Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury

Abstract

IntroductionSepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings.Methods and analysisThis is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with ‘moderate to severe’ chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial.Ethics and disseminationThe trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal.Trial registration numberEudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results. ClinicalTrials.gov number:NCT04411472.

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

“…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 ].…”