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

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.

• Authors: 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
• Journal: JAMA (JAMA) Vol. 320 Issue 19 Pg. 1998-2009 (11 20 2018) ISSN: 1538-3598 [Electronic] United States
• PMID: 30357272 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Creatinine
• Alkaline Phosphatase

Topics

• Acute Kidney Injury (drug therapy, etiology, metabolism)
• Aged
• Alkaline Phosphatase (administration & dosage, adverse effects, pharmacology)
• Area Under Curve
• Creatinine (metabolism)
• Critical Illness
• Double-Blind Method
• Female
• Follow-Up Studies
• Humans
• Intention to Treat Analysis
• Male
• Middle Aged
• Sepsis (complications)