Inhaled Heparin for Hospitalised Patients With Coronavirus Disease 2019 (COVID-19) (INHALE-HEP)

INHALEd Nebulised Unfractionated HEParin for the Treatment of Hospitalised Patients With COVID-19 (INHALE-HEP) Australia

Investigator-initiated, multi-centre, randomised, open-label trial of nebulised heparin sodium in addition to standard care compared to standard care alone in hospitalised patients with COVID-19 infection.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19
• Intervention / Treatment: Drug: Unfractionated Heparin

Detailed Description

Heparin has been used as a medicine for over 75 years. It is used mostly as an anticoagulant (blood thinner), injected under the skin or infused into a vein to prevent or treat large blood clots.

Most patients who are eligible for this study are already receiving heparin administered under the skin or into a vein, and this treatment would continue after enrolment in the study, as determined by the treating doctors according to best practice.

In this study heparin is administered using a nebuliser. A nebuliser is a device that changes a fluid into a mist of tiny droplets so it can be easily breathed into the lungs. A nebuliser is a commonly used and effective way of giving medications that work in the lungs. Nebulised heparin is not currently a standard treatment, but there are good reasons to think it could help.

Lung infections, including COVID-19, cause the widespread formation of tiny blood clots in the small blood vessels and air sacs of the lungs, which make breathing difficult and lead to lung damage. Previous studies of patients with serious breathing problems due to pneumonia and other conditions found that nebulised heparin reduced the formation of small blood clots in the lungs, reduced the amount of injury to the lungs and hastened recovery with faster return to living at home. The virus that causes COVID-19 (the SARS-CoV-2 virus) has 'spikes' on its surface that enable it to attach to cells of the body and enter those cells. Another way that nebulised heparin might help is by sticking to these spikes on the virus and inhibiting the ability of the virus to enter the cells.

The main aim is to determine if nebulised heparin reduces the chance that a patient needs help with their breathing from a mechanical ventilator. Other aims are to determine if nebulised heparin increases the chances of surviving and of getting better quicker.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Frank MP van Haren, PhD; Phone Number: +61 2 9113 3285; Email: frank.vanharen@anu.edu.au
• Study Contact Backup: Name: Sarah J Valle, BN; Phone Number: +61 2 9113 3285; Email: sarah.valle@health.nsw.gov.au

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or older
• Currently admitted to hospital
• There is a positive sample for COVID-19 within the past 14 days. The sample can be a nasal or pharyngeal swab, sputum, tracheal aspirate, bronchoalveolar lavage, or another sample from the patient
• Requiring oxygenation according to the modified ordinal clinical scale 4-5

Exclusion Criteria:

• Intubated and on mechanical ventilation, or requiring immediate intubation as per the treating clinician's assessment
• Heparin allergy or heparin-induced thrombocytopaenia
• Activated partial thromboplastin time (APTT) > 120 seconds, not due to anticoagulant therapy and does not correct with administration of fresh frozen plasma
• Platelet count < 20 x 10^9 per L within 48 hours of randomisation
• Pulmonary bleeding or uncontrolled bleeding within 48 hours of randomisation
• Known or suspected pregnancy
• Acute brain injury that may result in long-term disability
• Myopathy, spinal cord injury, or nerve injury or disease with a likely prolonged incapacity to breathe independently e.g. Guillain-Barre syndrome
• Treatment limitations in place, i.e. not for intubation, not for ICU admission
• Death is imminent or inevitable within 24 hours
• Clinician objection
• Participant consent declined

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nebulised heparin; Participants assigned to 'nebulised heparin' will receive nebulised heparin in addition to the standard care required as determined by the treating team.	Drug: Unfractionated Heparin; Heparin sodium will be administered as a nebulised aerosol dose of 25,000 IU heparin three times a day (TDS) via an Aerogen Solo (Aerogen, Ireland) vibrating mesh aerosol drug nebulizer.; Other Names: Heparin
No Intervention: Standard care; Participants assigned to 'standard care' will receive the standard care required as determined by the treating team and will not be treated with nebulised heparin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intubation	The primary outcome is intubation (or death, for patients who died before intubation) before or at day 28 after randomisation.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Survival to hospital discharge censored at day 60	60 days
Oxygenation	Daily ratio of oxygen saturation by pulse oximetry (SpO2) to the fraction of inspired oxygen (FiO2): (SpO2/FiO2 ratio, highest and lowest levels)	28 days
Length of hospitalisation	Duration of hospital length of stay censored at day 60	60 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator free days	The number of days without invasive mechanical ventilation censored at day 60	60 days
Length of Intensive Care Unit admission	Duration of intensive care unit (ICU) admission censored at day 60	60 days
Incidence of bleeding	The rate of bleeding including pulmonary bleeding or other major bleeding assessed daily during intervention censored at 21 days	Day 21

Collaborators and Investigators

• Sponsor: Australian National University
• Collaborators: St Vincent's Hospital Melbourne; The George Institute; Royal North Shore Hospital; St George Hospital, Australia; John Hunter Hospital
• Investigators: Principal Investigator: Frank MP van Haren, PhD, Australian National University

Publications and helpful links

General Publications

• 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.
• van Haren FMP, Richardson A, Yoon HJ, Artigas A, Laffey JG, Dixon B, Smith R, Vilaseca AB, Barbera RA, Ismail TI, Mahrous RS, Badr M, De Nucci G, Sverdloff C, van Loon LM, Camprubi-Rimblas M, Cosgrave DW, Smoot TL, Staas S, Sann K, Sas C, Belani A, Hillman C, Shute J, Carroll M, Wilkinson T, Carroll M, Singh D, Page C. INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and statistical analysis plan for an investigator-initiated international metatrial of randomised studies. Br J Clin Pharmacol. 2021 Aug;87(8):3075-3091. doi: 10.1111/bcp.14714. Epub 2021 Jan 19.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2023
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: January 6, 2022
• First Submitted That Met QC Criteria: January 6, 2022
• First Posted (Actual): January 11, 2022

Study Record Updates

• Last Update Posted (Actual): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 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: INHALE-HEP Australia Version 3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Planned international meta-trial see NCT04635241
• IPD Sharing Time Frame: real-time
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No