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

NCT ID: NCT04411472

Last Updated: 2024-06-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 676 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-02
• Study Completion Date: 2022-08-18

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.

Conditions

Acute Kidney Injury Due to Sepsis

Study Design

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

Study Groups

active

recombinant human alkaline phosphatase 1.6mg/kg 3 daily 1 hour infusions

Group Type: EXPERIMENTAL

Recombinant human alkaline phosphatase

Intervention Type: BIOLOGICAL

patients with SA-AKI are randomly assigned in a 1:1 ratio to either placebo or 1.6 mg/kg recAP.

placebo

matching placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

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.

Intervention Type: BIOLOGICAL

Placebo

Placebo

Intervention Type: OTHER

Other Intervention Names

ilofotase alfa

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.

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

Sponsors

AM-Pharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

A Legters

Role: STUDY_DIRECTOR

AM-Pharma

Locations

The University of Arizona Cancer Center

Tucson, Arizona, United States

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States

The George Washington University Medical Faculty Associates - Anesthesiology

Washington D.C., District of Columbia, United States

Emory Clinical Cardiovascular Research Institute

Atlanta, Georgia, 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

Regions Hospital

Saint Paul, Minnesota, United States

University of New Mexico School of Medicine

Albuquerque, New Mexico, United States

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 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

UPMC CancerCenter at Magee - Womens Hospital

Pittsburgh, Pennsylvania, United States

UPMC Presbyterian

Pittsburgh, Pennsylvania, United States

University of Virginia Health System

Charlottesville, Virginia, United States

Froedtert & the Medical College of Wisconsin Froedtert Hospital

Milwaukee, Wisconsin, United States

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, , Australia

Medizinische Universitaet Graz - Klinik fuer Innere Medizin

Graz, , Austria

Medizinische Universitaet Innsbruck - Universitaetsklinik fuer Innere Medizin I

Innsbruck, , Austria

Medizinische Universität Innsbruck

Innsbruck, , Austria

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

Ghent, , 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, , Belgium

Peter Lougheed Centre

Calgary, , Canada

Foothills Medical Centre

Calgary, , Canada

Rockyview General Hospital

Calgary, , Canada

Alberta Health Services - South Health Campus Hospital

Calgary, , Canada

The Ottawa Hospital - General Campus

Ottawa, , Canada

The Ottawa Hospital - Civic 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, , Canada

Aalborg Universitetshospital

Aalborg, , Denmark

Aarhus University Hospital

Aarhus N, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Herning Regional Hospital

Herning, , Denmark

Nordsjællands Hospital

Hillerød, , Denmark

Sjaellands Universitetshospital, Koge - Kardiologisk Afdeling

Køge, , Denmark

Odense Universitetshospital

Odense C, , Denmark

Regionshospitalet Randers

Randers, , Denmark

Slagelse Sygehus

Slagelse, , Denmark

Hospitalsenhed Midt

Viborg, , Denmark

Helsinki University Central Hospital (HUCH)

Helsinki, , Finland

Tampere University Hospital

Tampere, , Finland

Turku University Hospital (TYKS)

Turku, , Finland

Centre Hospitalier Universitaire d'Angers

Angers, , France

Centre Hospitalier d'Argenteuil

Argenteuil, , 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, , France

CHU de Nancy

Nancy, , France

CHU de Nantes - Hôtel-Dieu

Nantes, , France

CHU de Nimes - Hopital Universitaire Caremeau

Nîmes, , France

Hôpital La Source

Orléans, , France

Hôpital Lariboisière

Paris, , France

Hôpitaux Universitaires de Strasbourg - Hôpital Civil

Strasbourg, , France

CHRU de Tours - Hôpital Bretonneau

Tours, , France

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, , Germany

National University of Ireland, Galway

Galway, G, Ireland

St. James's Hospital

Dublin, , Ireland

Tallaght University Hospital

Dublin, , Ireland

St. Vincent's University Hospital

Dublin, , Ireland

Tokyo Medical University Hachioji Medical Center

Hachioji-Shi, , Japan

Hiroshima University Hospital

Hiroshima, , Japan

Aso Iizuka Hospital

Izuka-shi, , Japan

Rinku General Medical Center

Izumisano, , Japan

Nara Medical University Hospital

Kashihara-shi, , Japan

National Hospital Organization Kumamoto Medical Center

Kumamoto, , Japan

Osaka City General Hospital

Osaka, , Japan

Osaka Police Hospital

Osaka, , Japan

Omihachiman Community Medical Center

Ōmihachiman, , Japan

Fujita Health University Hospital

Toyoake-Shi, , Japan

National Hospital Organization - Yokohama Medical Center

Yokohama, , Japan

Jeroen Bosch Ziekenhuis lokatie GZG

's-Hertogenbosch, North Brabant, Netherlands

Amsterdam UMC - VUMC

Amsterdam, , Netherlands

Ziekenhuis Gelderse Vallei

Ede, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Zuyderland Medisch Centrum, Heerlen

Heerlen, , Netherlands

Radboud UMC

Nijmegen, , Netherlands

Canisius-Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

Wellington Hospital

Wellington, WGN, 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

Hospital Universitari Germans Trias i Pujol

Badalona, , Spain

Hospital del Mar

Barcelona, , Spain

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Universitari de Bellvitge (IDIBELL)

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, , Spain

University College London Hospitals NHS Foundation Trust - University College Hospital

London, LND, 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

Plymouth Hospitals NHS Trust - Derriford Hospital

Plymouth, , United Kingdom

Countries

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

References

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.

Reference Type: RESULT

PMID: 38172296 (View on PubMed)

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.

Reference Type: RESULT

PMID: 37012016 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

AP-recAP-AKI-03-01

Identifier Type: -

Identifier Source: org_study_id