Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury : A Randomized Clinical Trial
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.
| Errataetall: |
CommentIn: Anaesth Crit Care Pain Med. 2019 Feb;38(1):1-2. - PMID 30635097 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:320 |
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| Enthalten in: |
JAMA - 320(2018), 19 vom: 20. Nov., Seite 1998-2009 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pickkers, Peter [VerfasserIn] |
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| Links: |
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| Themen: |
AYI8EX34EU |
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| Anmerkungen: |
Date Completed 11.12.2018 Date Revised 29.10.2019 published: Print ClinicalTrials.gov: NCT02182440 CommentIn: Anaesth Crit Care Pain Med. 2019 Feb;38(1):1-2. - PMID 30635097 Citation Status MEDLINE |
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| doi: |
10.1001/jama.2018.14283 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM289914582 |
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| 245 | 1 | 0 | |a Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury |b A Randomized Clinical Trial |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 11.12.2018 | ||
| 500 | |a Date Revised 29.10.2019 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT02182440 | ||
| 500 | |a CommentIn: Anaesth Crit Care Pain Med. 2019 Feb;38(1):1-2. - PMID 30635097 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a Trial Registration: ClinicalTrials.gov Identifier: NCT02182440 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Creatinine |2 NLM | |
| 650 | 7 | |a AYI8EX34EU |2 NLM | |
| 650 | 7 | |a Alkaline Phosphatase |2 NLM | |
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| 700 | 1 | |a Mehta, Ravindra L |e verfasserin |4 aut | |
| 700 | 1 | |a Murray, Patrick T |e verfasserin |4 aut | |
| 700 | 1 | |a Joannidis, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Molitoris, Bruce A |e verfasserin |4 aut | |
| 700 | 1 | |a Kellum, John A |e verfasserin |4 aut | |
| 700 | 1 | |a Bachler, Mirjam |e verfasserin |4 aut | |
| 700 | 1 | |a Hoste, Eric A J |e verfasserin |4 aut | |
| 700 | 1 | |a Hoiting, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Krell, Kenneth |e verfasserin |4 aut | |
| 700 | 1 | |a Ostermann, Marlies |e verfasserin |4 aut | |
| 700 | 1 | |a Rozendaal, Wim |e verfasserin |4 aut | |
| 700 | 1 | |a Valkonen, Miia |e verfasserin |4 aut | |
| 700 | 1 | |a Brealey, David |e verfasserin |4 aut | |
| 700 | 1 | |a Beishuizen, Albertus |e verfasserin |4 aut | |
| 700 | 1 | |a Meziani, Ferhat |e verfasserin |4 aut | |
| 700 | 1 | |a Murugan, Raghavan |e verfasserin |4 aut | |
| 700 | 1 | |a de Geus, Hilde |e verfasserin |4 aut | |
| 700 | 1 | |a Payen, Didier |e verfasserin |4 aut | |
| 700 | 1 | |a van den Berg, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Arend, Jacques |e verfasserin |4 aut | |
| 700 | 0 | |a STOP-AKI Investigators |e verfasserin |4 aut | |
| 700 | 1 | |a Arend, Jacques |e investigator |4 oth | |
| 700 | 1 | |a Bachler, Mirjam |e investigator |4 oth | |
| 700 | 1 | |a Beishuizen, Albertus |e investigator |4 oth | |
| 700 | 1 | |a van den Berg, Erik |e investigator |4 oth | |
| 700 | 1 | |a Brealey, David |e investigator |4 oth | |
| 700 | 1 | |a de Geus, Hilde |e investigator |4 oth | |
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| 700 | 1 | |a Hoste, Eric |e investigator |4 oth | |
| 700 | 1 | |a Joannidis, Michael |e investigator |4 oth | |
| 700 | 1 | |a Kellum, John |e investigator |4 oth | |
| 700 | 1 | |a Krell, Kenneth |e investigator |4 oth | |
| 700 | 1 | |a Mehta, Ravindra |e investigator |4 oth | |
| 700 | 1 | |a Meziani, Ferhat |e investigator |4 oth | |
| 700 | 1 | |a Molitoris, Bruce |e investigator |4 oth | |
| 700 | 1 | |a Murugan, Raghaven |e investigator |4 oth | |
| 700 | 1 | |a Ostermann, Marlies |e investigator |4 oth | |
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| 700 | 1 | |a Artigas Raventos, Antonio |e investigator |4 oth | |
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| 700 | 1 | |a Cordasco, Edward |e investigator |4 oth | |
| 700 | 1 | |a Cruz, Dianna |e investigator |4 oth | |
| 700 | 1 | |a Devriendt, Jacques |e investigator |4 oth | |
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| 700 | 1 | |a Jauregui-Peredo, Luis |e investigator |4 oth | |
| 700 | 1 | |a Joannes-Boyau, Olivier |e investigator |4 oth | |
| 700 | 1 | |a Juncos, Luis |e investigator |4 oth | |
| 700 | 1 | |a Karlsson, Sari |e investigator |4 oth | |
| 700 | 1 | |a Kefale, Kallirroi |e investigator |4 oth | |
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| 700 | 1 | |a Monti, Giacomo |e investigator |4 oth | |
| 700 | 1 | |a Laru-Sompa, Raili |e investigator |4 oth | |
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| 700 | 1 | |a Lefrant, Jean-Yves |e investigator |4 oth | |
| 700 | 1 | |a Lerolle, Nicolas |e investigator |4 oth | |
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| 700 | 1 | |a Matejovic, Martin |e investigator |4 oth | |
| 700 | 1 | |a Meier-Hellmann, Andreas |e investigator |4 oth | |
| 700 | 1 | |a Mercier, Emmanuelle |e investigator |4 oth | |
| 700 | 1 | |a Novacek, Martin |e investigator |4 oth | |
| 700 | 1 | |a Nierhaus, Axel |e investigator |4 oth | |
| 700 | 1 | |a Pearl, Ronald |e investigator |4 oth | |
| 700 | 1 | |a Piacentini, Enrique |e investigator |4 oth | |
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| 700 | 1 | |a Plantefève, Gaetan |e investigator |4 oth | |
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