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

Acute Kidney Injury Clinical Trial

— STOP-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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02182440
• Other study ID #: AP-recAP-AKI-02-01
• Secondary ID: 2014-000761-40
• Status: Completed
• Phase: Phase 2
• Start date: December 18, 2014
• Est. completion date: September 27, 2017

Study information

• Verified date: March 2020
• Source: AM-Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 301
• Est. completion date: September 27, 2017
• Est. primary completion date: May 25, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Kidney Injury

Intervention

Biological:
• recAP
One hour infusions once daily for three days

Other:
• Placebo
1 hour IV infusion once daily for 3 days

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck	Tirol
Austria	Universitätsklinik für Allgemeine und Chirurgische Intensivmedizin	Innsbruck	Tirol
Belgium	University Hospital Antwerpen	Antwerpen
Belgium	CHU Brugmann	Brussels
Belgium	Cliniques Universitaires Saint Luc-UCL	Brussels
Belgium	Hôpital Erasme	Brussels	Brussel
Belgium	UZ Brussel	Brussels
Belgium	University Hospital Ghent	Gent	Oost Vlaanderen
Belgium	CHU UCL Mont Godinne	Yvoir	Namur
Czechia	Fakultni nemocnice u sv. Anny v Brne	Brno	Jihomoravský Kraj
Czechia	Oblastni nemocnice Kolin, a.s.	Kolin
Czechia	Fakultni nemocnice Plzen	Pilsen
Finland	Helsingin Yliopistollinen Keskussairaala	Helsinki
Finland	Kuopion Yliopistollinen Sairaala	Kuopio
Finland	Tampereen yliopistollinen sairaala	Tampere
France	CHU Angers	Angers
France	Centre Hospitalier Victor Dupouy - hopital	Argenteuil
France	Centre Hospitalier Departemental de Vendee	La Roche sur Yon	Vendée
France	Hôpital Universitaire Dupuytren	Limoges	Haute-Vienne
France	CHRU Nantes - Hospital	Nantes
France	Hôpital Lariboisière	Paris
France	Hôpital Charles Nicolle	Rouen	Seine-Maritime
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
Germany	Helios Klinikum Erfurt -Klinik fur Anaesthesie, Intensivmedizin und Schmerztherapie	Erfurt	Thüringen
Germany	University Hospital Frankfurt, Anaesthesia, Intensive Care Medicine & Pain Therapy	Frankfurt am Main,	Hessen
Germany	Universitätsmedizin Greifswald Klinik für Anästhesiologie, IntensivmedizinNotfallmedizin und Schmerzmedizin	Greifswald	Mecklenburg-Vorpommern
Germany	Universitätsklinikum Hamburg Eppendorf Department Intensive Care Medicine	Hamburg
Germany	Medizinische Hochschule Hannover Hospital - Zentrum Innere Medizin - Klinik fuer Pneumologie	Hannover	Niedersachsen
Germany	Universitatsklinikum Jena - Klinik für Anästhesiologie und Intensivmedzin	Jena	Thüringen
Germany	Universitätsklinikum Schleswig-Holstein - Klinik für Anästhesiologie und Operative Intensivmedizin	Kiel	Schleswig-Holstein
Ireland	St. Vincent's University Hospital	Dublin
Netherlands	Jeroen Bosch Ziekenhuis	's Hertogenbosch	Noord-Brabant
Netherlands	VU Medisch Centrum	Amsterdam	Noord-Holland
Netherlands	Gelre Ziekenhuizen - Hospital	Apeldoorn,
Netherlands	Medisch Spectrum Twente	Enschede	Overijssel
Netherlands	Medical Center Leeuwarden	Leeuwarden	Friesland
Netherlands	Canisius Wilhelmina Ziekenhuis	Nijmegen	Gelderland
Netherlands	Radboud University Nijmegen	Nijmegen	Gelderland
Netherlands	Erasmus Medisch Centrum	Rotterdam	Zuid-Holland
Netherlands	Ikazia Ziekenhuis	Rotterdam	Zuid-Holland
Spain	Hospital Universitario Germans Trias i Pujol Medicina Intensiva Hospital General,	Badalona	Barcelona
Spain	Hospital de La Santa Creu i Sant Pau	Barcelona	Cataluna
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario 12 de Octubre, Unidad de Cuidados Intensivos Hospital General	Madrid
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Cataluna
Spain	Hospital Universitari de Tarragona Joan XXIII	Tarragona
Spain	Hospital Mutua de Terrassa	Terrassa	Cataluña
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Royal Surrey County Hospital - Intensive Care Unit	Guildford	Surrey
United Kingdom	Royal London Hospital	London
United Kingdom	St James University Hospital	London
United Kingdom	University College London	London
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	University of Texas Houston Medical School	Houston	Texas
United States	Eastern Idaho Medical Consultants LLC	Idaho Falls	Idaho
United States	UPMC	Pittsburgh	Pennsylvania
United States	Tampa General Hospital, Division Emergency Medicine	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
AM-Pharma	PPD

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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	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