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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: unfractionated heparin
* Drug: 0.9%sodium chloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intranasal heparin<br>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<br>* intranasal<br>* Other names: heparin;|
| Placebo Comparator: intranasal saline<br>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<br>* intranasal<br>* Other names: normal saline;|

What is the study measuring?
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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,Colour Trails Test 1 and 2,Symbol Digit Modalities Test Wechsler Adult Intelligence Scale, Digit Span (Forward and Backward),Brief Visuospatial Memory Test - Revised,Hopkins Verbal Learning Test,9-hole pegboard test,Semantic Fluency (Animals) Coin in Hand 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,Colour Trails Test 1 and 2,Symbol Digit Modalities Test Wechsler Adult Intelligence Scale, Digit Span (Forward and Backward),Brief Visuospatial Memory Test - Revised,Hopkins Verbal Learning Test,9-hole pegboard test,Semantic Fluency (Animals) Coin in Hand test.Depression,Anxiety,Stress Scales | 12 months from randomisation |