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*, Alice Richardson, Hwan Jin Yoon, Antonio Artigas, John G. Laffey, Barry Dixon, Roger Smith, Alicia B. Vilaseca, Ruben A. Barbera, Tarek I. Ismail, Rabab S. Mahrous, Mohamed Badr, Gilberto De Nucci, Carlos Sverdloff, Lex M. van Loon, Marta Camprubi-Rimblas, David W. Cosgrave, Thomas L. Smoot, Sabrina Staas, Khine SannCaitlin Sas, Anusha Belani, Christopher Hillman, Janis Shute, Mary Carroll, Tom Wilkinson, Miles Carroll, Dave Singh, Clive Page

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn.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.

Original languageEnglish
Pages (from-to)3075-3091
Number of pages17
JournalBritish Journal of Clinical Pharmacology
Volume87
Issue number8
Early online date12 Jan 2021
DOIs
Publication statusPublished - Aug 2021

Bibliographical note

Funding Information: A.A. and M.C.R. report a research grant for preclinical research from Grifols and from Fisher&Paykel, and payment as Scientific Advisor for Grifols, outside the submitted work. J.L. reports receiving an Academic Collaboration grant funded by Science Foundation Ireland and Aerogen Inc. for a different study (CHARTER‐Ireland). J.S. is Scientific Advisor for and has shares in Ockham Biotech Ltd, which holds patents around the use of inhaled heparin. T.W. is Chief Investigator of the ACCORD COVID Research Programme. D.S. reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, personal fees from GlaxoSmithKline, personal fees from Glenmark, personal fees from Gossamerbio, personal fees from Menarini, personal fees from Mundipharma, personal fees from Novartis, personal fees from Peptinnovate, personal fees from Pfizer, personal fees from Pulmatrix, personal fees from Theravance, personal fees from Verona, outside the submitted work. C.P. reports receiving personal fees from Cipla, Immune Regulation, EpiEndo and Glycosynnovation, and has equity in Verona Pharma, outside of the submitted work. All other authors have nothing to disclose.

Open Access: Free to read, but no Open Access licence

Publisher Copyright: © 2020 British Pharmacological Society.

Citation: van Haren, FMP, Richardson, A, Yoon, H-J, et al. 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; 87: 3075– 3091.

DOI: https://doi.org/10.1111/bcp.14714

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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