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    Summary
    EudraCT Number:2019-004625-24
    Sponsor's Protocol Code Number:AP-recAP-AKI-03-01
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-10-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2019-004625-24
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Two-Arm Parallel Group, Multi-Center 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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Investigate the Efficacy and Safety of Alkaline Phosphatase in Patients With Sepsis-Associated Acute Kidney Injury
    A.4.1Sponsor's protocol code numberAP-recAP-AKI-03-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04411472
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAM-Pharma B.V.
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAM-Pharma B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAM-Pharma B.V.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressStadsplateau 6
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3521 AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+3130228 9222
    B.5.6E-mailregulatory@am-pharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRecombinant Human Alkaline Phosphatase, Ilofotase alfa
    D.3.2Product code recAP
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNrecAP
    D.3.9.2Current sponsor coderecAP
    D.3.9.3Other descriptive nameHUMAN ALKALINE PHOSPHATASE, RECOMBINANT
    D.3.9.4EV Substance CodeSUB183645
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Sepsis-associated acute kidney injury
    E.1.1.1Medical condition in easily understood language
    Sepsis-associated acute kidney injury
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10066593
    E.1.2Term Post procedural sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate an effect of recombinant human alkaline phosphatase (recAP) on 28 day all cause mortality.
    E.2.2Secondary objectives of the trial
    - To investigate the effect of recAP on long-term Major Adverse Kidney Events (MAKE).
    - To investigate the effect of recAP on use of organ support, i.e., mechanical ventilation (MV), RRT, vasopressors or inotropes.
    - To investigate the effect of recAP on length of stay (LOS) in intensive care unit (ICU).
    - To investigate the effect of recAP on 90-day all-cause mortality.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for this trial, a patient must meet all of the following 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.:
    a) suspected or proven bacterial or viral infection and
    b) 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.

    4. Have AKI according to at least one of the below Kidney Disease Improving Global Outcomes (KDIGO) criteria, a) to d):
    a) An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours or
    b) A relative increase in CR to ≥1.5 times pre-AKI reference CR value (see Section 8.3.3.3), which is known or presumed to have occurred within prior 7 days or
    c) 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 (see Section 8.3.3.3) 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. For Table 1, please refer to the Protocol.
    5. Provision of signed and dated informed consent form (ICF) in accordance with local regulations.
    E.4Principal exclusion criteria
    A patient who meets any of the following criteria is excluded from participation in this trial:
    1. Documented CKD as specified below:
    a) At selected 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. 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 lost to follow-up (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 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:
    a) 48 hours from AKI diagnosis, when AKI diagnosis precedes start of vasopressor therapy or
    b) 24 hours from AKI diagnosis, when AKI is diagnosed after start of vasopressor therapy.
    19. Pregnant or nursing women.
    E.5 End points
    E.5.1Primary end point(s)
    28-day all-cause mortality.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28th day
    E.5.2Secondary end point(s)
    - 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.

    - 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).

    - Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).

    - Time to death through Day 90.
    E.5.2.1Timepoint(s) of evaluation of this end point
    28th and 90th day
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA81
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Denmark
    Finland
    France
    Germany
    Ireland
    Japan
    Netherlands
    New Zealand
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 900
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 700
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    patients who will be eligible for this protocol may not be able to give fully informed consent themselves due to various reasons including disease severity, sedation or unconscious state
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1330
    F.4.2.2In the whole clinical trial 1600
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-10-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-08-18
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