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.

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

AUC_1-7 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 AUC_1-7 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 AUC_1–7 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.