(Revival) Study to Investigate the Efficacy and Safety of Alkaline Phosphatase in Patients With Sepsis-Associated AKI

Acute Kidney Injury Due to Sepsis Clinical Trial

Official title:

A DB, Placebo-Controlled, Two-Arm Parallel-Group, Phase 3 RCT to Investigate the Efficacy and Safety of Recombinant Human Alkaline Phosphatase for Treatment of Patients With SA-AKI

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04411472
• Other study ID #: AP-recAP-AKI-03-01
• Status: Terminated
• Phase: Phase 3
• Start date: November 2, 2020
• Est. completion date: August 18, 2022

Study information

• Verified date: June 2023
• Source: AM-Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Clinical phase 3 study to investigate the effect of recAP on 28 day mortality in patients admitted to the ICU with acute kidney injury that is caused by sepsis. The study has three distinct SA-AKI trial populations: 1. The main trial population: Patients with a pre-AKI reference eGFR ≥45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization. 2. A 'moderate' CKD population: Patients with a pre-AKI reference eGFR ≥25 and <45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization. 3. A Corona Virus Disease 2019 (COVID-19) population: Patients with proven or suspected SARS-CoV-2 at time of randomization with or without 'moderate' CKD. For patients in this population, COVID-19 should be the main cause of SA-AKI. In the main study population approximately 1400 patients will be enrolled and in the two cohorts with moderate CKD and COVID-19 each up to 100 patients. There are two arms in the study, one with active treatment and one with an inactive compound (placebo). Treatment is by 1 hour intravenous infusion, for three days. Patients are followed up for 28 days to see if there is an improvement on mortality, and followed for 90 and 180 days for mortality and other outcomes e.g. long-term kidney function and quality of life.

Description:

Sepsis is the leading cause of acute kidney injury (AKI) and a major cause of death. Patients with SA-AKI have a high mortality and morbidity and are at risk of developing chronic kidney disease. AP is a homodimeric endogenous enzyme present in many cells and organs, e.g., intestines, placenta, liver, bone, kidney, and granulocytes. It exerts detoxifying effects through dephosphorylation of endotoxins; pathogen associated molecular pattern molecules (PAMPS e.g., lipopolysaccharide) and damage-associated molecular pattern molecules (DAMPS e.g., adenosine tri- and di-phosphate). In animal models of sepsis and AKI, administration of AP attenuates the inflammatory response, improves renal function and/or reduces mortality. AM-Pharma B.V. is developing AP as a novel, recombinant chimeric human AP medicinal product, called recAP, to be used as an intravenous infusion for the treatment of SA-AKI. In the Phase 2 trial STOP-AKI, a survival benefit was observed in the two highest dose groups, 0.8 mg/kg and 1.6 mg/kg groups, compared to the placebo group. There were no safety or tolerability concerns for any of the doses tested (0.4, 0.8 and 1.6 mg/kg). The 1.6 mg/kg recAP dose was selected for this Phase 3 trial based on the significant survival benefit observed. PK/PD simulations also confirmed this dose to have the most pronounced treatment effect. The primary objective of this Phase 3 trial is to confirm the mortality benefit seen in STOP-AKI by demonstrating a reduction in 28 day all cause mortality in patients with SA-AKI treated with 1.6 mg/kg recAP.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 676
• Est. completion date: August 18, 2022
• Est. primary completion date: August 18, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 18 years or older.

2. In the ICU or intermediate care unit for clinical reasons.

3. Have sepsis requiring vasopressor (norepinephrine, epinephrine, dopamine,

phenylephrine, vasopressin, or angiotensin II) therapy, i.e.:

1. suspected or proven bacterial or viral infection. and

2. on vasopressor therapy (=0.1 µg/kg/min norepinephrine or equivalent) for sepsis-induced hypotension for at least one hour despite adequate fluid resuscitation according to clinical judgement. Following the initial one hour on at least 0.1 µg/kg/min norepinephrine or equivalent, any dose of vasopressor counts as vasopressor therapy. The combination of a) and b) automatically ensures that patients fulfill the Sepsis 3 criteria as 0.1 µg/kg/min norepinephrine corresponds to a score of +4 on the Cardiovascular sub-score of the SOFA score.

4. Have AKI according to at least one of the below KDIGO criteria, a to d:

1. An absolute increase in serum or plasma creatinine (CR) by =0.3 mg/dL (=26.5 µmol/L) within 48 hours. or

2. A relative increase in CR to =1.5 times the pre-AKI reference CR value which is known or presumed to have occurred within prior 7 days. or

3. A decrease in urinary output to <0.5 mL/kg/hour for a minimum of 6 hours following adequate fluid resuscitation. or d) If the patient does not have a known history of CKD and there is no pre-AKI reference CR value available from the past 12 months available from the past 12 months: a CR value greater or equal to the levels presented in Table 1, with the increase in CR presumed to have occurred within prior 7 days.

5. Provision of signed and dated ICF in accordance with local regulations.

Exclusion Criteria:

1. a) At sites where enrolment of 'moderate' CKD patients is allowed, patients with 'severe' CKD defined as a pre-AKI reference eGFR <25 mL/min/1.73 m2 are excluded.

• For patients with known CKD, the most recent eGFR prior to index hospitalization needs to be documented as =25 mL/min/1.73 m2.
• For patients with known CKD but no known eGFR prior to hospitalization, presentation eGFR between 25-60 mL/min/1.73 m2 can also be used to rule out 'severe' CKD. b) At sites where enrolment of 'moderate' CKD patients is NOT allowed, patients with 'moderate' and 'severe' CKD defined as a pre-AKI reference eGFR <45 mL/min/1.73 m2 are excluded.
• For patients with known CKD, the most recent eGFR prior to index hospitalization needs to be documented as =45 mL/min/1.73 m2.
• For patients with known CKD but no known eGFR prior to hospitalization, presentation eGFR between 45-60 mL/min/1.73 m2 can also be used to rule out 'moderate' and 'severe' CKD.

2. Advanced chronic liver disease, defined as a Child-Pugh score of 10 to 15 (Class C).

3. Acute pancreatitis without proven infection.

4. Urosepsis related to suspected or proven urinary tract obstruction.

5. Main cause of AKI not sepsis.

6. Proven or suspected SARS-CoV-2 infection. NOTE: This exclusion criterion does not apply to patients in the COVID-19 population, in which COVID-19 should be the main cause of SA-AKI.

7. Severe burns requiring ICU treatment.

8. Severely immunosuppressed, e.g. due to:

• hematopoietic cell transplantation within past 6 months prior to Screening or acute or chronic graft-versus-host disease
• solid organ transplantation
• leukopenia not related to sepsis, i.e., preceding sepsis
• Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS)
• receiving chemotherapy within 30 days prior to Screening.

9. At high risk of being LTFU, e.g., due to known current or recent (within the last 6 months) IV drug abuse or known to be homeless.

10. Limitations to use of mechanical ventilation (MV), RRT or vasopressors and inotropes (NOTE: limitation of cardiopulmonary resuscitation (CPR) only is not an exclusion criterion).

11. Previous administration of recAP.

12. Use of a non-marketed drug within the last month or concurrent or planned participation in a clinical trial for a non-marketed drug or device. (NOTE: Co-enrollment or concurrent participation in observational, non-interventional trials using no protocolized treatments or procedures are always allowed. Co-enrollment or concurrent participation in trials using protocolized treatments or procedures, e.g. blood draws, requires pre-approval by the TSC).

13. Current or planned extracorporeal membrane oxygenation (ECMO).

14. On RRT >24 hours before start of trial drug.

15. No longer on vasopressor therapy at time of randomization.

16. On continuous vasopressor therapy for >72 hours before start of trial drug.

17. Estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 based on the most recent available CR sample at time of screening (NOTE: will often be the sample used to diagnose AKI). eGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. In Japan, the CKD-EPI formula with Japanese coefficient should be used. If local regulations prohibit correcting for race in the calculation of eGFR, it is acceptable to use the formula without correcting for race.

18. Not feasible to start trial drug within:

1. 48 hours from AKI diagnosis, when AKI diagnosis precedes start of vasopressor therapy. or

2. 24 hours from AKI diagnosis, when AKI is diagnosed after start of vasopressor therapy.

19. Pregnant or nursing women.

Related Conditions & MeSH terms

• Acute Kidney Injury
• Acute Kidney Injury Due to Sepsis
• Sepsis

Intervention

Biological:
• Recombinant human alkaline phosphatase
patients with SA-AKI are randomly assigned in a 1:1 ratio to either placebo or 1.6 mg/kg recAP.

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park
Australia	Bendigo Hospital	Bendigo
Australia	Footscray Hospital	Footscray
Australia	Austin Hospital	Melbourne
Australia	John Hunter Hospital	New Lambton Heights
Australia	Sunshine Hospital ICU - Western Hospital	Saint Albans
Australia	Gold Coast University Hospital (GCUH)	Southport
Austria	Medizinische Universitaet Graz - Klinik fuer Innere Medizin	Graz
Austria	Medizinische Universitaet Innsbruck - Universitaetsklinik fuer Innere Medizin I	Innsbruck
Austria	Medizinische Universität Innsbruck	Innsbruck
Belgium	Centre Hospitalier Universitaire Brugmann	Brussels
Belgium	Centre Hospitalier Universitaire (CHU) de Charleroi - Hopital Civil Marie Curie	Charleroi
Belgium	Ziekenhuis Oost-Limburg	Genk
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Universitair Ziekenhuis Brussel	Jette
Belgium	Hôpital de JOLIMONT	La Louvière
Belgium	Clinique Saint-Pierre- Ottignies	Ottignies
Belgium	Cliniques Universitaires Saint-Luc	Woluwe-Saint-Lambert
Belgium	CHU UCL Namur - Mont-Godinne	Yvoir
Canada	Alberta Health Services - South Health Campus Hospital	Calgary
Canada	Foothills Medical Centre	Calgary
Canada	Peter Lougheed Centre	Calgary
Canada	Rockyview General Hospital	Calgary
Canada	The Ottawa Hospital - Civic Campus	Ottawa
Canada	The Ottawa Hospital - General Campus	Ottawa
Canada	Hôpital de l'Enfant-Jésus	Québec
Canada	St. Paul's Hospital	Vancouver
Canada	Royal Jubilee Hospital (RJH)	Victoria
Canada	Victoria General Hospital (VGH)	Victoria
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus N
Denmark	Herning Regional Hospital	Herning
Denmark	Nordsjællands Hospital	Hillerød
Denmark	Rigshospitalet	København
Denmark	Sjaellands Universitetshospital, Koge - Kardiologisk Afdeling	Køge
Denmark	Odense Universitetshospital	Odense C
Denmark	Regionshospitalet Randers	Randers
Denmark	Slagelse Sygehus	Slagelse
Denmark	Hospitalsenhed Midt	Viborg
Finland	Helsinki University Central Hospital (HUCH)	Helsinki
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital (TYKS)	Turku
France	Centre Hospitalier Universitaire d'Angers	Angers Cedex
France	Centre Hospitalier d'Argenteuil	Argenteuil Cedex
France	Centre Hospitalier de Bethune Germon et Gauthier	Béthune
France	Centre Hospitalier René-Dubos	Cergy-Pontoise
France	CHU Dijon - Hôpital François Mitterrand	Dijon
France	Centre Hospitalier Départemental de Vendée - Les Oudairies	La Roche-sur-Yon
France	Hôpital Bicêtre	Le Kremlin-Bicêtre
France	Centre Hospitalier du Mans	Le Mans
France	CHU Limoges - Hôpital Dupuytren	Limoges Cedex
France	CHU de Nancy	Nancy
France	CHU de Nantes - Hôtel-Dieu	Nantes
France	CHU de Nimes - Hopital Universitaire Caremeau	Nîmes cedex 9
France	Hôpital La Source	Orléans
France	Hôpital Lariboisière	Paris
France	Hôpitaux Universitaires de Strasbourg - Hôpital Civil	Strasbourg
France	CHRU de Tours - Hôpital Bretonneau	Tours cedex 9
Germany	Universitätsklinikum Aachen	Aachen
Germany	Universitätsklinikum Hamburg-Eppendorf (UKE)	Hamburg
Germany	University Hospital Jena - Klinik fur Neurologie	Jena
Germany	Universitaetsklinikum Leipzig - Klinik und Poliklinik fuer Gastroenterologie und Rheumatologie	Leipzig
Germany	University Hospital Münster	Münster
Ireland	St. James's Hospital	Dublin
Ireland	St. Vincent's University Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Ireland	National University of Ireland, Galway	Galway	G
Japan	Tokyo Medical University Hachioji Medical Center	Hachioji-Shi
Japan	Hiroshima University Hospital	Hiroshima-shi
Japan	Aso Iizuka Hospital	Izuka-shi
Japan	Rinku General Medical Center	Izumisano-Shi
Japan	Nara Medical University Hospital	Kashihara-Shi
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto-Shi
Japan	Omihachiman Community Medical Center	Omihachiman-Shi
Japan	Osaka City General Hospital	Osaka-Shi
Japan	Osaka Police Hospital	Osaka-shi
Japan	Fujita Health University Hospital	Toyoake-Shi
Japan	National Hospital Organization - Yokohama Medical Center	Yokohama-Shi
Netherlands	Jeroen Bosch Ziekenhuis lokatie GZG	's-Hertogenbosch	NB
Netherlands	Amsterdam UMC - VUMC	Amsterdam
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Zuyderland Medisch Centrum, Heerlen	Heerlen
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Radboud UMC	Nijmegen
New Zealand	Auckland City Hospital	Auckland
New Zealand	Middlemore Clinical Trials	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Dunedin Hospital	Dunedin
New Zealand	Auckland City Hospital	Grafton
New Zealand	Hawke's Bay Hospital Soldiers' Memorial	Hastings
New Zealand	Lakes District Health Board - Rotorua Hospital	Rotorua
New Zealand	Wellington Hospital	Wellington	WGN
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari de Bellvitge (IDIBELL)	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitari de Girona Doctor Josep Trueta	Girona
Spain	Hospital Clínico San Carlos	Madrid
Spain	Parc Taulí Sabadell Hospital Universitari	Sabadell
Spain	Universitat de Barcelona - Hospital Universitari Mutua Terrassa (HUMT)	Terrassa
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Guy's and St Thomas' NHS Foundation Trust - St Thomas' Hospital	London
United Kingdom	University College London Hospitals NHS Foundation Trust - University College Hospital	London	LND
United Kingdom	Plymouth Hospitals NHS Trust - Derriford Hospital	Plymouth
United States	University of New Mexico School of Medicine	Albuquerque	New Mexico
United States	Emory Clinical Cardiovascular Research Institute	Atlanta	Georgia
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University of Cincinnati Cancer Institute	Cincinnati	Ohio
United States	The Ohio State University - Dorothy M. Davis Heart and Lung Research Institute	Columbus	Ohio
United States	Glenbrook Hospital	Glenview	Illinois
United States	NorthShore Medical Group - Bannockburn	Highland Park	Illinois
United States	University of Kentucky College of Medicine (UKCM)	Lexington	Kentucky
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	Froedtert & the Medical College of Wisconsin Froedtert Hospital	Milwaukee	Wisconsin
United States	UPMC CancerCenter at Magee - Womens Hospital	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian	Pittsburgh	Pennsylvania
United States	Regions Hospital	Saint Paul	Minnesota
United States	The University of Arizona Cancer Center	Tucson	Arizona
United States	The George Washington University Medical Faculty Associates - Anesthesiology	Washington	District of Columbia
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AM-Pharma

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Ireland,  Japan,  Netherlands,  New Zealand,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	28-day all-cause mortality	To demonstrate an effect of recAP on 28 day all cause mortality	28 days
Secondary	To investigate the effect of recAP on long-term Major Adverse Kidney Events (MAKE).	MAKE 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or =25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-AKI reference level.	90 Days
Secondary	To investigate the effect of recAP on use of organ support, i.e., mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors or inotropes.	Days alive and free of organ support through Day 28, i.e., days alive with no MV, RRT, vasopressors or inotropes (with death within 28 days counting as zero days).	28 days
Secondary	To investigate the effect of recAP on length of stay (LOS) in ICU.	Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).	28 days
Secondary	To investigate the effect of recAP on 90-day allcause mortality	Time to death through Day 90.	90 days