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

Introduction: Sepsis, 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 analysis: This 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 dissemination: The 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 number: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results.

Clinicaltrials: gov number: NCT04411472.

Keywords: COVID-19; acute renal failure; intensive & critical care; nephrology.

Figure 1

Trial design. Up to 1400 patients in the main trial population, up to approximately 100 patients in the ‘moderate to severe’ CKD population and up to approximately 100 patients in the COVID-19 population will be enrolled. There will be a maximum of four interim analyses, after approximately 400, 700, 850 and 1000 evaluable patients (ie, treated patients in the main trial population who have reached day 28), respectively. At the interim analyses, the trial may be stopped for futility or, from 700 patients onwards, for success (ie, pre-defined p value for primary endpoint met in the main trial population). Safety will also be assessed at regular intervals and the trial may be stopped or modified for safety concerns¹. In the ‘moderate to severe’ CKD population and in the COVID-19 population, only safety will be assessed at the interim analyses. If the trial is not stopped at one of the interim analyses, a database snapshot will be executed after 1400 patients in the main trial population have reached day 28 to determine if the primary endpoint was met. No further analyses will be performed at this time. An interim lock will take place after all patients in the main trial population have reached day 90. Endpoints defined up to and including day 90 will be analysed and the results used to start the preparation of the CTR. The final DBL will take place after all patients have completed the trial (ie, all patients have completed day 180 or have withdrawn/are lost to follow-up prior to day 180). If patients in the ‘moderate to severe’ CKD population have not completed the trial at the time of the interim lock at day 90 and/or final DBL at day 180 for patients in the main trial population, a separate interim lock at day 90 and/or final DBL at day 180 may be performed for patients in the ‘moderate to severe’ CKD population in order for the analysis of data in the main trial population to commence. A separate interim lock may also be performed for the COVID-19 population. ¹A full safety review at the time of the 850-patient interim analysis will only be performed if a futility or success threshold is reached. CKD, chronic kidney disease; CTR, clinical trial report; DBL, database lock; eGFR, estimated glomerular filtration rate; ICF, informed consent form; mSOFA, modified Sequential Organ Failure Assessment score (excluding Glasgow coma score); recAP, recombinant human alkaline phosphatase.

Figure 2

Timelines for eligibility. To be eligible for the trial, patients must have both sepsis requiring vasopressor therapy and AKI. (1) When AKI is diagnosed before the start of vasopressor therapy, infusion of first dose of trial drug must start within 48 hours of AKI diagnosis. (2) When AKI is diagnosed after start of vasopressor therapy, infusion of first dose of trial drug must start within 24 hours of AKI diagnosis and no more than 72 hours from start of continuous vasopressor therapy for sepsis-induced hypotension. Start of AKI is defined as the timepoint where the patient for the first time meets any one of the inclusion criteria 4a–4d. Start of vasopressor therapy is defined as the start time of any dose of vasopressor in the first vasopressor treatment period that includes a continuous infusion of ≥0.1 µg/kg/min norepinephrine (or equivalent) for sepsis-induced hypotension for at least 1 hour in patients who have received adequate fluid resuscitation in accordance with clinical judgement and the recommendations of the surviving sepsis campaign guidelines. A minimum of 12 hours without any vasopressor is needed to consider start of vasopressor therapy as a new episode. AKI, acute kidney injury; recAP, recombinant human alkaline phosphatase; VP, vasopressor.