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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • on behalf of the REVIVAL investigators

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. Results: Six hundred fifty 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% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0–24] and 14 [0–24], number of days alive and discharged from the ICU through day 28 were 15 [0–22] and 10 [0–22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% 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 reduced MAKE90 events. No safety concerns were identified.

OriginalsprogEngelsk
TidsskriftIntensive Care Medicine
Vol/bind50
Udgave nummer1
Sider (fra-til)68-78
Antal sider11
ISSN0342-4642
DOI
StatusUdgivet - jan. 2024

Bibliografisk note

Funding Information:
PP has received travel reimbursements and consulting fees from AM-Pharma in relation to his role as PI for REVIVAL, and consulting fees from Adrenomed, EBI Paion, Sphingotec, and 4Teen4 outside the submitted work. DCA has received consulting fees from AM-Pharma. KB, AM-Pharma BV, The Netherlands. RB has received consulting fees and research support from AM-Pharma, Baxter, Paion, Viatris, Jafron Biomedical, and CSL Behring. EvdB, AM-Pharma BV, The Netherlands. JB, AM-Pharma BV, The Netherlands. MHB has received consulting fees from AM-Pharma in relation to his role for REVIVAL and has conducted contract research for Inotrem outside of the submitted work. KD has received consulting fees from AM-Pharma. CJD reports no conflicts of interest. RF has received consulting fees from AM-Pharma. BF has received consulting fees from AM-Pharma as a member of the REVIVAL steering committee, and consulting fees from Inotrem, Aridis, and Enlivex outside the submitted work. HG reports funding from various companies in the form of research grants to (and administered by) Aarhus University or Aarhus University Hospital. HG has received support for attending meetings by Baxter A/S. UGP reports no conflicts of interest. EH has received a travel grant from AM-Pharma. SI reports no conflicts of interest. Michael Joannidis has received honoraria or research support from Baxter Healthcare Corp, AM-Pharma, CLS Behring, Fresenius, Takeda, Sanofi and Novartis. JAK discloses fees paid by AM-Pharma in relation to his role as national PI for REVIVAL and is currently a full-time employee of Spectral Medical. KL has been a member of the REVIVAL Steering Committee for AM Pharma. She has been a consultant/member of the DSMB for Seastar, Novartis, BOA Medical, Baxter, and Biomerieux, and she holds stock in Amgen. MM has received lecture fees from Baxter and Fresenius Medical Care. RM reports honoraria for consulting from Baxter, Biomerieux, Mallinckrodt, GE Healthcare, Sanofi, Abiomed, NovaBiomed, Renasym, and advisory board reimbursements from AM Pharma, Renibus, Alexion, Novartis, and Guard. SM reports no conflicts of interest. PTM has received consulting fees from AM-Pharma (for Clinical Trial Steering Committee activities), Novartis, Renibus Therapeutics, and Alexion. AN reports an unrestricted grant from Baxter to support the renal substudy of the TAME trial. MO has received speaker honoraria from Fresenius Medical, Baxter and Biomerieux; her institution received research funding from Baxter, Fresenius Medical, Biomerieux, and LaJolla Pharma. CS reports no conflicts of interest. PV reports no conflicts of interest. MW, AM-Pharma BV, The Netherlands. PJY has received consulting fees from AM Pharma and from Baxter Healthcare Pty. AZ has received consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, Renibus, Fresenius, research funding from Astute-Biomerieux, Fresenius, Baxter, and speakers fees from Astute-Biomerieux, Fresenius, Baxter.

Funding Information:
This work was supported by AM-Pharma. The role of the sponsor in the design of the study was to coordinate and facilitate processes, where the scientific input was provided by the members of the protocol committee, steering committee, and specific input by external experts in data management and statistics. The sponsor contracted an external contract research organization to operationally conduct the study at the study sites. The contract research organization was responsible for setting up the technical systems, data collection, quality control, pharmacovigilance, statistics, and further overall management of the study, under coordination and supervision of the sponsor. The statistical analysis plan was prepared by the contract research organization with input by principal investigator, sponsor, and external experts in statistics. The analyses were performed by external contract research organizations. Data were interpreted by the members of the steering committee, and, in a later phase, all coauthors and external experts, coordinated by the sponsor, could provide input. The principal investigator was responsible for preparation of the manuscript. All coauthors reviewed, made adjustments, and approved the manuscript. The decision to submit the manuscript was made by the principal investigator and other coauthors.

Funding Information:
PIs of all enrolling sites and part of the REVIVAL investigators are depicted in supplementary file 2. The authors would like to thank all participating patients, their families for their support, as well as study coordinators and research nurses of all participating sites in delivering the REVIVAL trial. The members of the data monitoring committee are thanked for their rigorous review of the data throughout the trial process. The authors would also like to thank Danielle Forkink (AM-Pharma, Clinical Trial Coordinator), Mariam Hamed (Phastar Programming Consultant), Annelies Legters (AM-Pharma, Sr. Director, Global Clinical Trials), and Sharon Richards (Phastar Biostatistician Consultant) for their support. The REVIVAL investigators: Rinaldo Bellomo, Angus Carter, Dietmar Fries, Michael Joannidis, Philip Eller, Eric Hoste, Ludovic Gérard, Nicolas DeSchryver, Elisabeth Diltoer, Vincent Huberlant , Isabelle Michaux, Patrick Honore, Tom Fivez, Christopher Doig, Gordon Wood , John Boyd, Scott Millington, Alexis Turgeon, Maj Kamper, Thomas Strøm, Sussanne Iversen, Hendrik Gammelager, Bodil Steen Rasmussen, Christoffer Grant Sølling, Morten Hyllander Mæller, Thorbjoern Groefte , Nilanjan Dey, Ulf Gøttrup Pedersen, Mila Valkonen, Panu Uusalo, Ville Jalkanen, Ferhat Meziani, Jermie Lemarie, Gaetan Plantefeve, Konstantimos Bachoumas, Jean Louis Dufour, Anne-Laure Fedou, Pierre Asfar, Xavier Monnet, Christophe Vinsonneau, Sebastien Gibot, Christophe Guitton, Jean-Pierre Quenot, Gregoire Muller, Jean Yves Lefrant, Emmanuelle Mercier, Alexandre Mebazaa, Melanie Meersch, Andreas Kortgen, Sebastian Fichtner, Stefan Kluge, Gernot Marx, Alistair Nichol, Ignatio Martin-Loeches, 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, Peter Pickkers, Bert Beishuizen, Oscar Hoiting, Tom Dormans, Arthur Van Zanten, Paul Young, Anthony Williams, Colin McArthur, Pawel Twardowski, Shay McGuinness, Ricard Ferrer Roca, Carol Lorencio Cardenas, Anna Navas Perez, Fernando Martinez Sagasti, Marlies Ostermann, 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.

Publisher Copyright:
© 2024, The Author(s).

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