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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年1月3日

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  • 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 Pedersen,
  • 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 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,
  • Andreas Kortgen,
  • Sebastian Fichtner,
  • Stefan Kluge,
  • Gernot Marx,
  • 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,
  • 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,
  • 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

摘要

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.