Phase 3 Trial of Recombinant Human Alkaline Phosphatase for Patients with Sepsis-Associated Acute Kidney Injury (REVIVAL)

Abstract

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced MAKE90 in sepsis-associated acute kidney injury (SA-AKI) patients. ‘REVIVAL’, was aphase 3 trial, conducted to confirm its efficacy and safety. Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled <72 hours on vasopressor and <24 hours of AKI. The primary endpoint was 28-day all-cause mortality. The key secondary endpoint was Major Adverse Kidney Events up to day 90 (MAKE90). Results: 650 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% (nominal one-sided p-value of 0.50) at 28 days, and 33.9% and 34.8% (p=0.41) at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90 was 56.7% in the ilofotase alfa group vs. 64.6% in the placebo group (p=0.02), mainly due to the number of patients who received renal replacement therapy (28.2% vs. 36.4%). There was evidence of heterogeneity of treatment effect with a marked reduction in MAKE90 events in patients with pre-existent impaired renal function randomized to ilofotase alfa (p=0.024). Adverse events were reported in 67.9% and 75.0% 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 reno-protective properties, especially among patients with pre-existing renal disease. No safety concerns were identified. Trial registration and date of registration: ClinicalTrials.gov number NCT04411472, May-28-2020

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“…In 1997, Dr. Poelstra et al found that alkaline phosphatase can dephosphorylate and inactivate endotoxin, suggesting that alkaline phosphatase can be used to treat acute kidney injury, resulted from endotoxin-related sepsis [11][12][13][14]. A multicenter clinical study by Dr. Peters showed that a Human Recombinant AP (recAP) was safe and effective in patients with sepsis-associated acute kidney injury [15] In conclusion, recAP is one of the limited pharmaceutical treatment options for sepsis-associated acute kidney injury undergoing clinical trial testing [16].…”