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.

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.

Figures

Figure 1.. Flow of Patients Through the STOP-AKI Trial of Recombinant Alkaline Phosphatase in Acute Kidney Injury (AKI)

AKI indicates acute kidney injury; ITT, intention-to-treat; RRT, renal replacement therapy; and STOP-AKI, Safety, Tolerability, Efficacy, and Quality of Life Study of Human Recombinant Alkaline Phosphatase in the Treatment of Patients With Sepsis-Associated Acute Kidney Infection. Part 1 of the trial identified the optimal dose of recombinant alkaline phosphatase. Part 2 compared the optimal dose (1.6 mg/kg) with placebo. aThe ITT population included patients from whom informed consent was obtained and who were randomized to a treatment group. The ITT population did not include patients who were randomized during interim analysis and who were assigned to the human recombinant alkaline phosphatase 0.4 mg/kg or 0.8 mg/kg treatment group because these 2 treatment groups were dropped following interim analysis. bAn unblinded interim analysis was conducted on the part 1 data to determine the optimal recombinant alkaline phosphatase dose for part 2. This analysis compared the primary efficacy end point and a selection of the safety data for the 4 treatment groups from part 1. The interim analysis was conducted when the first 7 days of laboratory data had been collected for 120 patients from part 1.

Figure 2.. Endogenous Creatinine Clearance (ECC) Among Patients Who Were Critically Ill With Sepsis-Associated Acute Kidney Infection

AUC1-7 ECC indicates the area under the time-corrected (ie, measured per day) curve (AUC) for ECC from day 1 through 7, divided by 7 to provide a mean daily creatinine clearance. A, Median increase in ECC from baseline to day 28 from part 1 and part 2 (combined data) of the trial. Error bars indicate distribution free intervals. The data points of the 2 treatment groups were slightly staggered to avoid superimposition. B, Median AUC1-7 ECC for part 1 and part 2 (combined data) of the trial. The top and bottom of the boxes indicate the IQR, whiskers indicate 95% CI, and the circles indicate the individuals whose values were outside the 5th and 95th percentiles of the AUC1–7 ECC.

Figure 3.. Cumulative Incidence of Fatal Events From Baseline to 90 Days for All Treatment Groups in the Safety Data Population of Patients Who Were Critically Ill With Sepsis-Associated Acute Kidney Infection

The median observation time (95% CI) was 16.5 days (6-28) for the 0.4-mg/kg recombinant alkaline phosphatase group, 9.5 days (1-53) for the 0.8-mg/kg recombinant alkaline phosphatase group, 9 days (5-21) for the 1.6-mg/kg recombinant alkaline phosphatase group, and 8 days (4-16) for the placebo group. All patients who died were analyzed and classified as a fatal serious adverse event.