Clinical Trial

. 2024 Jan;50(1):68-78.

doi: 10.1007/s00134-023-07271-w. Epub 2024 Jan 3.

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

Peter Pickkers¹, Derek C Angus², Kristie Bass³, Rinaldo Bellomo^{4

5}, Erik van den Berg³, Juliane Bernholz³, Morten H Bestle^{6

7}, Kent Doi⁸, Chistopher J Doig⁹, Ricard Ferrer¹⁰, Bruno Francois¹¹, Henrik Gammelager¹², Ulf Goettrup Pedersen¹³, Eric Hoste^{14

15}, Susanne Iversen¹⁶, Michael Joannidis¹⁷, John A Kellum¹⁸, Kathleen Liu¹⁹, Melanie Meersch²⁰, Ravindra Mehta²¹, Scott Millington²², Patrick T Murray²³, Alistair Nichol^{5

24}, Marlies Ostermann²⁵, Ville Pettilä²⁶, Christoffer Solling²⁷, Matthias Winkel³, Paul J Young^{5

28

29

30}, Alexander Zarbock²⁰; REVIVAL investigators

Collaborators, Affiliations

Collaborators

REVIVAL investigators:
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

Affiliations

¹ Department of Intensive Care, Radboudumc, Nijmegen, The Netherlands. Peter.Pickkers@radboudumc.nl.
² Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ AM-Pharma, Utrecht, The Netherlands.
⁴ Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia.
⁵ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
⁶ Department of Anesthesiology and Intensive Care, Copenhagen University Hospital-North Zealand, Hilleroed, Denmark.
⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Emergency and Critical Care Medicine, The University of Tokyo, Tokyo, Japan.
⁹ Department of Critical Care Medicine, Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada.
¹⁰ Department of Intensive Care Medicine, SODIR-VHIR Research Group, Val d'Hebron University Hospital, Barcelona, Spain.
¹¹ Intensive Care, Inserm CIC 1435 & UMR 1092, CHU Limoges, Limoges, France.
¹² Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
¹³ Intensive Care Unit, Zealand University Hospital, Koege, Denmark.
¹⁴ Department of Internal Medicine and Pediatrics, Intensive Care Unit, Ghent University Hospital, Ghent University, Ghent, Belgium.
¹⁵ Research Foundation-Flanders, (FWO), Brussels, Belgium.
¹⁶ Department of Anaesthesiology and Intensive Care, Slagelse Hospital, Slagelse, Denmark.
¹⁷ Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
¹⁸ Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.
¹⁹ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
²¹ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
²² University of Ottawa/The Ottawa Hospital, Ottawa, Canada.
²³ School of Medicine, University College Dublin, Dublin, Ireland.
²⁴ University College Dublin-Clinical Research Centre at St Vincent's University Hospital, Dublin, Ireland.
²⁵ Department of Critical Care, Guys & St Thomas' Foundation Trust, London, UK.
²⁶ Department of Perioperative and Intensive Care, University of Helsinki and Helsinki University Hospital, HUS, Helsinki, Finland.
²⁷ Department of Anaestesiology and Intensive Care, Viborg Regional Hospital, Viborg, Denmark.
²⁸ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
²⁹ Medical Research Institute of New Zealand, Wellington, New Zealand.
³⁰ Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia.

PMID: 38172296
PMCID: PMC10810941
DOI: 10.1007/s00134-023-07271-w

Clinical Trial

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

Peter Pickkers et al. Intensive Care Med. 2024 Jan.

. 2024 Jan;50(1):68-78.

doi: 10.1007/s00134-023-07271-w. Epub 2024 Jan 3.

Authors

Collaborators

REVIVAL investigators:
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

Affiliations

¹ Department of Intensive Care, Radboudumc, Nijmegen, The Netherlands. Peter.Pickkers@radboudumc.nl.
² Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ AM-Pharma, Utrecht, The Netherlands.
⁴ Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia.
⁵ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
⁶ Department of Anesthesiology and Intensive Care, Copenhagen University Hospital-North Zealand, Hilleroed, Denmark.
⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Emergency and Critical Care Medicine, The University of Tokyo, Tokyo, Japan.
⁹ Department of Critical Care Medicine, Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada.
¹⁰ Department of Intensive Care Medicine, SODIR-VHIR Research Group, Val d'Hebron University Hospital, Barcelona, Spain.
¹¹ Intensive Care, Inserm CIC 1435 & UMR 1092, CHU Limoges, Limoges, France.
¹² Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
¹³ Intensive Care Unit, Zealand University Hospital, Koege, Denmark.
¹⁴ Department of Internal Medicine and Pediatrics, Intensive Care Unit, Ghent University Hospital, Ghent University, Ghent, Belgium.
¹⁵ Research Foundation-Flanders, (FWO), Brussels, Belgium.
¹⁶ Department of Anaesthesiology and Intensive Care, Slagelse Hospital, Slagelse, Denmark.
¹⁷ Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
¹⁸ Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.
¹⁹ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
²¹ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
²² University of Ottawa/The Ottawa Hospital, Ottawa, Canada.
²³ School of Medicine, University College Dublin, Dublin, Ireland.
²⁴ University College Dublin-Clinical Research Centre at St Vincent's University Hospital, Dublin, Ireland.
²⁵ Department of Critical Care, Guys & St Thomas' Foundation Trust, London, UK.
²⁶ Department of Perioperative and Intensive Care, University of Helsinki and Helsinki University Hospital, HUS, Helsinki, Finland.
²⁷ Department of Anaestesiology and Intensive Care, Viborg Regional Hospital, Viborg, Denmark.
²⁸ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
²⁹ Medical Research Institute of New Zealand, Wellington, New Zealand.
³⁰ Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia.

PMID: 38172296
PMCID: PMC10810941
DOI: 10.1007/s00134-023-07271-w

Erratum in

Correction: Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL).
Pickkers P, Angus DC, Bass K, Bellomo R, van den Berg E, Bernholz J, Bestle MH, Doi K, Doig CJ, Ferrer R, Francois B, Gammelager H, Pedersen UG, Hoste E, Iversen S, Joannidis M, Kellum JA, Liu K, Meersch M, Mehta R, Millington S, Murray PT, Nichol A, Ostermann M, Pettilä V, Solling C, Winkel M, Young PJ, Zarbock A; REVIVAL investigators. Pickkers P, et al. Intensive Care Med. 2024 Apr;50(4):614-615. doi: 10.1007/s00134-024-07357-z. Intensive Care Med. 2024. PMID: 38436728 Free PMC article. No abstract available.

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.

Trial registration: ClinicalTrials.gov NCT04411472.

Keywords: Acute kidney injury; Chronic kidney disease; MAKE90; Sepsis.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig. 1**
Flowchart of the patients participating in the REVIVAL trial

**Fig. 2**
Predicted probability of an MAKE90A event with 95% confidence limits. Predicted probabilities are taken from the results of the logistic regression model which included “MAKE through day 90” as the outcome of interest, and treatment, pre-AKI reference eGFR, and pre-AKI reference eGFR by treatment interaction (p for interaction = 0.0235). Patients who did not meet the criteria for having a confirmed “MAKE through day 90” event are assumed to not have a “MAKE through day 90” event in the logistic regression model

See this image and copyright information in PMC

References

1. Pickkers P, Angus DC, Arend J, Bellomo R, van den Berg E, Bernholz J, Bestle M, Broglio K, Carlsen J, Doig CJ, Ferrer R, Joannidis M, Francois B, Doi K, Kellum JA, Laterre PF, Liu K, Mehta RL, Murray PT, Ostermann M, Pettilä V, Richards S, Young P, Zarbock A, Kjølbye AL. Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury. BMJ Open. 2023;13:e065613. doi: 10.1136/bmjopen-2022-065613. - DOI - PMC - PubMed
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1. Zarbock A, Nadim MK, Pickkers P, Gomez H, Bell S, Joannidis M, Kashani K, Koyner JL, Pannu N, Meersch M, Reis T, Rimmelé T, Bagshaw SM, Bellomo R, Cantaluppi V, Deep A, De Rosa S, Perez-Fernandez X, Husain-Syed F, Kane-Gill SL, Kelly Y, Mehta RL, Murray PT, Ostermann M, Prowle J, Ricci Z, See EJ, Schneider A, Soranno DE, Tolwani A, Villa G, Ronco C, Forni LG. Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup. Nat Rev Nephrol. 2023;19:401–417. doi: 10.1038/s41581-023-00683-3. - DOI - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous