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

NCT04411472 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: AP-recAP-AKI-03-01
• Study Type: interventional
• Target: 676
• Locations: 14 countries
• Sites: 119

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. 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. 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. 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.

Conditions

Acute Kidney Injury Due to Sepsis

Outcome Measures

Primary Outcomes (3)

• 28-day All-cause Mortality: Main Trial Population

  To demonstrate an effect of recAP on 28 day all cause mortality

  28 days

• 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population

  To demonstrate an effect of recAP on 28 day all cause mortality

  28 days

• 28-day All-cause Mortality: COVID-19 Population

  To demonstrate an effect of recAP on 28 day all cause mortality

  28 days

Secondary Outcomes (13)

• Major Adverse Kidney Events 90: Main Trial Population

  90 Days

• Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population

  90 Days

• Major Adverse Kidney Events 90: COVID-19 Population

  90 Days

• Major Adverse Kidney Events Through Day 90: Combined Population

  90 Days

• Days Alive and Free of Organ Support Through Day 28: Main Trial Population

  28 days

Study Arms (2)

active

EXPERIMENTAL

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

Biological: Recombinant human alkaline phosphatase

placebo

PLACEBO COMPARATOR

matching placebo

Other: Placebo

Interventions

Recombinant human alkaline phosphatase BIOLOGICAL

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

Also known as: ilofotase alfa

active

Placebo OTHER

Placebo

placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or older.
• In the ICU or intermediate care unit for clinical reasons.
• Have sepsis requiring vasopressor (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, or angiotensin II) therapy, i.e.:
• suspected or proven bacterial or viral infection. and
• 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.
• Have AKI according to at least one of the below KDIGO criteria, a to d:
• An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours.
• 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.
• 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.
• Provision of signed and dated ICF in accordance with local regulations.

You may not qualify if:

• 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.
• Advanced chronic liver disease, defined as a Child-Pugh score of 10 to 15 (Class C).
• Acute pancreatitis without proven infection.
• Urosepsis related to suspected or proven urinary tract obstruction.
• Main cause of AKI not sepsis.
• Severe burns requiring ICU treatment.
• 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

Sponsors & Collaborators

• AM-Pharma: lead

Study Sites (122)

The University of Arizona Cancer Center

Tucson, Arizona, 85724-5057, United States

Location

Ronald Reagan UCLA Medical Center

Los Angeles, California, 90095-8358, United States

Location

The George Washington University Medical Faculty Associates - Anesthesiology

Washington D.C., District of Columbia, 20037-2342, United States

Location

Emory Clinical Cardiovascular Research Institute

Atlanta, Georgia, 30322-1007, United States

Location

Glenbrook Hospital

Glenview, Illinois, 60026-1301, United States

Location

NorthShore Medical Group - Bannockburn

Highland Park, Illinois, 60035, United States

Location

University of Kentucky College of Medicine (UKCM)

Lexington, Kentucky, 40508-3215, United States

Location

Regions Hospital

Saint Paul, Minnesota, 55101, United States

Location

University of New Mexico School of Medicine

Albuquerque, New Mexico, 87131, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati Cancer Institute

Cincinnati, Ohio, 45219, United States

Location

The Ohio State University - Dorothy M. Davis Heart and Lung Research Institute

Columbus, Ohio, 43210, United States

Location

UPMC CancerCenter at Magee - Womens Hospital

Pittsburgh, Pennsylvania, 15213-3108, United States

Location

UPMC Presbyterian

Pittsburgh, Pennsylvania, 15213-3108, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908-0817, United States

Location

Froedtert & the Medical College of Wisconsin Froedtert Hospital

Milwaukee, Wisconsin, 53226-3522, United States

Location

Flinders Medical Centre

Bedford Park, 5042, Australia

Location

Bendigo Hospital

Bendigo, 3550, Australia

Location

Footscray Hospital

Footscray, 3011, Australia

Location

Austin Hospital

Melbourne, 3084, Australia

Location

John Hunter Hospital

New Lambton Heights, 2305, Australia

Location

Sunshine Hospital ICU - Western Hospital

Saint Albans, 3021, Australia

Location

Gold Coast University Hospital (GCUH)

Southport, 4215, Australia

Location

Medizinische Universitaet Graz - Klinik fuer Innere Medizin

Graz, 8036, Austria

Location

Medizinische Universitaet Innsbruck - Universitaetsklinik fuer Innere Medizin I

Innsbruck, 6020, Austria

Location

Medizinische Universität Innsbruck

Innsbruck, 6020, Austria

Location

Centre Hospitalier Universitaire Brugmann

Brussels, 1020, Belgium

Location

Centre Hospitalier Universitaire (CHU) de Charleroi - Hopital Civil Marie Curie

Charleroi, 6042, Belgium

Location

Ziekenhuis Oost-Limburg

Genk, 3600, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

Location

Universitair Ziekenhuis Brussel

Jette, 1090, Belgium

Location

Hôpital de JOLIMONT

La Louvière, 7100, Belgium

Location

Clinique Saint-Pierre- Ottignies

Ottignies, 1340, Belgium

Location

Cliniques Universitaires Saint-Luc

Woluwe-Saint-Lambert, 1200, Belgium

Location

CHU UCL Namur - Mont-Godinne

Yvoir, 5530, Belgium

Location

Peter Lougheed Centre

Calgary, T1Y 6J4, Canada

Location

Foothills Medical Centre

Calgary, T2N 2T9, Canada

Location

Rockyview General Hospital

Calgary, T2V 1P9, Canada

Location

Alberta Health Services - South Health Campus Hospital

Calgary, T3M 1M4, Canada

Location

The Ottawa Hospital - General Campus

Ottawa, K1H 8L6, Canada

Location

The Ottawa Hospital - Civic Campus

Ottawa, K1Y 4E9, Canada

Location

Hôpital de l'Enfant-Jésus

Québec, G1J 1Z4, Canada

Location

St. Paul's Hospital

Vancouver, V6Z 1Y6, Canada

Location

Royal Jubilee Hospital (RJH)

Victoria, V8R 1J8, Canada

Location

Victoria General Hospital (VGH)

Victoria, V8R 1J8, Canada

Location

Aalborg Universitetshospital

Aalborg, 9000, Denmark

Location

Aarhus University Hospital

Aarhus N, 8200, Denmark

Location

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Herning Regional Hospital

Herning, 7400, Denmark

Location

Nordsjællands Hospital

Hillerød, 3400, Denmark

Location

Sjaellands Universitetshospital, Koge - Kardiologisk Afdeling

Køge, 4600, Denmark

Location

Odense Universitetshospital

Odense C, 5000, Denmark

Location

Regionshospitalet Randers

Randers, 8930, Denmark

Location

Slagelse Sygehus

Slagelse, 4200, Denmark

Location

Hospitalsenhed Midt

Viborg, 8800, Denmark

Location

Helsinki University Central Hospital (HUCH)

Helsinki, 290, Finland

Location

Tampere University Hospital

Tampere, 33521, Finland

Location

Turku University Hospital (TYKS)

Turku, 20521, Finland

Location

Centre Hospitalier Universitaire d'Angers

Angers, 49933, France

Location

Centre Hospitalier d'Argenteuil

Argenteuil, 95107, France

Location

Centre Hospitalier de Bethune Germon et Gauthier

Béthune, 62408, France

Location

Centre Hospitalier René-Dubos

Cergy-Pontoise, 95303, France

Location

CHU Dijon - Hôpital François Mitterrand

Dijon, 21079, France

Location

Centre Hospitalier Départemental de Vendée - Les Oudairies

La Roche-sur-Yon, 85000, France

Location

Hôpital Bicêtre

Le Kremlin-Bicêtre, 94270, France

Location

Centre Hospitalier du Mans

Le Mans, 72000, France

Location

CHU Limoges - Hôpital Dupuytren

Limoges, 87000, France

Location

CHU de Nancy

Nancy, 54000, France

Location

CHU de Nantes - Hôtel-Dieu

Nantes, 44000, France

Location

CHU de Nimes - Hopital Universitaire Caremeau

Nîmes, 30029, France

Location

Hôpital La Source

Orléans, 45067, France

Location

Hôpital Lariboisière

Paris, 75010, France

Location

Hôpitaux Universitaires de Strasbourg - Hôpital Civil

Strasbourg, 67091, France

Location

CHRU de Tours - Hôpital Bretonneau

Tours, 37044, France

Location

Universitätsklinikum Aachen

Aachen, 52074, Germany

Location

Universitätsklinikum Hamburg-Eppendorf (UKE)

Hamburg, 20246, Germany

Location

University Hospital Jena - Klinik fur Neurologie

Jena, 7747, Germany

Location

Universitaetsklinikum Leipzig - Klinik und Poliklinik fuer Gastroenterologie und Rheumatologie

Leipzig, 4103, Germany

Location

University Hospital Münster

Münster, 48149, Germany

Location

National University of Ireland, Galway

Galway, G, H91 YR71, Ireland

Location

St. James's Hospital

Dublin, D08 NHY1, Ireland

Location

Tallaght University Hospital

Dublin, D24NR0A, Ireland

Location

St. Vincent's University Hospital

Dublin, Dublin 4, Ireland

Location

Tokyo Medical University Hachioji Medical Center

Hachioji-Shi, 193-0998, Japan

Location

Hiroshima University Hospital

Hiroshima, Japan

Location

Aso Iizuka Hospital

Izuka-shi, 820-8505, Japan

Location

Rinku General Medical Center

Izumisano, 598-8577, Japan

Location

Nara Medical University Hospital

Kashihara-shi, 634-8522, Japan

Location

National Hospital Organization Kumamoto Medical Center

Kumamoto, 860-0008, Japan

Location

Osaka City General Hospital

Osaka, 534-0021, Japan

Location

Osaka Police Hospital

Osaka, 543-0035, Japan

Location

Omihachiman Community Medical Center

Ōmihachiman, 523-0082, Japan

Location

Fujita Health University Hospital

Toyoake-Shi, 470-1192, Japan

Location

National Hospital Organization - Yokohama Medical Center

Yokohama, 245-8575, Japan

Location

Jeroen Bosch Ziekenhuis lokatie GZG

's-Hertogenbosch, North Brabant, 5223 GZ, Netherlands

Location

Amsterdam UMC - VUMC

Amsterdam, 1081 HV, Netherlands

Location

Ziekenhuis Gelderse Vallei

Ede, 6716 RP, Netherlands

Location

Medisch Spectrum Twente

Enschede, KZ 7512, Netherlands

Location

Zuyderland Medisch Centrum, Heerlen

Heerlen, Heerlen, Netherlands

Location

Radboud UMC

Nijmegen, 6500 HB, Netherlands

Location

Canisius-Wilhelmina Ziekenhuis

Nijmegen, 6532 SZ, Netherlands

Location

Wellington Hospital

Wellington, WGN, 6021, New Zealand

Location

Auckland City Hospital

Auckland, 1023, New Zealand

Location

Middlemore Clinical Trials

Auckland, 2025, New Zealand

Location

Christchurch Hospital

Christchurch, 8140, New Zealand

Location

Dunedin Hospital

Dunedin, 9016, New Zealand

Location

Auckland City Hospital

Grafton, 1023, New Zealand

Location

Hawke's Bay Hospital Soldiers' Memorial

Hastings, 4172, New Zealand

Location

Lakes District Health Board - Rotorua Hospital

Rotorua, 3046, New Zealand

Location

Hospital Universitari Germans Trias i Pujol

Badalona, 8916, Spain

Location

Hospital del Mar

Barcelona, 8003, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 8035, Spain

Location

Hospital Universitari de Bellvitge (IDIBELL)

Barcelona, 8907, Spain

Location

Hospital Universitari de Girona Doctor Josep Trueta

Girona, 17007, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

Parc Taulí Sabadell Hospital Universitari

Sabadell, 8208, Spain

Location

Universitat de Barcelona - Hospital Universitari Mutua Terrassa (HUMT)

Terrassa, 8221, Spain

Location

University College London Hospitals NHS Foundation Trust - University College Hospital

London, LND, NW1 2BU, United Kingdom

Location

University Hospital of Wales

Cardiff, CF14 4XW, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, L7 8XP, United Kingdom

Location

Guy's and St Thomas' NHS Foundation Trust - St Thomas' Hospital

London, SE1 7EH, United Kingdom

Location

Plymouth Hospitals NHS Trust - Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 38172296 RESULT

• 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.

  PMID: 37012016 RESULT

Limitations and Caveats

The trial was terminated early due to futility being reached for the primary endpoint of all cause mortality at day 28 at the interim analysis.

Results Point of Contact

• Title: AM-Pharma Office
• Organization: AM-Pharma

office@am-pharma.com

+31 (0)30 22 89 222

Study Officials

• A Legters

  AM-Pharma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 2, 2020
• Study Start: November 2, 2020
• Primary Completion: August 18, 2022
• Study Completion: August 18, 2022
• Last Updated: June 3, 2024
• Results First Posted: June 3, 2024

Record last verified: 2024-05

Locations

CA (10); NZ (8); DK (10); NL (7); JP (11); ES (8); GB (5); DE (5); US (16); IE (4); AU (7); BE (9); FI (3); FR (16)