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    Summary
    EudraCT Number:2022-003797-23
    Sponsor's Protocol Code Number:KKS-305
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-27
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2022-003797-23
    A.3Full title of the trial
    Myeloperoxidase inhibition in patients with ischemic or non-ischemic cardiomyopathy and heart failure with reduced ejection fraction
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase IIa randomized, parallel-group, placebo-controlled double-blind, multi-center study on the safety and efficacy of Mitiperstat (AZD4831) in patients with ischemic or non-ischemic cardiomyopathy and heart failure with reduced ejection fraction
    A.4.1Sponsor's protocol code numberKKS-305
    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 SponsorPhilipps University Marburg
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKoordinierungszentrum für Klinische Studien (KKS) Marburg
    B.5.2Functional name of contact pointNelli Ens-Jäger
    B.5.3 Address:
    B.5.3.1Street AddressKarl-von-Frisch-Straße 4
    B.5.3.2Town/ cityMarburg
    B.5.3.3Post code35043
    B.5.3.4CountryGermany
    B.5.4Telephone number+4915114980915
    B.5.5Fax number+49642128666517
    B.5.6E-mailmystery-hf@kks.uni-marburg.de
    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 nameMitiperstat (AZD4831)
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMitiperstat
    D.3.9.4EV Substance CodeSUB253248
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ischemic or non-ischemic cardiomyopathy and heart failure with reduced ejection fraction.
    Danke
    E.1.1.1Medical condition in easily understood language
    Also called systolic heart failure. It occurs when the left ventricle, the heart's main pumping chamber, weakens and can't pump blood effectively. This condition is also called dilated cardiomyopathy.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10007554
    E.1.2Term Cardiac failure
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 26.1
    E.1.2Level LLT
    E.1.2Classification code 10078289
    E.1.2Term Heart failure with reduced ejection fraction
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10055222
    E.1.2Term Non-ischemic cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10055217
    E.1.2Term Ischemic cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac 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 assess the efficacy of 12 weeks treatment of mitiperstat (AZD4831) in patients by measuring the change in NTproBNP levels
    E.2.2Secondary objectives of the trial
    To assess the efficacy of 12 weeks of mitiperstat administration in patients with with ischemic or nonischemic cardiomyopathy and heart failure with reduced ejection fraction

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The patients from primary site Cologne will enter a substudy that will assess the following additional endpoints (from baseline to week 12):
    • Change in flow-mediated brachial dilation and retinal vessel analysis


    E.3Principal inclusion criteria
    1. Adult patients aged ≥18 years (male and female).
    2. Confirmed diagnosis of chronic HFrEF present for at least 6 months. HFrEF may be of any etiology, i.e. ischemic as well as non-ischemic cardiomyopathy.
    3. Documented LVEF ≤ 40% at screening (assessed by echocardiography).
    4. In stable condition (NYHA class II or III).
    5. On optimized, guideline-directed medical heart failure therapy; stable medication and dose for ≥ 4 weeks, diuretics ≥ 1 week).
    6. NT-proBNP > 300 pg/ml (sinus rhythm), >1000 pg/ml (atrial fibrillation). If available the average of NTproBNP values within the last 12 months should not be ≤25% than NTproBNP at time of inclusion to exclude decompensation
    7. 6MWD ≥100m at screening.
    8. Signed written informed consent.
    9. Capability and willingness to comply with study procedures.
    10. Females must have a negative pregnancy test at the screening visit and on admission to the clinical unit, must not be lactating and must be of non-child-bearing potential, confirmed at the screening visit by fulfilling one of the following criteria:
    a) Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments or alternatively FSH levels in the postmenopausal range.
    b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
    11. Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of mitiperstat/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period.
    E.4Principal exclusion criteria
    1. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction.
    2. Any high-grade valvular defect which, in judgement of the investigator, has an impact on LVEF (e.g. high-grade aortic valve stenosis or mitral valve regurgitation), expected to lead to surgery during the trial. High-grade tricuspid regurgitation in isolation is not an exclusion criterion.
    3. Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 months prior to Visit 1.
    4. Acutely decompensated heart failure.
    5. Recent device implant for heart failure (i.e. potential influence on LVEF such as cardiac resynchronization therapy, TAVR, MitraClip, LVAD, etc.) within 60 days prior to randomization. Recent ICD without CRT implantation is not an exclusion criterion.
    6. Inadequately controlled atrial or ventricular arrhythmia (e.g. Atrial fibrillation with average resting ventricular rate >110bpm).
    7. Current indication for percutaneous coronary intervention (PCI) or CABG (at the time of randomization).
    8. Significant cardiac ischemia in a stress test within 12 months of enrollment without revascularization since.
    9. Uncontrolled hypotension (<90/50mmHg) or hypertension (≥160/100 mmHg), at least one value is decreased/increased.
    10. Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation for exacerbation within 12 months, or significant chronic pulmonary disease in the opinion of the Investigator, or primary pulmonary arterial hypertension.
    11. Acute or Chronic kidney disease (CKD) with eGFR <30ml/min/1.73m2 (CKD-EPI).
    12. Severe liver disease (Child-Pugh class C, with or without cirrhosis); elevation of liver enzymes (AST/ALT) to > 2x ULN.
    13. Haemoglobin (HgB) <9 g/dl at Visit 1.
    14. Hypersensitivity to the active substance or one of the ingredients (see current IB).
    15. Participation in another interventional clinical study within 30 days before baseline.
    16. Any clinically significant disease or disorder (e.g. cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, infectious disease or major physical impairment) which, as judged by the Investigator, might put the patient at risk because of participation in the study, or probable alternative primary reason for patient’s symptoms in judgment of Investigator.
    17. Any active infection requiring oral, intravenous, or intramuscular treatment at Screening and/or Randomization.
    18. Participants with hyperthyroidism, uncontrolled hypothyroidism (including but not limited to TSH ≥10 mIU/mL) or any clinically significant thyroid disease as judged by the Investigator.
    19. History or ongoing severe allergy / hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria), that might put the patient at risk because of participation in the study, as judged by the Investigator.
    20. Drug or alcohol abuse, either current or within previous 12 months.
    21. Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
    22. Pregnant or breastfeeding women.
    23. Presence of any other disease than heart failure with a life expectancy of <1 years in the opinion of the Investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Change in log NTproBNP levels from baseline to week 12 (mitiperstat vs. placebo)
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 12 of treatment
    E.5.2Secondary end point(s)
    • Change in 6MWD from baseline to week 12
    • Change in KCCQ-TSS from baseline to week 12
    • Change in LVEF as assessed via transthoracic echocardiography (TTE) from baseline to week 12
    • Change in NYHA class from baseline to week 12
    • Change in HR, systolic and diastolic BP, mean arterial pressure
    • Incidence of major adverse cardiovascular events (MACE, i.e. cardiovascular death, hospitalization for heart failure, non-fatal acute myocardial infarction, non-fatal cerebrovascular accident (transient ischemic attack or stroke)
    • Change in use/dose of HF medication including diuretics




    Substudy:
    The patients from primary site Cologne will enter a substudy that will assess the following additional endpoints (from baseline to week 12):
    • Change in flow-mediated brachial dilation and retinal vessel analysis



    E.5.2.1Timepoint(s) of evaluation of this end point
    week 12 of treatment
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    “Last Patient Out” and data base Closure.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months16
    E.8.9.1In the Member State concerned days
    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: 63
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 63
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state112
    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)
    Further treatment after the end of the study will be decided individually between the Investigators and the patient and will take place as part of routine care at participating study sites, with the active substances approved for HFrEF indication (ACE-Inhibitors, AT1-receptor antagonists, Sacubitril, Betablockers, Mineralocorticoid receptor antagonists, SGLT2-inhibitors, diuretics (loop diuretics, thiazides) depending on the patient's condition and medical requirements.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-05-16
    P. End of Trial
    P.End of Trial StatusOngoing
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