Clinical trial NCT04490239: Intranasal Heparin Tolerability Study
Official title: Intranasal Heparin Tolerability Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Covid19
Lead sponsor: University of Mississippi, Oxford
Sponsor class: OTHER
First posted: 2020-07-29
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
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.
Primary purpose: PREVENTION

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1
timeFrame: 24 hours after a 1000 U intranasal dose of heparin
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2
timeFrame: 24 hours after 2000 U dose intranasal heparin
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14
timeFrame: Day 14, chronic phase
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15
timeFrame: 24 hours after the last 2000 U dose of the chronic phase
measure: Percent Change in Platelet Count From Pre-dose Baseline
timeFrame: Pre-dose baseline, Day 14 chronic phase
measure: Number of Incidents of Epistaxis, Acute Phase
timeFrame: Day 0 through Day 2, acute phase
measure: Number of Incidents of Epistaxis, Chronic Phase
timeFrame: Day 1 through Day 15, chronic phase
measure: Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14
timeFrame: Day 14, Chronic Phase
Secondary outcomes:
measure: Other Adverse Effects, Acute Phase
timeFrame: Day 0 through Day 2, acute phase
measure: Other Adverse Effects, Chronic Phase
timeFrame: Day 1 through Day 15, chronic phase
Other outcomes:
Locations:
city: University
country: United States
facility: The University of Mississippi National Center for Natural Products Research
state: Mississippi
Study officials:
affiliation: University of Mississippi Medical Center
name: Bill Gurley, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tandon R, Sharp JS, Zhang F, Pomin VH, Ashpole NM, Mitra D, Jin W, Liu H, Sharma P, Linhardt RJ. Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives. bioRxiv [Preprint]. 2020 Jul 28:2020.06.08.140236. doi: 10.1101/2020.06.08.140236.