Intranasal Heparin Treatment to Reduce Transmission Among Household Contacts of COVID 19 Positive Adults and Children (INHERIT)

A Randomised, Placebo-controlled Trial to Investigate the Efficacy of Intranasal Heparin Treatment to Reduce Transmission of SARS-CoV-2 Infection and COVID 19 Disease Among Household Contacts of SARS-CoV-2+ Adults and Children

Coronavirus-induced disease 2019 (COVID-19) is an infection caused by a virus whose full name is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is a new and rapidly-spreading infectious disease which carries a significant risk of death, has brought massive economic impact globally and has proved hard to contain through public health measures. While we currently have effective vaccines, they do not protect the whole community and the constant threat of new mutations means there is an urgent need to identify new approaches to reducing community spread of infection.

Heparin is a naturally occurring sugar molecule which has been used for a century to treat a range of medical problems including heart attacks, strokes, and blood clots. It has also been investigated as a treatment for pneumonias. Recent research suggests it binds to the SARS-CoV-2 virus in such a way it may reduce the virus' ability to enter cells. This may be an important way to tackle the early stages of infection which occurs inside the nose. Therefore, this medication could be used amongst people with early COVID-19 infection and amongst their household contacts to reduce the rate of virus transmission during local outbreaks. If proven effective there are many other potential uses as primary prophylaxis for people working in high risk areas, for travel, for protection in high risk crowded environments such as nightclubs, or sporting events. Heparin is safe, inexpensive, available worldwide and if effective could be rapidly used across the world to slow progression of the current pandemic.

Further there are recent studies suggesting that the risk of brain complications as part of "long COVID", are directly related to the amount of virus in the nose. Reducing the viral load in the nose is thought to be effective in reducing these "long COVID" complications. This study will explore the effect of the intervention on viral load and long COVID.

In this study, researchers want to investigate this medicine in people who have been identified by a COVID-19 swab test to be in the early stages of infection(defined as the index case), and amongst their household contacts. Each participant would take the medicine or a dummy control solution by spray into their nose three times a day for 10 days. The study will investigate if there are fewer people who contract SARS-CoV-2 infection by day 10 amongst households who receive the medicine than households which receive the dummy control.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: unfractionated heparin; Drug: 0.9%sodium chloride

Detailed Description

Multi-centre, prospective, randomised, placebo-controlled two-arm cluster randomised superiority clinical trial.

Individual households with at least one person with Polymerase chain reaction assay(PCR) or Rapid Antigen test (RAT) confirmed SARS-CoV-2 infection will be randomised so that all consenting people in that household receive intranasal heparin or placebo.

The rate of subsequent PCR confirmed SARS-CoV-2 infections in exposed households will be measured to determine the effect of intranasal heparin on reducing transmission to close contacts.

The rate of symptom development in all participants will be used to determine effect of treatment in preventing symptomatic disease The rate of hospitalisation of all participants will be measured to determine the effect of treatment on development of severe disease.

The presence of clinical neurological long COVID symptoms will be assessed at 6 and 12 months to determine the effect of treatment on long COVID.

Objectives Primary

• To test the efficacy of early treatment and post exposure prophylaxis to reduce transmission to household contacts on SARS-CoV-2 PCR assay by day 10.

Secondary

• To test the efficacy of intranasal heparin to reduce SARS-CoV-2 viral shedding: over 10 days from day of positive swab (health professional collected nasopharyngeal swab Day 3 and 5, and Day 10: self-administered anterior nasal swab swab days 1,2,3,4,5 and 10).
• To test the safety of intranasal heparin for treatment of adult and children outpatients with SARS CoV-2 infection
• To test whether intranasal heparin administration reduces symptomatic disease in index cases and household contacts
• To test the impact of intranasal heparin on peak severity of illness.
• Quantification of replication-competent virus.
• To assess the impact of intranasal heparin on long COVID neurological symptoms

• Study Type: Interventional
• Enrollment (Estimated): 1100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Paul Monagle, MD; Phone Number: +61393455165; Email: paul.monagle@rch.org.au
• Study Contact Backup: Name: Donald Campbell, MD; Phone Number: +6139485 9023; Email: donald.campbell@nh.org.au

Study Locations

• Australia
  • Victoria
    • Epping, Victoria, Australia, 3076
      • Recruiting
      • The Northern Hospital
      • Contact: Paul Monagle, MD; Phone Number: +61393455165; Email: paul.monagle@rch.org.au
      • Contact: Don Campbell, MD; Phone Number: +613 9485 9023; Email: donald.campbell@nh.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Any person > 5 years of age who tests positive to SARS-CoV-2 or is a household contact of someone of any age who tests positive is eligible for the trial.
• Index case must be within 72 hours of positive test.
• The positive test can be a RAT or a standard PCR nasal swab performed at an accredited laboratory for the diagnosis of COVID-19 as per the department of health regulations. If initial test is a RAT, then a a standard PCR nasal swab performed at an accredited laboratory for the diagnosis of COVID-19 as per the department of health regulations will be collected prior to randomisation but does not delay entry into the study awaiting the confirmatory result.
• All participants must provide a signed and dated consent form and for children < 16 years have a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf. Consent forms will be developed in multiple languages and provided in a language that the participants are fluent in speaking.
• At least one other person other than the index case in each household must consent to participation to enable the consenting members of the household to be randomised. Household members who do not consent to participate in the randomised trial but whom consent to have their COVID-19 status recorded can contribute to outcome measures where relevant.

Exclusion Criteria:

Children Age < 5 years are excluded from being randomised to therapy but can contribute to the outcome measures if they are swab negative on day 1.

• Documented Heparin allergy
• Previous documented heparin induced thrombocytopenia (HIT)
• Recurrent epistaxis that has required hospitalisation in last 3 months
• >72 hours since index case tested positive
• Inability to provide patient information and consent forms or study instructions in a language in which the patient is competent.
• Household members who are swab positive on day 1 are excluded from contributing to the primary outcome, but are randomised and still contribute to secondary outcomes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intranasal heparin; Unfractionated heparin (UFH) 1400u each nostril (as heparin solution 5,000u/ml, 140 microL/actuation, Two actuations each nostril) Three times daily via a plastic nasal inhalator device (APTAR, UK) for 10 days. This is a maximal dose per day of UFH of 8400u. ie 700 x 2 actuations per nostril (1400 x2) 3 times per day (1400x2x3 = 8400u)	Drug: unfractionated heparin; intranasal; Other Names: heparin
Placebo Comparator: intranasal saline; Comparator 0.9% saline (as saline solution, 140 microlitres/actuation, Two actuations each nostril) Three times daily via a plastic nasal inhalator device(APTAR, UK) for 10 days.	Drug: 0.9%sodium chloride; intranasal; Other Names: normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of household contacts (swab negative on day 1) testing positive for SARS-CoV-2 by PCR on either of three routine nasopharyngeal swabs on day 3,5 and 10 after enrolment or on nasopharyngeal swab in response to clinical symptoms in the first 14 days	household contacts who become COVID 19 positive at any time during study period	14 days from randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of household contacts (swab negative on day 1 of study) becoming symptomatic of COVID-19 in next 28 days	household contacts who develop symptomatic COVID 19 defined as : fever (≥38°C) PLUS ≥1 respiratory symptom (sore throat, cough, shortness of breath); OR 2 respiratory symptoms (sore throat, cough, shortness of breath); OR 1 respiratory symptom (sore throat, cough, shortness of breath) PLUS ≥2 non-respiratory symptoms (chills, nausea, vomiting, diarrhea, headache, conjunctivitis, myalgia, arthralgia, loss of taste or smell, fatigue or general malaise).	28 days from randomisation
total number of index cases and household contacts (nasopharyngeal swab positive on day 1) combined, who remain swab positive on day 3	proportion of COVID 19 positive participants becoming swab negative by day 3	3 days from randomisation
total number of index cases and household contacts (nasopharyngeal swab positive on day 1) combined, who remain swab positive on day 5	proportion of COVID 19 positive participants becoming swab negative by day 5	5 days from randomisation
total number of index cases and household contacts (nasopharyngeal swab positive on day 1) combined, who remain swab positive on day 10	proportion of COVID 19 positive participants becoming swab negative by day 10	10 days from randomisation
Time to swab negative based on daily anterior nasal swab for index cases and household contacts combined who were swab positive on day 1.	mean time to swab negative in all COVID 19 positive participants	10 days from randomisation
Quantitative replication sub genomic viral RNA at days 3 post randomisation.	The quantitative assay to generate these data will be the Q2 SARS-CoV-2 Viral Load Quantitation Assay, with lower limit of quantification of 500 copies/ml and upper limit of quantification of 500,000,000 copies/ml. Results below or above these limits will be included in the mean and the mean change from baseline, with imputed value 499 and 500,000,001, respectively. High viral load is defined as >106 copies/mL, low viral load is defined as ≤106 copies/mL, and undetectable viral load is defined as < 500 copies/ml	3 days from randomisation
Quantitative replication sub genomic viral RNA at days 5 post randomisation.	The quantitative assay to generate these data will be the Q2 SARS-CoV-2 Viral Load Quantitation Assay, with lower limit of quantification of 500 copies/ml and upper limit of quantification of 500,000,000 copies/ml. Results below or above these limits will be included in the mean and the mean change from baseline, with imputed value 499 and 500,000,001, respectively. High viral load is defined as >106 copies/mL, low viral load is defined as ≤106 copies/mL, and undetectable viral load is defined as < 500 copies/ml	5 days from randomisation
Quantitative replication sub genomic viral RNA at days 10 post randomisation.	The quantitative assay to generate these data will be the Q2 SARS-CoV-2 Viral Load Quantitation Assay, with lower limit of quantification of 500 copies/ml and upper limit of quantification of 500,000,000 copies/ml. Results below or above these limits will be included in the mean and the mean change from baseline, with imputed value 499 and 500,000,001, respectively. High viral load is defined as >106 copies/mL, low viral load is defined as ≤106 copies/mL, and undetectable viral load is defined as < 500 copies/ml	10 days from randomisation
The number of participants who discontinue treatment prior to day 10 from randomisation	treatment tolerability	10 days from randomisation
Number of index cases and household contacts swab positive on day 1, hospitalized with COVID-19 by day 28 from randomization	symptomatic progression of COVID 19	28 days from randomisation
Number of household contacts swab negative on day 1, hospitalized with COVID-19 by day 28 from randomization	symptomatic progression of COVID 19	28 days from randomisation
Maximum severity score of participants (index case and household contacts swab positive on day 1 compared to household contacts swab negative on day 1) during the study period as recorded by daily symptom diary up to day 28	A COVID-19 Composite Subjective Symptom Severity Score will be generated using the 11 common symptoms for COVID 19 infection listed at the Center for disease control website and a self-rated symptom severity assessment generated for each symptom on a daily basis using a Likert scale for each symptom (Scale 0-3: not present mild, moderate, severe). Common symptoms: Fever or chills; Cough; Shortness of breath or difficulty breathing; Fatigue; Muscle or body aches; Headache; New loss of taste or smell; Sore throat; Congestion or runny nose; Nausea or vomiting; Diarrhea Index cases and household contacts will be asked to complete symptom severity checklists daily. Analysis will utilise a summative score	28 days from randomisation
time to symptom resolution analysis for index case and household contacts swab positive on day 1 compared to household contacts swab negative on day 1, during the study period as measured with daily symptom diary until on day 28	hazard ratio of time to sustained improvement or resolution of symptoms based on daily symptoms reports up to day 28 specific to the 11 common symptoms for COVID 19 infection listed at the Center for Disease Control website and a self-rated symptom severity assessment generated for each symptom on a daily basis using a Likert scale for each symptom (Scale 0-3: not present mild, moderate, severe). Common symptoms: Fever or chills; Cough; Shortness of breath or difficulty breathing; Fatigue; Muscle or body aches; Headache; New loss of taste or smell; Sore throat; Congestion or runny nose; Nausea or vomiting; Diarrhea Index cases and household contacts will be asked to complete symptom severity checklists daily.	28 days from randomisation
Number of participants with clinical symptoms of neurological long COVID at 6 months post initial positive COVID-19 test.	Telehealth self-rated symptom assessment using a Likert scale(0-3: absent, mild, moderate, severe). for each symptom Symptoms screened: fatigue, malaise, daytime tiredness, impaired concentration, brain fog, sleep disturbance, forgetfulness, confusion, Headache, dizziness, nausea, Hypo/anosmia , hypo/ageusia, Impaired walking, tingling feet or hands, burning feet or hands, numb feet or hands, impaired fine motor skills, muscle pain, Epilepsy, anxiety, depression. Cognition and mood will be assessed using the harmonised procedures developed by the Neuro-COVID Neuropsychology International Task force. Telephone - Montreal Cognitive Assessment,Patient's Assessment of Own Functioning, Wechsler Adult Intelligence Scale, Digit Span (Forward and Backward),Brief Visuospatial Memory Test - Revised,Hopkins Verbal Learning Test, Depression, Anxiety, Stress Scales	6 months from randomisation
Number of participants with clinical symptoms of neurological long COVID at 12 months post initial positive COVID-19 test.	Telehealth self-rated symptom assessment using a Likert scale(0-3: absent, mild, moderate, severe). for each symptom Symptoms screened: fatigue, malaise, daytime tiredness, impaired concentration, brain fog, sleep disturbance, forgetfulness, confusion, Headache, dizziness, nausea, Hypo/anosmia , hypo/ageusia, Impaired walking, tingling feet or hands, burning feet or hands, numb feet or hands, impaired fine motor skills, muscle pain, Epilepsy, anxiety, depression. Cognition and mood will be assessed using the harmonised procedures developed by the Neuro-COVID Neuropsychology International Task force. Telephone - Montreal Cognitive Assessment,Patient's Assessment of Own Functioning, Wechsler Adult Intelligence Scale, Digit Span (Forward and Backward),Brief Visuospatial Memory Test - Revised,Hopkins Verbal Learning Test, Depression, Anxiety, Stress Scales	12 months from randomisation

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Monash University; St Vincent's Hospital Melbourne; University of Melbourne; The Peter Doherty Institute for Infection and Immunity; Northern Hospital, Australia
• Investigators: Principal Investigator: Paul Monagle, MD, University of Melbourne; Principal Investigator: Donald Campbell, MD, Northern Hospital

Publications and helpful links

General Publications

• Clausen TM, Sandoval DR, Spliid CB, Pihl J, Perrett HR, Painter CD, Narayanan A, Majowicz SA, Kwong EM, McVicar RN, Thacker BE, Glass CA, Yang Z, Torres JL, Golden GJ, Bartels PL, Porell RN, Garretson AF, Laubach L, Feldman J, Yin X, Pu Y, Hauser BM, Caradonna TM, Kellman BP, Martino C, Gordts PLSM, Chanda SK, Schmidt AG, Godula K, Leibel SL, Jose J, Corbett KD, Ward AB, Carlin AF, Esko JD. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell. 2020 Nov 12;183(4):1043-1057.e15. doi: 10.1016/j.cell.2020.09.033. Epub 2020 Sep 14.
• van Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, Smith R, Shute J, Carroll M, Tree J, Carroll M, Singh D, Wilkinson T, Dixon B. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care. 2020 Jul 22;24(1):454. doi: 10.1186/s13054-020-03148-2.
• Monagle K, Ryan A, Hepponstall M, Mertyn E, Monagle P, Ignjatovic V, Newall F. Inhalational use of antithrombotics in humans: Review of the literature. Thromb Res. 2015 Dec;136(6):1059-66. doi: 10.1016/j.thromres.2015.10.011. Epub 2015 Oct 9.
• Dixon B, Smith RJ, Campbell DJ, Moran JL, Doig GS, Rechnitzer T, MacIsaac CM, Simpson N, van Haren FMP, Ghosh AN, Gupta S, Broadfield EJC, Crozier TME, French C, Santamaria JD; CHARLI Study Group. Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2021 Apr;9(4):360-372. doi: 10.1016/S2213-2600(20)30470-7. Epub 2021 Jan 22.
• Conzelmann C, Muller JA, Perkhofer L, Sparrer KM, Zelikin AN, Munch J, Kleger A. Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19. Clin Med (Lond). 2020 Nov;20(6):e218-e221. doi: 10.7861/clinmed.2020-0351. Epub 2020 Aug 30.
• Mycroft-West CJ, Su D, Pagani I, Rudd TR, Elli S, Gandhi NS, Guimond SE, Miller GJ, Meneghetti MCZ, Nader HB, Li Y, Nunes QM, Procter P, Mancini N, Clementi M, Bisio A, Forsyth NR, Ferro V, Turnbull JE, Guerrini M, Fernig DG, Vicenzi E, Yates EA, Lima MA, Skidmore MA. Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin. Thromb Haemost. 2020 Dec;120(12):1700-1715. doi: 10.1055/s-0040-1721319. Epub 2020 Dec 23.
• Tandon R, Sharp JS, Zhang F, Pomin VH, Ashpole NM, Mitra D, McCandless MG, Jin W, Liu H, Sharma P, Linhardt RJ. Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives. J Virol. 2021 Jan 13;95(3):e01987-20. doi: 10.1128/JVI.01987-20. Print 2021 Jan 13.
• Ozsoy Y, Gungor S, Cevher E. Nasal delivery of high molecular weight drugs. Molecules. 2009 Sep 23;14(9):3754-79. doi: 10.3390/molecules14093754.
• Figueroa JM, Lombardo ME, Dogliotti A, Flynn LP, Giugliano R, Simonelli G, Valentini R, Ramos A, Romano P, Marcote M, Michelini A, Salvado A, Sykora E, Kniz C, Kobelinsky M, Salzberg DM, Jerusalinsky D, Uchitel O. Efficacy of a Nasal Spray Containing Iota-Carrageenan in the Postexposure Prophylaxis of COVID-19 in Hospital Personnel Dedicated to Patients Care with COVID-19 Disease. Int J Gen Med. 2021 Oct 1;14:6277-6286. doi: 10.2147/IJGM.S328486. eCollection 2021.
• Stelmach I, Jerzynska J, Stelmach W, Majak P, Brzozowska A, Gorski P, Kuna P. The effect of inhaled heparin on airway responsiveness to histamine and leukotriene D4. Allergy Asthma Proc. 2003 Jan-Feb;24(1):59-65.
• Stelmach I, Jerzynska J, Bobrowska M, Brzozowska A, Majak P, Kuna P. [The effect of inhaled heparin on post-leukotriene bronchoconstriction in children with bronchial asthma]. Pol Merkur Lekarski. 2002 Feb;12(68):95-8. Polish.
• Valencia Sanchez C, Theel E, Binnicker M, Toledano M, McKeon A. Autoimmune Encephalitis After SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes. Neurology. 2021 Dec 7;97(23):e2262-e2268. doi: 10.1212/WNL.0000000000012931. Epub 2021 Oct 11.
• Misra S, Kolappa K, Prasad M, Radhakrishnan D, Thakur KT, Solomon T, Michael BD, Winkler AS, Beghi E, Guekht A, Pardo CA, Wood GK, Hsiang-Yi Chou S, Fink EL, Schmutzhard E, Kheradmand A, Hoo FK, Kumar A, Das A, Srivastava AK, Agarwal A, Dua T, Prasad K. Frequency of Neurologic Manifestations in COVID-19: A Systematic Review and Meta-analysis. Neurology. 2021 Dec 7;97(23):e2269-e2281. doi: 10.1212/WNL.0000000000012930. Epub 2021 Oct 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 21, 2022
• First Submitted That Met QC Criteria: January 21, 2022
• First Posted (Actual): January 24, 2022

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: 83609

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the primary publication and subsequent publications(text, tables, figures, and appendices), after deidentification. Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, Study Principal Investigators must see and approve the analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgement and any additional costs involved must be covered. Should the Study Principal Investigators be unavailable, this role is delegated to the Murdoch Children's Research Institute. Data will only be shared with a recognised research institution which has approved the proposed analysis plan.
• IPD Sharing Time Frame: 6 months after primary publication of the study data for 10 years
• IPD Sharing Access Criteria: 1) Data access agreement; 2) Approval by Principal Investigators; 3) Recognised research institutions; 4) Project has received ethics approval
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No