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

doi:10.1016/j.ijcard.2021.11.016

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. SelvanayagamPauline Quinn, Leong Ng, Mark Roth, Michael A. Insko, Ben Haber, Stephen Hill, Lori Siegel, Simon Tulloch, Keith M. Channon (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1-7
Number of pages	7
Journal	International Journal of Cardiology
Volume	347
Early online date	11 Nov 2021
DOIs	https://doi.org/10.1016/j.ijcard.2021.11.016
Publication status	Published - 15 Jan 2022

Keywords

Myocardial infarction
Primary PCI
Reperfusion injury

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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Adlam, D., Zarebinski, M., Uren, N. G., Ptaszynski, P., Oldroyd, K. G., Munir, S., Zaman, A., Contractor, H., Kiss, R. G., Édes, I., Szachniewicz, J., Nagy, G. G., Garcia, M. J., Tomcsanyi, J., Irving, J., Sharp, A. S. P., Musialek, P., Lupkovics, G., Shirodaria, C., ... Channon, K. M. (2022). A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute stemi patients undergoing primary PCI. International Journal of Cardiology, 347, 1-7. https://doi.org/10.1016/j.ijcard.2021.11.016

@article{a46d23c364c04b75911097fc987635a0,

title = "A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute stemi patients undergoing primary PCI",

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.",

keywords = "Myocardial infarction, Primary PCI, Reperfusion injury",

author = "David Adlam and Maciej Zarebinski and Uren, {Neal G.} and Pawel Ptaszynski and Oldroyd, {Keith G.} and Shahzad Munir and Azfar Zaman and Hussain Contractor and Kiss, {R{\'o}bert G{\'a}bor} and Istv{\'a}n {\'E}des and Joanna Szachniewicz and Nagy, {Gergely Gyorgy} and Garcia, {Mario J.} and J{\'a}nos Tomcsanyi and John Irving and Sharp, {Andrew S. P.} and Piotr Musialek and G{\'e}za Lupkovics and Cheerag Shirodaria and Selvanayagam, {Joseph B.} and Pauline Quinn and Leong Ng and Mark Roth and Insko, {Michael A.} and Ben Haber and Stephen Hill and Lori Siegel and Simon Tulloch and Channon, {Keith M.}",

note = "Funding Information: Dr. Adlam has received funding to support a clinical research fellow from Abbott Vascular. He has also received funding and in-kind support from Astra Zeneca Inc. for unrelated research and has conducted unrelated consultancy for GE Inc. to support research funds. Dr. Oldroyd reports speaker fees from Abbott Vascular and Biosensors and institutional support for unrelated research from Boston Scientific. Funding Information: The clinical trial of FDY-5301 was supported by Faraday Pharmaceuticals . KMC is supported by the British Heart Foundation (BHF; Chair Award CH/16/1/32013 ), and the National Institute for Health (NIHR) Oxford Biomedical Research Centre . DA acknowledges the support of Ian Hudson, Jan Kovac, Elved Roberts, Anthony Gershlick, Andrew Ladwiniec, Shazia Hussain, Amerjeet Banning, Emma Parker Reenamol Abraham, the Leicester NIHR Biomedical Research Centre and the cardiac catheter laboratory staff at Glenfield Hospital, Leicester, UK.",

year = "2022",

month = jan,

day = "15",

doi = "10.1016/j.ijcard.2021.11.016",

language = "English",

volume = "347",

pages = "1--7",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "Elsevier",

}

Adlam, D, Zarebinski, M, Uren, NG, Ptaszynski, P, Oldroyd, KG, Munir, S, Zaman, A, Contractor, H, Kiss, RG, Édes, I, Szachniewicz, J, Nagy, GG, Garcia, MJ, Tomcsanyi, J, Irving, J, Sharp, ASP, Musialek, P, Lupkovics, G, Shirodaria, C, Selvanayagam, JB, Quinn, P, Ng, L, Roth, M, Insko, MA, Haber, B, Hill, S, Siegel, L, Tulloch, S & Channon, KM 2022, 'A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute stemi patients undergoing primary PCI', International Journal of Cardiology, vol. 347, pp. 1-7. https://doi.org/10.1016/j.ijcard.2021.11.016

TY - JOUR

T1 - A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute stemi patients undergoing primary PCI

AU - Adlam, David

AU - Zarebinski, Maciej

AU - Uren, Neal G.

AU - Ptaszynski, Pawel

AU - Oldroyd, Keith G.

AU - Munir, Shahzad

AU - Zaman, Azfar

AU - Contractor, Hussain

AU - Kiss, Róbert Gábor

AU - Édes, István

AU - Szachniewicz, Joanna

AU - Nagy, Gergely Gyorgy

AU - Garcia, Mario J.

AU - Tomcsanyi, János

AU - Irving, John

AU - Sharp, Andrew S. P.

AU - Musialek, Piotr

AU - Lupkovics, Géza

AU - Shirodaria, Cheerag

AU - Selvanayagam, Joseph B.

AU - Quinn, Pauline

AU - Ng, Leong

AU - Roth, Mark

AU - Insko, Michael A.

AU - Haber, Ben

AU - Hill, Stephen

AU - Siegel, Lori

AU - Tulloch, Simon

AU - Channon, Keith M.

N1 - Funding Information: Dr. Adlam has received funding to support a clinical research fellow from Abbott Vascular. He has also received funding and in-kind support from Astra Zeneca Inc. for unrelated research and has conducted unrelated consultancy for GE Inc. to support research funds. Dr. Oldroyd reports speaker fees from Abbott Vascular and Biosensors and institutional support for unrelated research from Boston Scientific. Funding Information: The clinical trial of FDY-5301 was supported by Faraday Pharmaceuticals . KMC is supported by the British Heart Foundation (BHF; Chair Award CH/16/1/32013 ), and the National Institute for Health (NIHR) Oxford Biomedical Research Centre . DA acknowledges the support of Ian Hudson, Jan Kovac, Elved Roberts, Anthony Gershlick, Andrew Ladwiniec, Shazia Hussain, Amerjeet Banning, Emma Parker Reenamol Abraham, the Leicester NIHR Biomedical Research Centre and the cardiac catheter laboratory staff at Glenfield Hospital, Leicester, UK.

PY - 2022/1/15

Y1 - 2022/1/15

N2 - 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.

AB - 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.

KW - Myocardial infarction

KW - Primary PCI

KW - Reperfusion injury

UR - http://www.scopus.com/inward/record.url?scp=85119438551&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2021.11.016

DO - 10.1016/j.ijcard.2021.11.016

M3 - Article

C2 - 34774885

SN - 0167-5273

VL - 347

SP - 1

EP - 7

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

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

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