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Open Access 03-01-2024 | Acute Kidney Injury | Original

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

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 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, on behalf of the REVIVAL investigators

Published in: Intensive Care Medicine | Issue 1/2024

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Abstract

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.
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Metadata
Title
Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)
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 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
on behalf of the REVIVAL investigators
Publication date
03-01-2024
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine / Issue 1/2024
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-023-07271-w