Intranasal Heparin Tolerability Study
Condition: Covid19
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Intranasal heparin sodium (porcine)
Intervention type(s): Drug
Intervention description(s): Intranasal heparin sodium
Other intervention name(s): NDC (National Drug Code) 0409-2721-30; NDC 0409-2723-01
Intervention MeSH terms: Heparin; Calcium heparin
Intervention model: Sequential Assignment
Intervention model description: This study will evaluate the acute and multi-day (14 days) tolerability of intranasally administered heparin. Two doses will be tested in the acute phase: 1000 U/day, then 2000 U/day. In the multi-day phase, the highest tolerated dose from the acute phase will be tested over a 14-day period of daily self-administration.
Masking: None (Open Label)
Primary purpose: Prevention