Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Autor:	Lamy A; Department of Perioperative Medicine and Surgery, Population Health Research Institute, Hamilton, Ontario, Canada., Chertow GM; Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA., Jessen M; Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA., Collar A; Department of Thoracic Surgery and Vascular Surgery, MyMichigan Health, Midland, MI, USA., Brown CD; Department of Cardiac Surgery, New Brunswick Heart Centre, Saint John, New Brunswick, Canada., Mack CA; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA., Marzouk M; Department of Cardiac Surgery, Québec Heart and Lung Institute, Québec, Québec, Canada., Scavo V; Department of Cardiovascular and Thoracic Surgery, Lutheran Medical Group, Fort Wayne, Indiana, USA., Washburn TB; Department of Cardiothoracic Surgery, Huntsville Hospital Heart Center, Huntsville, AL, USA., Savage D; Department of Cardiothoracic Surgery, Indiana University Health, Bloomington, IN, USA., Smith J; Department of Surgery (School of Clinical Sciences at Monash Health), Monash University and Department of Cardiothoracic Surgery, Monash Health, Melbourne, Victoria, Australia., Bennetts J; Department of Cardiothoracic Surgery, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia.; Department of Surgery, College of Medicine and Public Health, Flinders University, Adelaide, Australia., Assi R; Department of Cardiac Surgery, Yale University School of Medicine, New Haven, CT, USA., Shults C; Department of Cardiac Surgery, MedStar Heart and Vascular Institute, Washington, DC, USA., Arghami A; Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA., Butler J; Department of Medicine, University of Mississippi, Jackson, MS, USA.; Baylor Scott and White Research Institute, Dallas, TX, USA., Devereaux PJ; Department of Perioperative Medicine and Surgery, Population Health Research Institute, Hamilton, Ontario, Canada., Zager R; Department of Drug Development & Medical Affairs, Renibus Therapeutics Inc, Southlake, TX, USA., Wang C; Pharma Data Associates LLC, Piscataway, NJ, USA., Snapinn S; Seattle-Quilcene Biostatistics LLC, Seattle, WA, USA., Browne A; Department of Perioperative Medicine and Surgery, Population Health Research Institute, Hamilton, Ontario, Canada., Rodriguez J; Department of Drug Development & Medical Affairs, Renibus Therapeutics Inc, Southlake, TX, USA., Ruiz S; Department of Drug Development & Medical Affairs, Renibus Therapeutics Inc, Southlake, TX, USA., Singh B; Department of Drug Development & Medical Affairs, Renibus Therapeutics Inc, Southlake, TX, USA.
Jazyk:	angličtina
Zdroj:	EClinicalMedicine [EClinicalMedicine] 2024 Jan 08; Vol. 68, pp. 102364. Date of Electronic Publication: 2024 Jan 08 (Print Publication: 2024).
DOI:	10.1016/j.eclinm.2023.102364
Abstrakt:	Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc. Competing Interests: JBu declares consultant fees and speaker fees from 3ivelabs, Abbott, Amgen, American Regent, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element, Faraday, G3 Pharmaceutical, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Janssen, LivaNova, Lexicon, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Occlutech, PharmaCosmos, Roche, Sanofi, Secretome, Sequana, Tricog, and Vifor, outside the submitted work. GMC declares consultant fees, personal fees, stock and grants as advisory board and non-profit board from Akebia, AstraZeneca, Bayer, CloudCath, CSL Behring, Durect, Eliaz Therapeutics, Mineralys, Miromatrix, NIAID, NIDDK, Outset, Physiowave, ReCor, Renibus, Sanifit, Satellite Healthcare, Unicycive, and Vertex, outside the submitted work. JBe declares personal fees and stock as advisory board and speaker fee from Anteris Pty Ltd, Medtronic, Edwards LifeSicences, Abbott Medical, Anteris, LivaNova, Johnson and Johnson, Prostheses List Advisory Committee—Dept of Health (Govt of Australia), Australia & New Zealand Society Cardiac & Thoracic Surgeons (ANZSCTS), and Cardiac Society Australia and New Zealand (CSANZ), outside the submitted work. PJD declares grants, personal fees and equipment as advisory board and consultant from Abbott Diagnostics, Roche Diagnostics, Siemens, Trimedic Canada, Renibus, PEPPER, Bayer AG, Quidel, CloudDX, and Philips Healthcare, outside the submitted work. CAM declares payment for expert testimony and is chair of the membership committee for the New York Society for Thoracic Surgery, outside the submitted work. DHS declares personal fees from Renibus Therapeutics for the submitted manuscript. BS declares personal fees from Renibus Therapeutics for the submitted manuscript and personal fees, patents, and stock as advisory board from Allakos, Nephcentric, Transplant First Academy, and Cardiorenal Society. SS declares consultant fees from Renibus for the submitted work and consultant fees and advisory board from Advarra, Allogene, Apellis, Athira, Blue Note, Equillium, Genescence, GSK, Latigo, Mironid, Moderna, Neumora, Nurix, Oculis, Prolaio, Prolocor, Sail Bio, Transcenta, University of Vermont, Acadia, Oxthera, Vertex, Wildwood, Labcorp/Fortrea, IQVIA, Syneos, PPD, ICON, Parexel, Medpace, Castle Creek, Acelyrin, Aerovate, Affinivax, Alexion, Kyverna, Moderna, Pharvaris, and Horizon, outside the submitted work. CW declares consultant fees from Renibus Therapeutics for the submitted work. RZ declares support from Renibus Therapeutics for the submitted work and grants, speaking fees, stock, and equipment from Renibus Therapeutics, outside the submitted work. SR declares support from Renibus Therapeutics for the submitted work as well as patents and stock from Renibus Therapeutics, outside the submitted work. JR declares support from Renibus Therapeutics for the submitted work and stock from Renibus Therapeutics, outside the submitted work. RZ, JR, SR, and BS are employees of Renibus Therapeutics Inc. All other authors declare no competing interests. (© 2023 The Author(s).)
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