
Turnbull, J. E.; Guerrini, M.; Fernig, D. G.; Vicenzi, E.; Yates, E. A.; Lima, M. A.; Skidmore, M. A., Heparin 
inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein 
(spike) S1 receptor binding domain with heparin. bioRxiv 2020, 2020.04.28.066761. 
7. 
Bendstrup, K. E.; Chambers, C. B.; Jensen, J. I.; Newhouse, M. T., Lung deposition and clearance of 
inhaled (99m)Tc-heparin in healthy volunteers. Am J Respir Crit Care Med 1999, 160 (5 Pt 1), 1653-8. 
8. 
Bendstrup, K. E.; Gram, J.; Jensen, J. I., Effect of inhaled heparin on lung function and coagulation in 
healthy volunteers. Eur Respir J 2002, 19 (4), 606-10. 
9. 
Arnold, J.; Ahsan, F.; Meezan, E.; Pillion, D. J., Nasal administration of low molecular weight heparin. 
J Pharm Sci 2002, 91 (7), 1707-14. 
10. 
Zhou, P.; Yang, X. L.; Wang, X. G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H. R.; Zhu, Y.; Li, B.; Huang, C. 
L.; Chen, H. D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R. D.; Liu, M. Q.; Chen, Y.; Shen, X. R.; Wang, X.; Zheng, 
X. S.; Zhao, K.; Chen, Q. J.; Deng, F.; Liu, L. L.; Yan, B.; Zhan, F. X.; Wang, Y. Y.; Xiao, G. F.; Shi, Z. L., A 

20 
V20 9.1.2020 
pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579 (7798), 270-
273. 
11. 
Wolfel, R.; Corman, V. M.; Guggemos, W.; Seilmaier, M.; Zange, S.; Muller, M. A.; Niemeyer, D.; 
Jones, T. C.; Vollmar, P.; Rothe, C.; Hoelscher, M.; Bleicker, T.; Brunink, S.; Schneider, J.; Ehmann, R.; 
Zwirglmaier, K.; Drosten, C.; Wendtner, C., Virological assessment of hospitalized patients with COVID-2019. 
Nature 2020. 
12. 
Sungnak, W.; Huang, N.; Becavin, C.; Berg, M.; Queen, R.; Litvinukova, M.; Talavera-Lopez, C.; 
Maatz, H.; Reichart, D.; Sampaziotis, F.; Worlock, K. B.; Yoshida, M.; Barnes, J. L.; Network, H. C. A. L. B., 
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. 
Nat Med 2020. 
13. 
Johansen, K. B. Pharmaceutical Composition for the Nasal Administration of Heparin and Method for 
Treatment of Patients. 1987. 
14. 
Gross, E. A.; Swenberg, J. A.; Fields, S.; Popp, J. A., Comparative morphometry of the nasal cavity in 
rats and mice. J Anat 1982, 135 (Pt 1), 83-8. 
15. 
Liu, Y.; Johnson, M. R.; Matida, E. A.; Kherani, S.; Marsan, J., Creation of a standardized geometry of 
the human nasal cavity. J Appl Physiol (1985) 2009, 106 (3), 784-95.