Clinical trial NCT04411472: (Revival) Study to Investigate the Efficacy and Safety of Alkaline Phosphatase in Patients With Sepsis-Associated AKI
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Kidney Injury Due to Sepsis
Lead sponsor: AM-Pharma
Sponsor class: INDUSTRY
First posted: 2020-06-02
Enrollment: 676
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 28-day All-cause Mortality: Main Trial Population
timeFrame: 28 days
measure: 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population
timeFrame: 28 days
measure: 28-day All-cause Mortality: COVID-19 Population
timeFrame: 28 days
Secondary outcomes:
measure: Major Adverse Kidney Events 90: Main Trial Population
timeFrame: 90 Days
measure: Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population
timeFrame: 90 Days
measure: Major Adverse Kidney Events 90: COVID-19 Population
timeFrame: 90 Days
measure: Major Adverse Kidney Events Through Day 90: Combined Population
timeFrame: 90 Days
measure: Days Alive and Free of Organ Support Through Day 28: Main Trial Population
timeFrame: 28 days
measure: Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population
timeFrame: 28 days
measure: Days Alive and Free of Organ Support Through Day 28: COVID-19 Population
timeFrame: 28 days
measure: Days Alive and Out of the ICU Through Day 28: Main Trial Population
timeFrame: 28 days
measure: Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population
timeFrame: 28 days
measure: Days Alive and Out of the ICU Through Day 28: COVID-19 Population
timeFrame: 28 days
measure: 90-day All Cause Mortality: Main Trial Population
timeFrame: 90 days
measure: 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population
timeFrame: 90 days
measure: 90-day All Cause Mortality: COVID-19 Population
timeFrame: 90 days
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Washington
country: United States
facility: The George Washington University Medical Faculty Associates - Anesthesiology
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Clinical Cardiovascular Research Institute
state: Georgia
city: Glenview
country: United States
facility: Glenbrook Hospital
state: Illinois
city: Highland Park
country: United States
facility: NorthShore Medical Group - Bannockburn
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky College of Medicine (UKCM)
state: Kentucky
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Albuquerque
country: United States
facility: University of New Mexico School of Medicine
state: New Mexico
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University - Dorothy M. Davis Heart and Lung Research Institute
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC CancerCenter at Magee - Womens Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin Froedtert Hospital
state: Wisconsin
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
city: Bendigo
country: Australia
facility: Bendigo Hospital
city: Footscray
country: Australia
facility: Footscray Hospital
city: Melbourne
country: Australia
facility: Austin Hospital
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
city: Saint Albans
country: Australia
facility: Sunshine Hospital ICU - Western Hospital
city: Southport
country: Australia
facility: Gold Coast University Hospital (GCUH)
city: Graz
country: Austria
facility: Medizinische Universitaet Graz - Klinik fuer Innere Medizin
city: Innsbruck
country: Austria
facility: Medizinische Universitaet Innsbruck - Universitaetsklinik fuer Innere Medizin I
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Brussels
country: Belgium
facility: Centre Hospitalier Universitaire Brugmann
city: Charleroi
country: Belgium
facility: Centre Hospitalier Universitaire (CHU) de Charleroi - Hopital Civil Marie Curie
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: La Louvière
country: Belgium
facility: Hôpital de JOLIMONT
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre- Ottignies
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Yvoir
country: Belgium
facility: CHU UCL Namur - Mont-Godinne
city: Calgary
country: Canada
facility: Peter Lougheed Centre
city: Calgary
country: Canada
facility: Foothills Medical Centre
city: Calgary
country: Canada
facility: Rockyview General Hospital
city: Calgary
country: Canada
facility: Alberta Health Services - South Health Campus Hospital
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
city: Québec
country: Canada
facility: Hôpital de l'Enfant-Jésus
city: Vancouver
country: Canada
facility: St. Paul's Hospital
city: Victoria
country: Canada
facility: Royal Jubilee Hospital (RJH)
city: Victoria
country: Canada
facility: Victoria General Hospital (VGH)
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital
city: Herning
country: Denmark
facility: Herning Regional Hospital
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital
city: København
country: Denmark
facility: Rigshospitalet
city: Køge
country: Denmark
facility: Sjaellands Universitetshospital, Koge - Kardiologisk Afdeling
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Randers
country: Denmark
facility: Regionshospitalet Randers
city: Slagelse
country: Denmark
facility: Slagelse Sygehus
city: Viborg
country: Denmark
facility: Hospitalsenhed Midt
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital (HUCH)
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital (TYKS)
city: Angers Cedex
country: France
facility: Centre Hospitalier Universitaire d'Angers
city: Argenteuil Cedex
country: France
facility: Centre Hospitalier d'Argenteuil
city: Béthune
country: France
facility: Centre Hospitalier de Bethune Germon et Gauthier
city: Cergy-Pontoise
country: France
facility: Centre Hospitalier René-Dubos
city: Dijon
country: France
facility: CHU Dijon - Hôpital François Mitterrand
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental de Vendée - Les Oudairies
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital Bicêtre
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Limoges Cedex
country: France
facility: CHU Limoges - Hôpital Dupuytren
city: Nancy
country: France
facility: CHU de Nancy
city: Nantes
country: France
facility: CHU de Nantes - Hôtel-Dieu
city: Nîmes cedex 9
country: France
facility: CHU de Nimes - Hopital Universitaire Caremeau
city: Orléans
country: France
facility: Hôpital La Source
city: Paris
country: France
facility: Hôpital Lariboisière
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg - Hôpital Civil
city: Tours cedex 9
country: France
facility: CHRU de Tours - Hôpital Bretonneau
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE)
city: Jena
country: Germany
facility: University Hospital Jena - Klinik fur Neurologie
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig - Klinik und Poliklinik fuer Gastroenterologie und Rheumatologie
city: Münster
country: Germany
facility: University Hospital Münster
city: Galway
country: Ireland
facility: National University of Ireland, Galway
state: G
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Hachioji-Shi
country: Japan
facility: Tokyo Medical University Hachioji Medical Center
city: Hiroshima-shi
country: Japan
facility: Hiroshima University Hospital
city: Izuka-shi
country: Japan
facility: Aso Iizuka Hospital
city: Izumisano-Shi
country: Japan
facility: Rinku General Medical Center
city: Kashihara-Shi
country: Japan
facility: Nara Medical University Hospital
city: Kumamoto-Shi
country: Japan
facility: National Hospital Organization Kumamoto Medical Center
city: Omihachiman-Shi
country: Japan
facility: Omihachiman Community Medical Center
city: Osaka-Shi
country: Japan
facility: Osaka City General Hospital
city: Osaka-shi
country: Japan
facility: Osaka Police Hospital
city: Toyoake-Shi
country: Japan
facility: Fujita Health University Hospital
city: Yokohama-Shi
country: Japan
facility: National Hospital Organization - Yokohama Medical Center
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis lokatie GZG
state: NB
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - VUMC
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum, Heerlen
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: Wellington
country: New Zealand
facility: Wellington Hospital
state: WGN
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Clinical Trials
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Grafton
country: New Zealand
facility: Auckland City Hospital
city: Hastings
country: New Zealand
facility: Hawke's Bay Hospital Soldiers' Memorial
city: Rotorua
country: New Zealand
facility: Lakes District Health Board - Rotorua Hospital
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge (IDIBELL)
city: Girona
country: Spain
facility: Hospital Universitari de Girona Doctor Josep Trueta
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Sabadell
country: Spain
facility: Parc Taulí Sabadell Hospital Universitari
city: Terrassa
country: Spain
facility: Universitat de Barcelona - Hospital Universitari Mutua Terrassa (HUMT)
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust - University College Hospital
state: LND
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust - St Thomas' Hospital
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust - Derriford Hospital
Study officials:
affiliation: AM-Pharma
name: A Legters
role: STUDY_DIRECTOR
References:
citation: Pickkers P, Angus DC, Bass K, Bellomo R, van den Berg E, Bernholz J, Bestle MH, Doi K, Doig CJ, Ferrer R, Francois B, Gammelager H, Pedersen UG, Hoste E, Iversen S, Joannidis M, Kellum JA, Liu K, Meersch M, Mehta R, Millington S, Murray PT, Nichol A, Ostermann M, Pettila V, Solling C, Winkel M, Young PJ, Zarbock A; REVIVAL investigators. Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL). Intensive Care Med. 2024 Jan;50(1):68-78. doi: 10.1007/s00134-023-07271-w. Epub 2024 Jan 3.
citation: Pickkers P, Angus DC, Arend J, Bellomo R, van den Berg E, Bernholz J, Bestle M, Broglio K, Carlsen J, Doig CJ, Ferrer R, Joannidis M, Francois B, Doi K, Kellum JA, Laterre PF, Liu K, Mehta RL, Murray PT, Ostermann M, Pettila V, Richards S, Young P, Zarbock A, Kjolbye AL. Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury. BMJ Open. 2023 Apr 3;13(4):e065613. doi: 10.1136/bmjopen-2022-065613.