Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)

• DOI: 10.1007/s00134-023-07271-w
• Publication Date: 2024-01-03T19:03:02Z
• Authors: Peter Pickkers; Derek C. Angus; Kristie Bass; Rinaldo Bellomo; Erik van den Berg; Juliane Bernholz; Morten H. Bestle; Kent Doi; Chistopher J. Doig; Ricard Ferrer; Bruno Francois; Henrik Gammelager; Ulf Goettrup Pede...; Eric Hoste; Susanne Iversen; Michael Joannidis; John A. Kellum; Kathleen Liu; Melanie Meersch; Ravindra Mehta; Scott Millington; Patrick T. Murray; Alistair Nichol; Marlies Ostermann; Ville Pettilä; Christoffer Solling; Matthias Winkel; Paul J. Young; Alexander Zarbock; ; Angus Carter; Dietmar Fries; Philip Eller; Ludovic Gérard; Nicolas DeSchryver; Elisabeth Diltoer; Vincent Huberlant; Isabelle Michaux; Patrick M. Honore; Tom Fivez; Christopher Doig; Gordon Wood; John Boyd; Alexis Turgeon; Maj Kamper; Thomas Strøm; Sussanne Iversen; Hendrik Gammelager; Bodil Steen Rasmu...; Christoffer Grant...; Morten Hyllander ...; Thorbjoern Groefte; Nilanjan Dey; Ulf Gøttrup Pedersen; Mila Valkonen; Panu Uusalo; Ville Jalkanen; Ferhat Meziani; Jermie Lemarie; Gaetan Plantefeve; Konstantimos Bach...; Jean Louis Dufour; Anne-Laure Fedou; Pierre Asfar; Xavier Monnet; Christophe Vinson...; Sebastien Gibot; Christophe Guitton; Jean-Pierre Quenot; Gregoire Muller; Jean Yves Lefrant; Emmanuelle Mercier; Alexandre Mebazaa; Andreas Kortgen; Sebastian Fichtner; Stefan Kluge; Gernot Marx; Ignatio Martin-Lo...; Bairbre McNicolas; Hidenobu Kamohara; Masahiro Harada; Takuo Nakagami; Shingo Adachi; Kohei Ota; Ryo Furuya; Ayumu Tsuruoka; Yasuaki Mizushima; Satoki Inoue; Pieter Tuinman; F Wim Roozendaal; Bert Beishuizen; Oscar Hoiting; Tom Dormans; Arthur Van Zanten; Paul Young; Anthony Williams; Colin McArthur; Pawel Twardowski; Shay McGuinness; Ricard Ferrer Roca; Carol Lorencio Ca...; Anna Navas Perez; Fernando Martinez...; Ingeborg Welters; Matt Wise; Sam Waddy; Niall MacCallum; Raghaven Murugan; Hernando Gomez; Larry Busse; David Boldt; Andrew Bernard; Daniel Files; Benjamin Margolis; Jarrod Mosier; Jonathon Truwit; Felix Zamora; Danielle Davison; Matthew Exline; Nathan Nielsen; Duncan Hite
• Keywords: :enfermedades urogenitales masculinas::enfermedades urológicas::enfermedades renales::insuficiencia renal::lesión renal aguda [ENFERMEDADES]; Original; Intensive Care - Radboud University Medical Center; 610; Alkaline Phosphatase/therapeutic use; :Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Acute Kidney Injury [DISEASES]; :afecciones patológicas, signos y síntomas::procesos patológicos::inflamación::síndrome de respuesta inflamatoria sistémica::sepsis [ENFERMEDADES]; Acute kidney injury; :enzimas y coenzimas::enzimas::hidrolasas::esterasas::monoéster fosfórico hidrolasas::fosfatasa alcalina [COMPUESTOS QUÍMICOS Y DROGAS]; Intensive Care Units; Septicèmia - Tractament; Sepsis/complications; Acute Kidney Injury/drug therapy; Chronic kidney disease; Sepsis; Humans; Insuficiència renal aguda - Tractament; :Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Monoester Hydrolases::Alkaline Phosphatase [CHEMICALS AND DRUGS]; MAKE90; :Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation::Systemic Inflammatory Response Syndrome::Sepsis [DISEASES]

Abstract Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced MAKE90 in sepsis-associated acute kidney injury (SA-AKI) patients. ‘REVIVAL’, was aphase 3 trial, conducted to confirm its efficacy and safety. Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled <72 hours on vasopressor and <24 hours of AKI. The primary endpoint was 28-day all-cause mortality. The key secondary endpoint was Major Adverse Kidney Events up to day 90 (MAKE90). Results: 650 patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n=330; placebo n=319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% (nominal one-sided p-value of 0.50) at 28 days, and 33.9% and 34.8% (p=0.41) at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90 was 56.7% in the ilofotase alfa group vs. 64.6% in the placebo group (p=0.02), mainly due to the number of patients who received renal replacement therapy (28.2% vs. 36.4%). There was evidence of heterogeneity of treatment effect with a marked reduction in MAKE90 events in patients with pre-existent impaired renal function randomized to ilofotase alfa (p=0.024). Adverse events were reported in 67.9% and 75.0% patients in the ilofotase and placebo group. Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may however be reno-protective properties, especially among patients with pre-existing renal disease. No safety concerns were identified. Trial registration and date of registration: ClinicalTrials.gov number NCT04411472, May-28-2020