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 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.

Phenotype-specific therapeutic efficacy of ilofotase alfa in patients with sepsis-associated acute kidney injury

“…Patients with phenotype 2, displaying more severe disease and corresponding metabolic and respiratory impairment, were at the highest risk for a MAKE90 event and displayed a clear benefit from treatment with ilofotase alfa. For this phenotype, ilofotase alfa treatment was associated with a 14% decrease in MAKE90 events, an effect size greater than the 8% decrease previously reported in the undifferentiated patient population [ 5 ].…”

“…In total, 650 patients were enrolled into the trial of whom 329 received 1.6 mg/kg ilofotase alfa and 319 received placebo. The study protocol, detailing all in- and exclusion criteria and procedures, as well as the overall results of the trial were previously published [ 4 , 5 ]. For the current analysis, patients with confirmed COVID-19 ( n = 33), or those who had received renal replacement therapy prior to study drug administration ( n = 23) were excluded, leaving 592 patients for further analyses.…”

“…The phase 2 ‘STOP-AKI’ trial evaluated the potential of ilofotase alfa (human recombinant alkaline phosphatase) in 301 SA-AKI patients, showing long-term renal function improvements and significantly reduced mortality [ 3 ]. Subsequently, the phase 3 global ‘REVIVAL’ trial, with 28-day all-cause mortality as the primary endpoint, was discontinued early due to futility [ 4 , 5 ]. However, ilofotase alfa did show therapeutic efficacy on the main secondary endpoint, Major Adverse Kidney Event up to day 90 (MAKE90) [ 4 , 5 ].…”

“…Subsequently, the phase 3 global ‘REVIVAL’ trial, with 28-day all-cause mortality as the primary endpoint, was discontinued early due to futility [ 4 , 5 ]. However, ilofotase alfa did show therapeutic efficacy on the main secondary endpoint, Major Adverse Kidney Event up to day 90 (MAKE90) [ 4 , 5 ]. This is consistent with findings obtained in two earlier studies using bovine alkaline phosphatase [ 6 , 7 ], and with the STOP-AKI study results [ 3 ].…”

“…This is consistent with findings obtained in two earlier studies using bovine alkaline phosphatase [ 6 , 7 ], and with the STOP-AKI study results [ 3 ]. In addition, patients enrolled in REVIVAL who had pre-existent renal impairment, e.g., chronic kidney disease (CKD), showed more therapeutic efficacy of ilofotase alfa, illustrating the potential of a personalized treatment approach [ 5 ]. Clinical phenotyping is a machine learning-based approach which has been shown to identify more homogeneous subgroups within diverse patient populations [ 8 , 9 ].…”