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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental Arm | Experimental | Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL. Acute phase: On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. Chronic phase: The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intranasal heparin sodium (porcine) | Drug | Intranasal heparin sodium |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin | 24 hours after a 1000 U intranasal dose of heparin |
| Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin | 24 hours after 2000 U dose intranasal heparin |
| Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin | Day 14, chronic phase |
| Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin | 24 hours after the last 2000 U dose of the chronic phase |
| Percent Change in Platelet Count From Pre-dose Baseline | Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase. | Pre-dose baseline, Day 14 chronic phase |
| Measure | Description | Time Frame |
|---|---|---|
| Other Adverse Effects, Acute Phase | Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation | Day 0 through Day 2, acute phase |
| Other Adverse Effects, Chronic Phase |
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Inclusion Criteria:
Normal, healthy adults aged 18 to 65 years
Exclusion Criteria:
NOTE: Subjects will be instructed to abstain from alcohol for the duration of the study.
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| Name | Affiliation | Role |
|---|---|---|
| Bill Gurley, PhD | University of Mississippi Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Mississippi National Center for Natural Products Research | University | Mississippi | 38677-1848 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32577638 | Background | 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. |
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Individual participant data that underlie the results reported, after deidentification
Beginning 3 months and ending 36 months following publication
Proposals should be directed to jsharp@olemiss.edu. To gain access, requestors will need to sign a data access agreement.
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental Arm | Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL. Acute phase: On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. Chronic phase: The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records. Intranasal heparin sodium (porcine): Intranasal heparin sodium |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1000 U Acute (One Dose, Day 1) |
| |||||||||||||
| 2000 U Acute (One Dose, Day 3) |
| |||||||||||||
| 2000 U Chronic (Daily, 14 Days) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental Arm | Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL. Acute phase: On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. Chronic phase: The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records. Intranasal heparin sodium (porcine): Intranasal heparin sodium |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin | Posted | Count of Participants | Participants | 24 hours after a 1000 U intranasal dose of heparin |
|
From date of first dose in acute phase through sixteen days after last dose in chronic phase; 38 days total
Adverse event collection was obtained by vital sign measurement, INR measurements from blood collection, and subject self-reporting
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Experimental Arm | Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL. Acute phase: On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects. Chronic phase: The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records. Intranasal heparin sodium (porcine): Intranasal heparin sodium |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mild nasal irritation lasting less than 1 min after administration | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Mild nasal irritation immediately after administration, lasting less than one minute. Includes mild burning sensation in the nose, itchiness and sneezing. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Joshua Sharp | University of Mississippi | 662-915-1758 | jsharp@olemiss.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 1, 2020 | Dec 15, 2020 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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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.
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| Number of Incidents of Epistaxis, Acute Phase | Number of incidents of blood coming from the nose during the acute phase | Day 0 through Day 2, acute phase |
| Number of Incidents of Epistaxis, Chronic Phase | Blood coming from the nose or pink tinged nasal secretions | Day 1 through Day 15, chronic phase |
| Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14 | Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase. | Day 14, Chronic Phase |
Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing
| Day 1 through Day 15, chronic phase |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Primary | Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin | Posted | Count of Participants | Participants | 24 hours after 2000 U dose intranasal heparin |
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| Primary | Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin | Posted | Count of Participants | Participants | Day 14, chronic phase |
|
|
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| Primary | Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15 | A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin | Posted | Count of Participants | Participants | 24 hours after the last 2000 U dose of the chronic phase |
|
|
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| Primary | Percent Change in Platelet Count From Pre-dose Baseline | Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase. | Posted | Mean | Full Range | percent change from baseline | Pre-dose baseline, Day 14 chronic phase |
|
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| Primary | Number of Incidents of Epistaxis, Acute Phase | Number of incidents of blood coming from the nose during the acute phase | Posted | Number | Reported incidents | Day 0 through Day 2, acute phase |
|
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| Primary | Number of Incidents of Epistaxis, Chronic Phase | Blood coming from the nose or pink tinged nasal secretions | Posted | Number | Reported incidents | Day 1 through Day 15, chronic phase |
|
|
|
| Primary | Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14 | Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase. | Posted | Count of Participants | Participants | Day 14, Chronic Phase |
|
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| Secondary | Other Adverse Effects, Acute Phase | Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation | Posted | Number | Reported incidents | Day 0 through Day 2, acute phase |
|
|
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| Secondary | Other Adverse Effects, Chronic Phase | Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing | Posted | Number | Reported incidents | Day 1 through Day 15, chronic phase |
|
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|
| 0 |
| 6 |
| 0 |
| 6 |
| 3 |
| 6 |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Incidents of mild nose bleeds and/or pink tinged nasal secretions (NOTE: affected subject disclosed prior history of epistaxis not initially disclosed during screening) |
|
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |