TY - JOUR

T1 - Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)

AU - Pickkers, Peter

AU - Angus, Derek C.

AU - Bass, Kristie

AU - Bellomo, Rinaldo

AU - van den Berg, Erik

AU - Bernholz, Juliane

AU - Bestle, Morten H.

AU - Doi, Kent

AU - Doig, Christopher

AU - Ferrer, Ricard

AU - Francois, Bruno

AU - Gammelager, Henrik

AU - Pedersen, Ulf Goettrup

AU - Hoste, Eric

AU - Iversen, Susanne

AU - Joannidis, Michael

AU - Kellum, John A.

AU - Liu, Kathleen

AU - Meersch, Melanie

AU - Mehta, Ravindra

AU - Millington, Scott

AU - Murray, Patrick T.

AU - Nichol, Alistair

AU - Ostermann, Marlies

AU - Pettilä, Ville

AU - Sølling, Christoffer Grant

AU - Winkel, Matthias

AU - Young, Paul J.

AU - Zarbock, Alexander

AU - Carter, Angus

AU - Fries, Dietmar

AU - Eller, Philip

AU - Gérard, Ludovic

AU - DeSchryver, Nicolas

AU - Diltoer, Elisabeth

AU - Huberlant, Vincent

AU - Michaux, Isabelle

AU - Honore, Patrick

AU - Fivez, Tom

AU - Doig, Christopher

AU - Wood, Gordon

AU - Boyd, John

AU - Turgeon, Alexis

AU - Kamper, Maj

AU - Strøm, Thomas

AU - Iversen, Sussanne

AU - Gammelager, Hendrik

AU - Rasmussen, Bodil Steen

AU - Sølling, Christoffer Grant

AU - on behalf of the REVIVAL investigators

N1 - Publisher Copyright: © 2024, The Author(s).

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

KW - Acute kidney injury

KW - Chronic kidney disease

KW - MAKE90

KW - Sepsis

UR - http://www.scopus.com/inward/record.url?scp=85181437573&partnerID=8YFLogxK

U2 - 10.1007/s00134-023-07271-w

DO - 10.1007/s00134-023-07271-w

M3 - Journal article

C2 - 38172296

AN - SCOPUS:85181437573

VL - 50

SP - 68

EP - 78

JO - European Journal of Intensive Care Medicine

JF - European Journal of Intensive Care Medicine

SN - 0935-1701

IS - 1

ER -