Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)

Abstract

Acute kidney injury; Chronic kidney disease; Sepsis

Daño renal agudo; Enfermedad renal crónica; Sepsis

Dany renal agut; Malaltia renal crònica; Sèpsia

Purpose Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. Methods In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. Results Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0–24] and 14 [0–24], number of days alive and discharged from the ICU through day 28 were 15 [0–22] and 10 [0–22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group. Conclusion Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified.

This work was supported by AM-Pharma. The role of the sponsor in the design of the study was to coordinate and facilitate processes, where the scientific input was provided by the members of the protocol committee, steering committee, and specific input by external experts in data management and statistics. The sponsor contracted an external contract research organization to operationally conduct the study at the study sites. The contract research organization was responsible for setting up the technical systems, data collection, quality control, pharmacovigilance, statistics, and further overall management of the study, under coordination and supervision of the sponsor. The statistical analysis plan was prepared by the contract research organization with input by principal investigator, sponsor, and external experts in statistics. The analyses were performed by external contract research organizations. Data were interpreted by the members of the steering committee, and, in a later phase, all coauthors and external experts, coordinated by the sponsor, could provide input. The principal investigator was responsible for preparation of the manuscript. All coauthors reviewed, made adjustments, and approved the manuscript. The decision to submit the manuscript was made by the principal investigator and other coauthors.