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Title: Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury.
Austin Authors: Pickkers, Peter;Angus, Derek C;Arend, Jacques;Bellomo, Rinaldo ;van den Berg, Erik;Bernholz, Juliane;Bestle, Morten;Broglio, Kristine;Carlsen, Jan;Doig, Christopher J;Ferrer, Ricard;Joannidis, Michael;Francois, Bruno;Doi, Kent;Kellum, John A;Laterre, Pierre-François;Liu, Kathleen;Mehta, Ravindra L;Murray, Patrick T;Ostermann, Marlies;Pettilä, Ville;Richards, Sharon;Young, Paul;Zarbock, Alexander;Kjølbye, Anne Louise
Affiliation: Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands peter.
Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
AM-Pharma BV, Bunnik, The Netherlands.
Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia.;
Intensive Care
Department of Anaesthesiology and Intensive care, Nordsjaellands Hospital, Hillerod, Denmark.;Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Berry Consultants, Austin, Texas, USA.
Department of Critical Care Medicine, University of Calgary Medical Centre, Calgary, Alberta, Canada.
Intensive Care Department, Universitat Autònoma de Barcelona, Barcelona, Spain.
Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria.
ICU and Inserm C1C, University of Limoges, Limoges, France.
Emergency and Critical Care Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Department of Critical Care Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Divisions of Critical Care Medicine and Nephrology, Departments of Anesthesia and Medicine, University of California San Fransisco, San Francisco, California, USA.
Department of Medicine, University of California, San Diego, California, USA.
School of Medicine, University College Dublin, Dublin, Ireland.
Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.
Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, Helsingin Yliopisto Laaketieteellinen tiedekunta, Helsinki, Finland.
PHASTAR, London, UK.
Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
Department of Anesthesiology, Intensive Care and Pain Medicine, Universität Münster, Münster, Germany.
Issue Date: 3-Apr-2023
Date: 2023-04
Publication information: BMJ Open 2023-04-03; 13(4)
Abstract: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings. This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial. The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal. EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results. gov number: NCT04411472.
DOI: 10.1136/bmjopen-2022-065613
ORCID: 0000-0002-1104-4303
Journal: BMJ Open
Start page: e065613
PubMed URL: 37012016
ISSN: 2044-6055
Type: Journal Article
Subjects: COVID-19
acute renal failure
intensive & critical care
Alkaline Phosphatase/therapeutic use
Sepsis/drug therapy
Acute Kidney Injury/etiology
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