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JAMA. 2018 Nov 20;320(19):1998-2009. doi: 10.1001/jama.2018.14283.

Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial.

Author information

1
Department of Intensive Care Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
2
Department of Medicine, University of California, San Diego, Medical Center.
3
School of Medicine, University College Dublin, Dublin, Ireland.
4
Department of Internal Medicine, Division of Intensive Care and Emergency Medicine, Medical University Innsbruck, Innsbruck, Austria.
5
Indiana University, Indianapolis.
6
Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania.
7
Department of General and Surgical Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria.
8
Intensive Care, Ghent University, Ghent, Belgium.
9
Clinical Research Foundation Flanders, Brussels, Belgium.
10
Intensive Care, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.
11
Internal Medicine, Eastern Idaho Regional Medical Center, Idaho Falls.
12
Guy's and St Thomas' Hospital, King's College London, London, United Kingdom.
13
Intensive Care, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands.
14
Division of Anesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland.
15
Division of Critical Care, University College London Hospitals National Institute for Health Research Biomedical Research Centre, London, United Kingdom.
16
Bloomsbury Institute of Intensive Care Medicine, University College Hospital, London, United Kingdom.
17
Intensive Care, Medisch Spectrum Twente, Enschede, the Netherlands.
18
Faculté de Médecine, Service de Réanimation, Université de Strasbourg, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.
19
Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
20
Department of Intensive Care, Erasmus Medical Centre, Rotterdam, the Netherlands.
21
Unité Mixte de Recherche INSERM 1160, University Paris 7 Denis Diderot, Paris, France.
22
Department of Anaesthesiology and Critical Care, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France.
23
Clinical Department, AM-Pharma BV, Bunnik, the Netherlands.

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.

PMID:
30357272
PMCID:
PMC6248164
DOI:
10.1001/jama.2018.14283
[Indexed for MEDLINE]
Free PMC Article

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