Clinical trial NCT02182440: A Safety, Tolerability, Efficacy and QoL Study of Human recAP in the Treatment of Patients With SA-AKI
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Kidney Injury
Keywords: SA-AKI
Sepsis
AKI
Recombinant Alkaline Phosphatase
recAP
Lead sponsor: AM-Pharma
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2014-07-08
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Time Corrected Endogenous Creatinine Clearance From Day 1 to Day 7 (AUC1-7)
timeFrame: 7 days
Secondary outcomes:
measure: Number of Participants Who Had Renal Replacement Therapy (RRT) During the Period Day 1 to Day 28, Inclusive
timeFrame: 28 days
Other outcomes:
measure: All-cause Mortality at Day 28
timeFrame: Day 28
measure: All-cause Mortality at Day 90
timeFrame: Day 90
measure: Number of Participants Meeting at Least One MAKE 60 Criteria
timeFrame: Day 60
measure: Number of Patients Who Meet at Least One of the MAKE 90 Criteria
timeFrame: Day 90
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tampa
country: United States
facility: Tampa General Hospital, Division Emergency Medicine
state: Florida
city: Idaho Falls
country: United States
facility: Eastern Idaho Medical Consultants LLC
state: Idaho
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas Houston Medical School
state: Texas
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
state: Tirol
city: Innsbruck
country: Austria
facility: Universitätsklinik für Allgemeine und Chirurgische Intensivmedizin
state: Tirol
city: Brussels
country: Belgium
facility: Hôpital Erasme
state: Brussel
city: Yvoir
country: Belgium
facility: CHU UCL Mont Godinne
state: Namur
city: Gent
country: Belgium
facility: University Hospital Ghent
state: Oost Vlaanderen
city: Antwerpen
country: Belgium
facility: University Hospital Antwerpen
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc-UCL
city: Brussels
country: Belgium
facility: CHU Brugmann
city: Brussels
country: Belgium
facility: UZ Brussel
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne
state: Jihomoravský Kraj
city: Kolin
country: Czechia
facility: Oblastni nemocnice Kolin, a.s.
city: Pilsen
country: Czechia
facility: Fakultni nemocnice Plzen
city: Helsinki
country: Finland
facility: Helsingin Yliopistollinen Keskussairaala
city: Kuopio
country: Finland
facility: Kuopion Yliopistollinen Sairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Limoges
country: France
facility: Hôpital Universitaire Dupuytren
state: Haute-Vienne
city: Rouen
country: France
facility: Hôpital Charles Nicolle
state: Seine-Maritime
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Departemental de Vendee
state: Vendée
city: Angers
country: France
facility: CHU Angers
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy - hopital
city: Nantes
country: France
facility: CHRU Nantes - Hospital
city: Paris
country: France
facility: Hôpital Lariboisière
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Frankfurt am Main,
country: Germany
facility: University Hospital Frankfurt, Anaesthesia, Intensive Care Medicine & Pain Therapy
state: Hessen
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald Klinik für Anästhesiologie, IntensivmedizinNotfallmedizin und Schmerzmedizin
state: Mecklenburg-Vorpommern
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Hospital - Zentrum Innere Medizin - Klinik fuer Pneumologie
state: Niedersachsen
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein - Klinik für Anästhesiologie und Operative Intensivmedizin
state: Schleswig-Holstein
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt -Klinik fur Anaesthesie, Intensivmedizin und Schmerztherapie
state: Thüringen
city: Jena
country: Germany
facility: Universitatsklinikum Jena - Klinik für Anästhesiologie und Intensivmedzin
state: Thüringen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf Department Intensive Care Medicine
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Leeuwarden
country: Netherlands
facility: Medical Center Leeuwarden
state: Friesland
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
state: Gelderland
city: 's Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord-Holland
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
state: Zuid-Holland
city: Apeldoorn,
country: Netherlands
facility: Gelre Ziekenhuizen - Hospital
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol Medicina Intensiva Hospital General,
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
state: Cataluna
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
state: Cataluna
city: Terrassa
country: Spain
facility: Hospital Mutua de Terrassa
state: Cataluña
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos Hospital General
city: Tarragona
country: Spain
facility: Hospital Universitari de Tarragona Joan XXIII
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital - Intensive Care Unit
state: Surrey
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: University College London
city: London
country: United Kingdom
facility: St James University Hospital
Study officials:
affiliation: AM Pharma BV
name: Jacques Arend, MD DiMD
role: STUDY_DIRECTOR
affiliation: Department Intensive Care, Radboud University Medical Center
name: Peter Pickkers, Prof MD. PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.