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

Frank M P van Haren^{1

2}, Alice Richardson³, Hwan-Jin Yoon³, Antonio Artigas⁴, John G Laffey^{5

6}, Barry Dixon⁷, Roger Smith⁷, Alicia B Vilaseca⁸, Ruben A Barbera⁸, Tarek I Ismail⁹, Rabab S Mahrous¹⁰, Mohamed Badr¹¹, Gilberto De Nucci^{12

13}, Carlos Sverdloff¹², Lex M van Loon¹, Marta Camprubi-Rimblas⁴, David W Cosgrave⁶, Thomas L Smoot¹⁴, Sabrina Staas¹⁴, Khine Sann¹⁴, Caitlin Sas¹⁴, Anusha Belani¹⁴, Christopher Hillman¹⁴, Janis Shute¹⁵, Mary Carroll¹⁶, Tom Wilkinson¹⁶, Miles Carroll¹⁷, Dave Singh¹⁸, Clive Page¹⁹

Affiliations

¹ Australian National University, College of Health and Medicine, Canberra, Australia.
² Faculty of Health, University of Canberra, Canberra, Australia.
³ Statistical Consulting Unit, Australian National University, Canberra, Australia.
⁴ Critical Center, Corporació Universitaria Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain.
⁵ Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland.
⁶ Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland.
⁷ Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia.
⁸ Service of Haematology and Haemostasis, San Camilo Clinic, Buenos Aires, Argentina.
⁹ Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Helwan University, Cairo, Egypt.
¹⁰ Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
¹¹ Department of Critical Care Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt.
¹² Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
¹³ Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
¹⁴ Frederick Memorial Hospital, Frederick, Maryland, USA.
¹⁵ School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK.
¹⁶ Department of Respiratory Medicine, University of Southampton, Southampton, UK.
¹⁷ National Infection Service, Public Health England, Porton Down, UK.
¹⁸ Medicines Evaluation Unit, University of Manchester, Manchester, UK.
¹⁹ Sackler Institute of Pulmonary Pharmacology, King's College London, UK.

PMID: 33377218
DOI: 10.1111/bcp.14714

Free article

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

Frank M P van Haren et al. Br J Clin Pharmacol. 2021 Aug.

Free article

. 2021 Aug;87(8):3075-3091.

doi: 10.1111/bcp.14714. Epub 2021 Jan 19.

Authors

Affiliations

¹ Australian National University, College of Health and Medicine, Canberra, Australia.
² Faculty of Health, University of Canberra, Canberra, Australia.
³ Statistical Consulting Unit, Australian National University, Canberra, Australia.
⁴ Critical Center, Corporació Universitaria Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain.
⁵ Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland.
⁶ Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland.
⁷ Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia.
⁸ Service of Haematology and Haemostasis, San Camilo Clinic, Buenos Aires, Argentina.
⁹ Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Helwan University, Cairo, Egypt.
¹⁰ Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
¹¹ Department of Critical Care Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt.
¹² Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
¹³ Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
¹⁴ Frederick Memorial Hospital, Frederick, Maryland, USA.
¹⁵ School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK.
¹⁶ Department of Respiratory Medicine, University of Southampton, Southampton, UK.
¹⁷ National Infection Service, Public Health England, Porton Down, UK.
¹⁸ Medicines Evaluation Unit, University of Manchester, Manchester, UK.
¹⁹ Sackler Institute of Pulmonary Pharmacology, King's College London, UK.

PMID: 33377218
DOI: 10.1111/bcp.14714

Abstract

Aims: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus' entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis.

Methods: The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) metatrial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes.

Analysis: We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn.

Trial registration, ethics and dissemination: The metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.

Keywords: COVID-19; SARS; SARS-CoV-2; acute respiratory distress syndrome; inhaled heparin; metatrial; nebulised heparin; pandemic; randomised controlled trial; respiratory failure; unfractionated heparin.

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References

REFERENCES

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1. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581.
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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

Affiliations

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

Authors

Affiliations

Abstract

References

REFERENCES

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous