Intranasal Heparin Tolerability Study
Intranasal Heparin Tolerability Study
The investigators are investigating the tolerability of Heparin Sodium (porcine) administered
 topically via a nasal spray. This agent is being investigated as a potential prophylactic
 treatment to prevent infection by SARS(severe acute respiratory syndrome)-CoV-2, the novel
 coronavirus that causes COVID-19. Heparin Sodium (porcine) is an FDA-approved anticoagulant
 drug administered by injection. Recent work from multiple groups have found that heparin can
 prevent the infection of cells by SARS-CoV-2, indicating a possible use as a topical
 anti-viral. Numerous studies in both rodent models and humans have shown that heparin
 administered via a pulmonary or intranasal route enters the blood stream in negligible
 amounts, suggesting intranasal administration of heparin should be safe even at very large
 doses. Data from mouse models indicate that repeated daily nasal administration of heparin
 had no adverse effects in mice over a two week period (including weight loss, nose bleeds,
 loss of sense of smell, nasal discharge, or decreased blood clotting time). However, no data
 of repeated nasal administration of heparin in humans is available.

 The investigators will test nasal administration of FDA-approved heparin sodium (porcine),
 originally formulated for injection. The formulations the investigators will be testing
 consist of heparin, sodium chloride, and 1% benzyl alcohol as a preservative bottled in a
 nasal sprayer dispensing 0.1 mL(millilitres) per spray. The investigation is planned in two
 phases. A single-dose phase will test the acute tolerability of the drug. In this phase,
 subjects will be administered 0.1 mL of Heparin Sodium in each nostril formulated at one of
 two doses: Day 1 will test a formulation of 5000 U(units)/mL, and Day 2 will test a
 formulation of 10000 U(units) /mL. After each dose, subjects will be tested for systemic
 exposure via blood aPTT tests and platelet count, as well as for local topical toxicity via
 examination for epistaxis and anosmia, along with any other adverse events. In the chronic
 phase, subjects will be administered the highest dose that was tolerated in the acute phase
 daily for fourteen days. Subjects will be tested for aPTT and platelet count, as well as
 epistaxis, anosmia and any other adverse events.
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(millilitre) 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
 units in each nostril) and then escalated to 2000 units. Should a clinically relevant aPTT
 prolongation (>50% increase from subject baseline) or decrease in platelet count (below
 clinical lab normal limit) be observed at either dose, the study will be halted and a series
 of lower doses evaluated.

 Study Overview

 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.

 Test Article

 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 (units) or 2000U of heparin sodium. Doses will be prepared and
 administered as follows:

 1000 U = (2 x 0.1 mL(milliliter) of 5000U(units)/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)

 The test article will be administered 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 for each individual subject.

 The test article will be administered within 4 weeks of preparation, and the remainder
 discarded after study completion.

 Supplier The test article (Heparin Sodium USP) will be obtained from appropriate commercial
 sources.

 Safety Assessments

 Safety assessments will be completed as part of this single and multi-dose, pharmacokinetic
 study. Safety will be assessed prior to test article administration and at 24 post dose, in
 the acute phase. For safety assessments during the chronic phase, safety assessments will be
 assessed prior to test article administration , day 14 and day 15-post study. Test subject
 will be called every three (3) days for updates and subjective reports (adverse events),
 during 14 day, daily dose phase. Subject safety will be assessed by monitoring adverse
 events, clinical laboratory tests, vital signs, and physical examinations.

 Laboratory parameters will be evaluated during screening and daily, to include the following:

 -  Complete Blood Count (WBC, RBC(red blood cell count), Hematocrit, Hemoglobin, MCV (mean
 corpuscular volume), Platelet Count)

 -  PT(prothrombin time)/INR (international normalized ratio) Baseline and post study

 -  Serum/Urine hCG ( human chorionic gonadotropin)baseline and predose

 -  Activated Partial Thromboplastin Time (aPTT)

 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.
Inclusion Criteria:

 Normal, healthy adults aged 18 to 65 years

 Exclusion Criteria:

 -  Allergy to Heparin

 -  Currently taking any prescription blood thinners or anti-coagulants, or currently
 taking any intranasal medication

 -  Known history of anemia, thrombocytopenia, or other blood disorder

 -  Autoimmune disorders

 -  Known history of Neurologic/Psychiatric disorders

 -  Report of an active infection

 -  Subject is pregnant or breast-feeding, or is expecting to conceive during the study.

 NOTE: Subjects will be instructed to abstain from alcohol for the duration of the study.