(Revival) Study to Investigate the Efficacy and Safety of Alkaline Phosphatase in Patients With Sepsis-Associated AKI

Sepsis is the leading cause of acute kidney injury (AKI) and a major cause of death. Patients with SA-AKI have a high mortality and morbidity and are at risk of developing chronic kidney disease. AP is a homodimeric endogenous enzyme present in many cells and organs, e.g., intestines, placenta, liver, bone, kidney, and granulocytes. It exerts detoxifying effects through dephosphorylation of endotoxins; pathogen associated molecular pattern molecules (PAMPS e.g., lipopolysaccharide) and damage-associated molecular pattern molecules (DAMPS e.g., adenosine tri- and di-phosphate). In animal models of sepsis and AKI, administration of AP attenuates the inflammatory response, improves renal function and/or reduces mortality.

AM-Pharma B.V. is developing AP as a novel, recombinant chimeric human AP medicinal product, called recAP, to be used as an intravenous infusion for the treatment of SA-AKI. In the Phase 2 trial STOP-AKI, a survival benefit was observed in the two highest dose groups, 0.8 mg/kg and 1.6 mg/kg groups, compared to the placebo group. There were no safety or tolerability concerns for any of the doses tested (0.4, 0.8 and 1.6 mg/kg). The 1.6 mg/kg recAP dose was selected for this Phase 3 trial based on the significant survival benefit observed. PK/PD simulations also confirmed this dose to have the most pronounced treatment effect.

The primary objective of this Phase 3 trial is to confirm the mortality benefit seen in STOP-AKI by demonstrating a reduction in 28 day all cause mortality in patients with SA-AKI treated with 1.6 mg/kg recAP.

Primary Outcome Measures

1. 28-day All-cause Mortality: Main Trial Population
   To demonstrate an effect of recAP on 28 day all cause mortality
2. 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population
   To demonstrate an effect of recAP on 28 day all cause mortality
3. 28-day All-cause Mortality: COVID-19 Population
   To demonstrate an effect of recAP on 28 day all cause mortality

Secondary Outcome Measures

1. Major Adverse Kidney Events 90: Main Trial Population
   Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
2. Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population
   Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
3. Major Adverse Kidney Events 90: COVID-19 Population
   Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
4. Major Adverse Kidney Events Through Day 90: Combined Population
   Major Adverse Kidney Events through day 90 (MAKE90A) : * death until day 90 * greater than 25% drop in estimated glomerular filtration rate at Day 90 * on renal replacement therapy (RRT) at day 90 OR on RRT through Day 28
5. Days Alive and Free of Organ Support Through Day 28: Main Trial Population
   Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
6. Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population
   Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
7. Days Alive and Free of Organ Support Through Day 28: COVID-19 Population
   Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
8. Days Alive and Out of the ICU Through Day 28: Main Trial Population
   Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
9. Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population
   Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
10. Days Alive and Out of the ICU Through Day 28: COVID-19 Population
    Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
11. 90-day All Cause Mortality: Main Trial Population
    90-Day all-cause mortality
12. 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population
    90-Day all-cause mortality
13. 90-day All Cause Mortality: COVID-19 Population
    90-Day all-cause mortality