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 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 & 1 others Jacques Arend

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJAMA - Journal of the American Medical Association
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Acute Kidney Injury
Alkaline Phosphatase
Creatinine
Sepsis
Randomized Controlled Trials
Placebos
Kidney
Critical Illness
Intention to Treat Analysis
Survival
Therapeutic Uses
Area Under Curve
Intensive Care Units
Outcome Assessment (Health Care)
Incidence
Enzymes
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients with Sepsis-Associated Acute Kidney Injury : A Randomized Clinical Trial. / Pickkers, Peter; Mehta, Ravindra L.; Murray, Patrick T.; Joannidis, Michael; Molitoris, Bruce; Kellum, John A.; Bachler, Mirjam; Hoste, Eric A.J.; Hoiting, Oscar; Krell, Kenneth; Ostermann, Marlies; Rozendaal, Wim; Valkonen, Miia; Brealey, David; Beishuizen, Albertus; Meziani, Ferhat; Murugan, Raghavan; De Geus, Hilde; Payen, Didier; Van Den Berg, Erik; Arend, Jacques.

In: JAMA - Journal of the American Medical Association, 01.01.2018.

Research output: Contribution to journalArticle

Pickkers, P, Mehta, RL, Murray, PT, Joannidis, M, Molitoris, B, Kellum, JA, Bachler, M, Hoste, EAJ, Hoiting, O, Krell, K, Ostermann, M, Rozendaal, W, Valkonen, M, Brealey, D, Beishuizen, A, Meziani, F, Murugan, R, De Geus, H, Payen, D, Van Den Berg, E & Arend, J 2018, 'Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients with Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial', JAMA - Journal of the American Medical Association. https://doi.org/10.1001/jama.2018.14283
Pickkers, Peter ; Mehta, Ravindra L. ; Murray, Patrick T. ; Joannidis, Michael ; Molitoris, Bruce ; Kellum, John A. ; Bachler, Mirjam ; Hoste, Eric A.J. ; Hoiting, Oscar ; Krell, Kenneth ; Ostermann, Marlies ; Rozendaal, Wim ; Valkonen, Miia ; Brealey, David ; Beishuizen, Albertus ; Meziani, Ferhat ; Murugan, Raghavan ; De Geus, Hilde ; Payen, Didier ; Van Den Berg, Erik ; Arend, Jacques. / Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients with Sepsis-Associated Acute Kidney Injury : A Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2018.
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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.",
author = "Peter Pickkers and Mehta, {Ravindra L.} and Murray, {Patrick T.} and Michael Joannidis and Bruce Molitoris and Kellum, {John A.} and Mirjam Bachler and Hoste, {Eric A.J.} and Oscar Hoiting and Kenneth Krell and Marlies Ostermann and Wim Rozendaal and Miia Valkonen and David Brealey and Albertus Beishuizen and Ferhat Meziani and Raghavan Murugan and {De Geus}, Hilde and Didier Payen and {Van Den Berg}, Erik and Jacques Arend",
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TY - JOUR

T1 - Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients with Sepsis-Associated Acute Kidney Injury

T2 - A Randomized Clinical Trial

AU - Pickkers, Peter

AU - Mehta, Ravindra L.

AU - Murray, Patrick T.

AU - Joannidis, Michael

AU - Molitoris, Bruce

AU - Kellum, John A.

AU - Bachler, Mirjam

AU - Hoste, Eric A.J.

AU - Hoiting, Oscar

AU - Krell, Kenneth

AU - Ostermann, Marlies

AU - Rozendaal, Wim

AU - Valkonen, Miia

AU - Brealey, David

AU - Beishuizen, Albertus

AU - Meziani, Ferhat

AU - Murugan, Raghavan

AU - De Geus, Hilde

AU - Payen, Didier

AU - Van Den Berg, Erik

AU - Arend, Jacques

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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