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

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Other: Placebo; Biological: recAP

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 301
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Medizinische Universität Innsbruck
    • Innsbruck, Tirol, Austria, 6020
      • Universitätsklinik für Allgemeine und Chirurgische Intensivmedizin
• Belgium
  • Antwerpen, Belgium, B-2650
    • University Hospital Antwerpen
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc-UCL
  • Brussels, Belgium, B-1020
    • CHU Brugmann
  • Brussels, Belgium, B-1090
    • UZ Brussel
  • Brussel
    • Brussels, Brussel, Belgium, B-1070
      • Hopital Erasme
  • Namur
    • Yvoir, Namur, Belgium, B-5530
      • CHU UCL Mont Godinne
  • Oost Vlaanderen
    • Gent, Oost Vlaanderen, Belgium, 9000
      • University Hospital Ghent
• Czechia
  • Kolin, Czechia, 280 02
    • Oblastni nemocnice Kolin, a.s.
  • Pilsen, Czechia, 30460
    • Fakultní nemocnice Plzeň
  • Jihomoravský Kraj
    • Brno, Jihomoravský Kraj, Czechia, 656 91
      • Fakultni nemocnice u sv. Anny v Brne
• Finland
  • Helsinki, Finland, FI-00290
    • Helsingin Yliopistollinen Keskussairaala
  • Kuopio, Finland, 70210
    • Kuopion Yliopistollinen Sairaala
  • Tampere, Finland, 33520
    • Tampereen yliopistollinen Sairaala
• France
  • Angers, France, 49933
    • CHU Angers
  • Argenteuil, France
    • Centre Hospitalier Victor Dupouy - hopital
  • Nantes, France
    • CHRU Nantes - Hospital
  • Paris, France, 75010
    • Hopital Lariboisiere
  • Strasbourg, France, 67090
    • Hôpitaux Universitaires de Strasbourg
  • Haute-Vienne
    • Limoges, Haute-Vienne, France, 87042
      • Hôpital Universitaire Dupuytren
  • Seine-Maritime
    • Rouen, Seine-Maritime, France, 76031
      • Hopital Charles Nicolle
  • Vendée
    • La Roche sur Yon, Vendée, France, 85925
      • Centre Hospitalier Départemental de Vendée
• Germany
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf Department Intensive Care Medicine
  • Hessen
    • Frankfurt am Main,, Hessen, Germany, 60590
      • University Hospital Frankfurt, Anaesthesia, Intensive Care Medicine & Pain Therapy
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
      • Universitätsmedizin Greifswald Klinik für Anästhesiologie, IntensivmedizinNotfallmedizin und Schmerzmedizin
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover Hospital - Zentrum Innere Medizin - Klinik fuer Pneumologie
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Universitätsklinikum Schleswig-Holstein - Klinik für Anästhesiologie und Operative Intensivmedizin
  • Thüringen
    • Erfurt, Thüringen, Germany, 99089
      • Helios Klinikum Erfurt -Klinik fur Anaesthesie, Intensivmedizin und Schmerztherapie
    • Jena, Thüringen, Germany, 07747
      • Universitatsklinikum Jena - Klinik für Anästhesiologie und Intensivmedzin
• Ireland
  • Dublin, Ireland
    • St. Vincent's University Hospital
• Netherlands
  • Apeldoorn,, Netherlands, 7334 DZ
    • Gelre Ziekenhuizen - Hospital
  • Friesland
    • Leeuwarden, Friesland, Netherlands, 8934 AD
      • Medical Center Leeuwarden
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6532 SZ
      • Canisius Wilhelmina Ziekenhuis
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud University Nijmegen
  • Noord-Brabant
    • 's Hertogenbosch, Noord-Brabant, Netherlands, 5223 GZ
      • Jeroen Bosch Ziekenhuis
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • VU Medisch Centrum
  • Overijssel
    • Enschede, Overijssel, Netherlands, 7513 ER
      • Medisch Spectrum Twente
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 CE
      • Erasmus Medisch Centrum
    • Rotterdam, Zuid-Holland, Netherlands, 3083 AN
      • Ikazia Ziekenhuis
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos Hospital General
  • Tarragona, Spain, 43007
    • Hospital Universitari de Tarragona Joan XXIII
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitario Germans Trias i Pujol Medicina Intensiva Hospital General,
  • Cataluna
    • Barcelona, Cataluna, Spain, 08025
      • Hospital de la Santa Creu i Sant Pau
    • Sabadell, Cataluna, Spain, 08208
      • Corporació Sanitària Parc Taulí
  • Cataluña
    • Terrassa, Cataluña, Spain, 08221
      • Hospital Mutua De Terrassa
• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SB
    • Royal Infirmary of Edinburgh
  • London, United Kingdom, E1 1BB
    • Royal London Hospital
  • London, United Kingdom, NW1 2BU
    • University College London
  • London, United Kingdom
    • St James University Hospital
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 7XX
      • Royal Surrey County Hospital - Intensive Care Unit
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Florida
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital, Division Emergency Medicine
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Eastern Idaho Medical Consultants LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Houston Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 1 hour IV infusion once daily for 3 days	Other: Placebo; 1 hour IV infusion once daily for 3 days
Experimental: 0.4 mg/kg (250 U/kg) recAP; 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase
Experimental: 0.8 mg/kg (500 U/kg) recAP; 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase
Experimental: 1.6 mg/kg (1000 U/kg) recAP; 1 hour IV infusion once daily for 3 days	Biological: recAP; One hour infusions once daily for three days; Other Names: Recombinant Alkaline Phosphatase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Time Corrected Endogenous Creatinine Clearance From Day 1 to Day 7 (AUC1-7)	Primary endpoint is calculated as the average of the standardized endogenous creatinine clearance values over the first seven days between the placebo and 1.6 mg/kg recAP arm. Standardized endogenous creatinine clearance is assessed on each days from D1 to Day 7 during a 6 +/- 1 hour period and calculated in mL/min as the mean creatinine clearance over the period. The study started with 4 treatment arms of which 0.4 mg/kg recAP and the 0.8 mg/kg recAP were dropped after the interim analysis. The number of the patients in the dropped arm are respectively 30 and 32. Therefore the statistical analysis has been performed only on the placebo and 1.6 mg/kg group.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Had Renal Replacement Therapy (RRT) During the Period Day 1 to Day 28, Inclusive	During the study the days on Renal Replacement Therapy (RRT) was recorded for each patients. During the first 7 days of the study (D1 to D7 included), patients were only allowed to receive continuous RRT, thereafter patients were also allowed to receive intermittent RRT. Standardization of RRT was attempted by providing guidelines to start and stop RRT (see protocol). Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality at Day 28	Number of patients in the ITT set, who died in the period between day 1 to day 28. Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.	Day 28
All-cause Mortality at Day 90	Number of patients in the ITT set, who died in the period between Day 1 and Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.	Day 90
Number of Participants Meeting at Least One MAKE 60 Criteria	Make 60 is composed of patients that meet at least one of the following criteria at day 60: had eGFR < 60 mL/min (calculated by using the CKD-EPI formula) or; became dialysis dependent up to Day 60 or; died prior to Day 60 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.	Day 60
Number of Patients Who Meet at Least One of the MAKE 90 Criteria	Make 90 includes patients who meet at least one of the following parameters at Day 90: had eGFR <60 ml/min at Day 90, estimated by the CKD-EPI formula based on a serum creatinine or; was dialysis dependent up to Day 90 or; was hospitalized for a new episode of acute kidney injury prior to Day 90 or; died, prior to Day 90 Statistical analysis was only performed on the placebo and 1.6 mg/kg recAP arm due to the small number of patients treated with the doses of 0.4 mg/kg and 0.8 mg/kg recAP. Those two doses were dropped in part 2 of the study.	Day 90

Collaborators and Investigators

• Sponsor: AM-Pharma
• Collaborators: PPD
• Investigators: Study Director: Jacques Arend, MD DiMD, AM Pharma BV; Study Chair: Peter Pickkers, Prof MD. PhD, Department Intensive Care, Radboud University Medical Center

Publications and helpful links

General Publications

• Pickkers P, Mehta RL, Murray PT, Joannidis M, Molitoris BA, Kellum JA, Bachler M, Hoste EAJ, Hoiting O, Krell K, Ostermann M, Rozendaal W, Valkonen M, Brealey D, Beishuizen A, Meziani F, Murugan R, de Geus H, Payen D, van den Berg E, Arend J; STOP-AKI Investigators. Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial. JAMA. 2018 Nov 20;320(19):1998-2009. doi: 10.1001/jama.2018.14283.
• Peters E, Mehta RL, Murray PT, Hummel J, Joannidis M, Kellum JA, Arend J, Pickkers P. Study protocol for a multicentre randomised controlled trial: Safety, Tolerability, efficacy and quality of life Of a human recombinant alkaline Phosphatase in patients with sepsis-associated Acute Kidney Injury (STOP-AKI). BMJ Open. 2016 Sep 27;6(9):e012371. doi: 10.1136/bmjopen-2016-012371.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2014
• Primary Completion (Actual): May 25, 2017
• Study Completion (Actual): September 27, 2017

Study Registration Dates

• First Submitted: June 27, 2014
• First Submitted That Met QC Criteria: July 3, 2014
• First Posted (Estimate): July 8, 2014

Study Record Updates

• Last Update Posted (Actual): March 23, 2020
• Last Update Submitted That Met QC Criteria: March 4, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Sepsis; AKI; SA-AKI; Recombinant Alkaline Phosphatase; recAP
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: AP-recAP-AKI-02-01; 2014-000761-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED