A Safety, Tolerability, Efficacy and QoL Study of Human recAP in the Treatment of Patients With SA-AKI

A DB Four-Arm, Parallel Group, Proof of Concept, Dose-Finding Adaptive Phase 2a/2b RCT to Investigate the Safety, Tolerability and Efficacy and Effect on QoL of Human Recombinant Alkaline Phosphatase in Patients With Sepsis-Associated AKI

The purpose of this study is to determine whether recombinant Alkaline Phosphatase (recAP) is effective and save, and to determine the most effective dose, in the treatment of patients with acute kidney injury caused by sepsis.

Design:

Adaptive trial with two stages and interim analysis

• Stage 1: four arms; three dose groups and placebo. n=30/arm. (n=120)
• Interim analysis based on 120 subjects, with continued recruitment, adding 11 subjects to Stage 1 safety population (n=131): to evaluate safety and select dose for stage 2
• Stage 2: one dose group and placebo. N=85/arm. (n=170) Total n in the study: 301.

Primary objectives

• To investigate the effect of recAP on renal function (measured creatinine clearance D1-D7 period, incidence and duration of renal replacement therapy (RRT) over 28 days, eGFR at D60 and D90) and related clinical parameters (ICU stay, Hospital stay, Mechanical ventilation over 28 days, SOFA and SAPS2 scores 28 days) in patients with SA-AKI.
• To determine effective therapeutic dose(s) of recAP.

Secondary objectives

• To investigate the safety and tolerability of recAP in patients with SA AKI. (assessed by independent Data Monitoring Board, adverse events over 90 days study period, laboratory values, ECG, physical examniations, vital signs, Anti Drug Antibodies)
• To investigate the pharmacokinetic profile (PK) of recAP in a subset of patients (part 1, n=120) with SA AKI. (Population PK; AUC D1-7, Cmax, Cmin, Tmax, terminal T1/2)
• To investigate the immunogenic potential of recAP in patients with SA AKI. (anti-drug antibodies at D14, D28, D60 and D90)
• To investigate the effect on quality of life (using the EuroQol, EQ-5D) following study inclusion, at ICU discharge, and Day 90.

Other objectives

• To evaluate whether specific patient groups can be identified that benefit most from recAP treatment or patient groups that are non-responders

Inclusion Criteria:

1. Signed Informed Consent Form (patient, legal representative or independent investigator)

2. Age 18 to 85 years, inclusive

3. Is admitted to the ICU or Intermediate Care Unit

4. Has diagnosis of sepsis (< 96 hrs prior to first study drug), according to criteria defined by the American College of Chest Physicians/Society of Critical Care Medicine:

   1. Has a proven or strongly suspected bacterial infection.
   2. Has at least 2 of 4 SIRS criteria 72 hrs < screening and 96 hrs < first study drug

5. First diagnosis of AKI: AKI Stage 1 or greater, according to the AKIN criteria (time-window adjusted):

   1. Increase in serum creatinine > 26.2 µmol/L (0.30 mg/dL) in 48 hrs prior to screening, or
   2. Increase in serum creatinine to > 150% (> 1.5-fold) from reference creatinine value in 48 hrs prior to screening
   3. Urinary output < 0.5 mL/kg/h for > 6 hours following adequate fluid resuscitation

6. Continuing AKI needs to be confirmed by a confirmative fluid corrected serum creatinine measure, or

7. When the AKI diagnosis was made according to the AKIN urine output criteria (urinary output < 0.5 mL/kg/h for > 6 hours), the oliguria or anuria should still meet the AKIN urine output criteria prior to randomization.

Exclusion Criteria:

1. Woman of childbearing potential with a positive pregnancy test, pregnant, or breastfeeding.
2. Weighs more than 115 kg (253 lb).
3. Has life support limitations.
4. Is known to be human immunodeficiency virus positive.
5. Has urosepsis.
6. Is already on dialysis (RRT) or anticipated to receive RRT within 24 hours after study drug dosing due to the underlying disease.
7. Is receiving immunosuppressant treatment or is on chronic high doses of steroids equivalent to prednisone/prednisolone 0.5 mg/kg/day, including solid organ transplant patients. Patients with septic shock treated with hydrocortisone (e.g., 3 × 100 mg) can be included.
8. Is expected to have rapidly fatal outcome (within 24 hours).
9. Has known, confirmed fungal sepsis.
10. Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10 to 15.
11. Has acute pancreatitis with no established source of infection.
12. Has participated in another investigational study within 30 days prior to enrollment.
13. Is not expected to survive for 28 days due to medical conditions other than SA AKI, including cancer, end-stage cardiac disease, cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 30 days, end stage lung disease, and end stage liver disease.
14. Has known prior history of Chronic Kidney Disease with a documented estimated Glomerular Filtration Rate (eGFR) < 60 mL/min by Modification of Diet in Renal Disease MDRD or CKD-EPI formula, known GFR < 60 mL/min, or a known history of persistent creatinine level > 150 µmol/L (1.70 mg/dL) for reasons other than the current sepsis condition.
15. Has diagnosis of malaria or other parasite infections.
16. Has burns on > 20% of body surface.
17. Has had AKI diagnosis according to inclusion criteria > 24 hours prior to study drug administration.
18. Is anticipated to be treated with non-continuous RRT from Day 1 to Day 7.
19. During Day 1 to Day 7 continuous RRT is anticipated to be started or stopped not according to per protocol criteria.
20. The AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs and renal perfusion-related.
21. Improvement in serum creatinine of at least 0.30 mg/dL or (26.2 µmol/L) prior to administration of the study drug.
22. Patients who use nephrotoxic medication and who fulfill the SA-AKI inclusion criteria at screening are not eligible if the use of this nephrotoxic medication is to continue when alternative, medically appropriate, non-nephrotoxic medication is available.
23. Has a history of known IV drug abuse.
24. Is an employee or family member of the investigator or study site personnel.
25. Has active hematological malignancy.