Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial
Peter Pickkers, Ravindra L Mehta, Patrick T Murray, Michael Joannidis, Bruce A Molitoris, John A Kellum, Mirjam Bachler, Eric A J Hoste, Oscar Hoiting, Kenneth Krell, Marlies Ostermann, Wim Rozendaal, Miia Valkonen, David Brealey, Albertus Beishuizen, Ferhat Meziani, Raghavan Murugan, Hilde de Geus, Didier Payen, Erik van den Berg, Jacques Arend, STOP-AKI Investigators, Jacques Arend, Mirjam Bachler, Albertus Beishuizen, Erik van den Berg, David Brealey, Hilde de Geus, Oscar Hoiting, Eric Hoste, Michael Joannidis, John Kellum, Kenneth Krell, Ravindra Mehta, Ferhat Meziani, Bruce Molitoris, Raghaven Murugan, Marlies Ostermann, Didier Payen, Peter Pickkers, Wim Rozendaal, Miia Valkonen, Antonio Artigas Raventos, Frederic Bellec, Antoni Betbese Roig, Azra Bihorac, Thierry Boulain, Edward Cordasco, Dianna Cruz, Jacques Devriendt, Alain Dive, Joseph Eustace, Lui G. Forni, Kevin Finkel, Bruno Francois, Rita Galeiras, Herwig Gerlach, Richard Gerritsen, Matthias Gründling, Luis Jauregui-Peredo, Olivier Joannes-Boyau, Luis Juncos, Sari Karlsson, Kallirroi Kefale, Andreas Kortgen, Giacomo Monti, Raili Laru-Sompa, Pierre-Francois Laterre, Jean-Yves Lefrant, Nicolas Lerolle, Bruno Levy, Andrew Lewington, Jose Lorente, Rafael Manez Mendiluce, Laurent Martin-Lefevre, Martin Matejovic, Andreas Meier-Hellmann, Emmanuelle Mercier, Martin Novacek, Axel Nierhaus, Ronald Pearl, Enrique Piacentini, Michaël Piagnerelli, Gaetan Plantefève, John R. Prowle, Jean-Pierre Quenot, Anjay Rastogi, Jean Reignier, Rene Robert, Ricard Ferrer Roca, Monica Rocco, Alejandro Rodriguez Oviedo, Ignacio Saez de la Fuente, Fernando Martinez Sagasti, Martin Sauer, Fenna J. Schoonderbeek, Matthew Sims, Herbert Spapen, Peter E Spronk, Vladimir Sramek, Thomas Staudinger, Jay Steingrub, Charuhas V Thakar, Robert Thompson, Ashita J Tolwani, Teresa Maria Tomasa Irriguible, Pieter R. Tuinman, Ari Uusaro, Benoît Veber, Jean-Louis Vincent, Jacques Creteur, Anitha Vijayan, Norbert Weiler, James Welker, Tobias Welte, Jason Wilson, Kai Zacharowski, Pleun Hemelaar, Rob ten Pas, Willem Raaben, Annelies Resink, Alistair Nichol, Peter Pickkers, Ravindra L Mehta, Patrick T Murray, Michael Joannidis, Bruce A Molitoris, John A Kellum, Mirjam Bachler, Eric A J Hoste, Oscar Hoiting, Kenneth Krell, Marlies Ostermann, Wim Rozendaal, Miia Valkonen, David Brealey, Albertus Beishuizen, Ferhat Meziani, Raghavan Murugan, Hilde de Geus, Didier Payen, Erik van den Berg, Jacques Arend, STOP-AKI Investigators, Jacques Arend, Mirjam Bachler, Albertus Beishuizen, Erik van den Berg, David Brealey, Hilde de Geus, Oscar Hoiting, Eric Hoste, Michael Joannidis, John Kellum, Kenneth Krell, Ravindra Mehta, Ferhat Meziani, Bruce Molitoris, Raghaven Murugan, Marlies Ostermann, Didier Payen, Peter Pickkers, Wim Rozendaal, Miia Valkonen, Antonio Artigas Raventos, Frederic Bellec, Antoni Betbese Roig, Azra Bihorac, Thierry Boulain, Edward Cordasco, Dianna Cruz, Jacques Devriendt, Alain Dive, Joseph Eustace, Lui G. Forni, Kevin Finkel, Bruno Francois, Rita Galeiras, Herwig Gerlach, Richard Gerritsen, Matthias Gründling, Luis Jauregui-Peredo, Olivier Joannes-Boyau, Luis Juncos, Sari Karlsson, Kallirroi Kefale, Andreas Kortgen, Giacomo Monti, Raili Laru-Sompa, Pierre-Francois Laterre, Jean-Yves Lefrant, Nicolas Lerolle, Bruno Levy, Andrew Lewington, Jose Lorente, Rafael Manez Mendiluce, Laurent Martin-Lefevre, Martin Matejovic, Andreas Meier-Hellmann, Emmanuelle Mercier, Martin Novacek, Axel Nierhaus, Ronald Pearl, Enrique Piacentini, Michaël Piagnerelli, Gaetan Plantefève, John R. Prowle, Jean-Pierre Quenot, Anjay Rastogi, Jean Reignier, Rene Robert, Ricard Ferrer Roca, Monica Rocco, Alejandro Rodriguez Oviedo, Ignacio Saez de la Fuente, Fernando Martinez Sagasti, Martin Sauer, Fenna J. Schoonderbeek, Matthew Sims, Herbert Spapen, Peter E Spronk, Vladimir Sramek, Thomas Staudinger, Jay Steingrub, Charuhas V Thakar, Robert Thompson, Ashita J Tolwani, Teresa Maria Tomasa Irriguible, Pieter R. Tuinman, Ari Uusaro, Benoît Veber, Jean-Louis Vincent, Jacques Creteur, Anitha Vijayan, Norbert Weiler, James Welker, Tobias Welte, Jason Wilson, Kai Zacharowski, Pleun Hemelaar, Rob ten Pas, Willem Raaben, Annelies Resink, Alistair Nichol
Abstract
Importance: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival.
Objective: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI.
Design, setting, and participants: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017.
Interventions: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86).
Main outcomes and measures: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined.
Results: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, -23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group.
Conclusions and relevance: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes.
Trial registration: ClinicalTrials.gov Identifier: NCT02182440.
Conflict of interest statement
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Pickkers reported receiving travel reimbursements and fees for medical monitoring of this trial from AM-Pharma. Dr Mehta reported receiving consulting fees from AM-Pharma. Dr Murray reported receiving consulting fees from AM-Pharma. Dr Joannidis reported receiving travel reimbursements and consulting fees from AM-Pharma; consulting fees from Baxter Healthcare; speakers’ fees from CLS Behring and Astute Medical; and a research grant and speakers’ fees from Fresenius. Dr Molitoris reported adjudicating creatinine clearances in the study, which was paid for by AM-Pharma, and has conducted preclinical studies for AM-Pharma. Dr Kellum reported receiving consulting fees from AM-Pharma. Dr Bachler reported receiving travel reimbursements for meetings of this trial from AM-Pharma; personal fees and travel grants from LFB Biomedicaments; travel grants from Baxter; travel grants and research funding from CSL Behring and Mitsubishi Tanabe; and nonfinancial support from TEM International outside the submitted work. Dr Hoste reported receiving travel reimbursements from AM-Pharma; and speakers’ fees from Alexion. Dr Krell reported receiving support from AM-Pharma for attendance to the CRRT meeting in San Diego 2017. Dr Murugan reported receiving financial support from AM-Pharma to screen and enroll patients in the trial; financial support for other trials through the University of Pittsburgh from La Jolla Pharmaceuticals; grant support from the National Institute of Diabetes and Digestive and Kidney Diseases; and grant funding from Bioporto Inc. Dr van den Berg is an employee of AM-Pharma and holds equity interest in the company; he also has patents or licenses filed via AM-Pharma for which he receives no personal compensation. Dr Arend is an employee of AM-Pharma and holds equity interest in the company; he also has patents or licenses filed via AM-Pharma for which he receives no personal compensation.
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Source: PubMed