A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI.

David Adlam, Maciej Zarebinski, Neal G Uren, Pawel Ptaszynski, Keith G Oldroyd, Shahzad Munir, Azfar Zaman, Hussain Contractor, Róbert Gábor Kiss, István Édes, Joanna Szachniewicz, Gergely Gyorgy Nagy, Mario J Garcia, János Tomcsanyi, John Irving, Andrew S P Sharp, Piotr Musialek, Géza Lupkovics, Cheerag Shirodaria, Joseph B Selvanayagam, Pauline Quinn, Leong Ng, Mark Roth, Michael A Insko, Ben Haber, Stephen Hill, Lori Siegel, Simon Tulloch, Keith M Channon

Journal: International journal of cardiology 2022;347():1-7

PMID: 34774885

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI.

METHODS

STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points.

RESULTS

Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo.

CONCLUSIONS

Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes.

CLINICAL TRIAL REGISTRATION

CT.govNCT03470441; EudraCT 2017-000047-41.

Address: Department of Cardiovascular Sciences, NIHR Leicester Biomedical Research Centre, University of Leicester, UK.; Invasive Cardiology Dept. Western Hospital, Grodzisk Mazowiecki, Poland.; Edinburgh Heart Centre, Royal Infirmary, Edinburgh, UK.; Department of Electrocardiology, Medical University of Lodz, Poland; Central University Hospital, Lodz, Poland.; West of Scotland Regional Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, UK.; Cardiology Department, Wolverhampton Heart and Lung Centre, New Cross Hospital, Wolverhampton Road, Wolverhampton, UK.; Freeman Hospital and Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.; Department of Cardiovascular Medicine, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK.; Department of Cardiology, Military Hospital, Budapest, Hungary.; Department of Cardiology, Debrecen University, Debrecen, Hungary.; Centre for Heart Diseases, Military Hospital, Wroclaw, Poland.; Borsod-Abauj-Zemplen County Central Hospital and University Teaching Hospital, 1st Department of Internal Medicine and Cardiology, Miskolc, Hungary.; Division of Cardiology, Montefiore Medical Center, Bronx, NY, USA.; Department of Cardiology, St. John of Brother of God Hospital, Budapest, Hungary.; Department of Cardiology, Ninewells Hospital, Dundee, UK.; University Hospital of Wales, UK; University of Exeter, UK.; Jagiellonian University Department of Cardiac and Vascular Diseases, John Paul II Hospital, Krakow, Poland.; Department of Cardiology, St. Raphael Hospital of Zala County, Zalaegerszeg, Hungary.; Covance Clinical and Periapproval Services Limited, Maidenhead, UK.; Flinders University and South Australian Health and Medical Research Institute, Adelaide, SA, Australia.; Faraday Pharmaceuticals Inc., Seattle, USA.; Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and University of Oxford, John Radcliffe Hospital, Oxford, UK. Electronic address: [email protected].

DOI: 10.1016/j.ijcard.2021.11.016