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

NCT ID: NCT02182440

Last Updated: 2020-03-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 301 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-18
• Study Completion Date: 2017-09-27

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

Conditions

Acute Kidney Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

1 hour IV infusion once daily for 3 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

1 hour IV infusion once daily for 3 days

0.4 mg/kg (250 U/kg) recAP

1 hour IV infusion once daily for 3 days

Group Type: EXPERIMENTAL

recAP

Intervention Type: BIOLOGICAL

One hour infusions once daily for three days

0.8 mg/kg (500 U/kg) recAP

1 hour IV infusion once daily for 3 days

Group Type: EXPERIMENTAL

recAP

Intervention Type: BIOLOGICAL

One hour infusions once daily for three days

1.6 mg/kg (1000 U/kg) recAP

1 hour IV infusion once daily for 3 days

Group Type: EXPERIMENTAL

recAP

Intervention Type: BIOLOGICAL

One hour infusions once daily for three days

Interventions

recAP

One hour infusions once daily for three days

Intervention Type: BIOLOGICAL

Placebo

1 hour IV infusion once daily for 3 days

Intervention Type: OTHER

Other Intervention Names

Recombinant Alkaline Phosphatase

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.

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.

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.

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PPD Development, LP

INDUSTRY

Sponsor Role: collaborator

AM-Pharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jacques Arend, MD DiMD

Role: STUDY_DIRECTOR

AM Pharma BV

Peter Pickkers, Prof MD. PhD

Role: STUDY_CHAIR

Department Intensive Care, Radboud University Medical Center

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Tampa General Hospital, Division Emergency Medicine

Tampa, Florida, United States

Eastern Idaho Medical Consultants LLC

Idaho Falls, Idaho, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

UPMC

Pittsburgh, Pennsylvania, United States

University of Texas Houston Medical School

Houston, Texas, United States

Medizinische Universität Innsbruck

Innsbruck, Tyrol, Austria

Universitätsklinik für Allgemeine und Chirurgische Intensivmedizin

Innsbruck, Tyrol, Austria

Hôpital Erasme

Brussels, Brussels Capital, Belgium

CHU UCL Mont Godinne

Yvoir, Namur, Belgium

University Hospital Ghent

Ghent, Oost Vlaanderen, Belgium

University Hospital Antwerpen

Antwerp, , Belgium

Cliniques Universitaires Saint Luc-UCL

Brussels, , Belgium

CHU Brugmann

Brussels, , Belgium

UZ Brussel

Brussels, , Belgium

Fakultni nemocnice u sv. Anny v Brne

Brno, South Moravian, Czechia

Oblastni nemocnice Kolin, a.s.

Kolín, , Czechia

Fakultni nemocnice Plzen

Pilsen, , Czechia

Helsingin Yliopistollinen Keskussairaala

Helsinki, , Finland

Kuopion Yliopistollinen Sairaala

Kuopio, , Finland

Tampereen yliopistollinen sairaala

Tampere, , Finland

Hôpital Universitaire Dupuytren

Limoges, Haute-Vienne, France

Hôpital Charles Nicolle

Rouen, Seine-Maritime, France

Centre Hospitalier Departemental de Vendee

La Roche-sur-Yon, Vendée, France

CHU Angers

Angers, , France

Centre Hospitalier Victor Dupouy - hopital

Argenteuil, , France

CHRU Nantes - Hospital

Nantes, , France

Hôpital Lariboisière

Paris, , France

Hôpitaux Universitaires de Strasbourg

Strasbourg, , France

University Hospital Frankfurt, Anaesthesia, Intensive Care Medicine & Pain Therapy

Frankfurt am Main, Hesse, Germany

Medizinische Hochschule Hannover Hospital - Zentrum Innere Medizin - Klinik fuer Pneumologie

Hanover, Lower Saxony, Germany

Universitätsmedizin Greifswald Klinik für Anästhesiologie, IntensivmedizinNotfallmedizin und Schmerzmedizin

Greifswald, Mecklenburg-Vorpommern, Germany

Universitätsklinikum Schleswig-Holstein - Klinik für Anästhesiologie und Operative Intensivmedizin

Kiel, Schleswig-Holstein, Germany

Helios Klinikum Erfurt -Klinik fur Anaesthesie, Intensivmedizin und Schmerztherapie

Erfurt, Thuringia, Germany

Universitatsklinikum Jena - Klinik für Anästhesiologie und Intensivmedzin

Jena, Thuringia, Germany

Universitätsklinikum Hamburg Eppendorf Department Intensive Care Medicine

Hamburg, , Germany

St. Vincent's University Hospital

Dublin, , Ireland

Radboud University Nijmegen

Nijmegen, Gelderland, Netherlands

Canisius Wilhelmina Ziekenhuis

Nijmegen, Gelderland, Netherlands

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, North Brabant, Netherlands

VU Medisch Centrum

Amsterdam, North Holland, Netherlands

Medisch Spectrum Twente

Enschede, Overijssel, Netherlands

Medical Center Leeuwarden

Leeuwarden, Provincie Friesland, Netherlands

Erasmus Medisch Centrum

Rotterdam, South Holland, Netherlands

Ikazia Ziekenhuis

Rotterdam, South Holland, Netherlands

Gelre Ziekenhuizen - Hospital

Apeldoorn, , Netherlands

Hospital Universitario Germans Trias i Pujol Medicina Intensiva Hospital General,

Badalona, Barcelona, Spain

Hospital de La Santa Creu i Sant Pau

Barcelona, Catalonia, Spain

Corporacio Sanitaria Parc Tauli

Sabadell, Catalonia, Spain

Hospital Mutua de Terrassa

Terrassa, Catalonia, Spain

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos Hospital General

Madrid, , Spain

Hospital Universitari de Tarragona Joan XXIII

Tarragona, , Spain

Royal Surrey County Hospital - Intensive Care Unit

Guildford, Surrey, United Kingdom

Royal Infirmary of Edinburgh

Edinburgh, , United Kingdom

Royal London Hospital

London, , United Kingdom

University College London

London, , United Kingdom

St James University Hospital

London, , United Kingdom

Countries

United States; Austria; Belgium; Czechia; Finland; France; Germany; Ireland; Netherlands; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 30357272 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27678541 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-000761-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AP-recAP-AKI-02-01

Identifier Type: -

Identifier Source: org_study_id