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    Summary
    EudraCT Number:2022-000780-48
    Sponsor's Protocol Code Number:J3E-MC-EZDB
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-09-13
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2022-000780-48
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart Failure with Preserved Ejection Fraction (HFpEF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart Failure with Preserved Ejection Fraction
    A.4.1Sponsor's protocol code numberJ3E-MC-EZDB
    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 SponsorEli Lilly and Company
    B.1.3.4CountryUnited States
    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 supportEli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly and Company
    B.5.2Functional name of contact pointClinical Trial Registry Office
    B.5.3 Address:
    B.5.3.1Street AddressLilly Corporate Center DC 1526
    B.5.3.2Town/ cityIndianapolis
    B.5.3.3Post code46285
    B.5.3.4CountryUnited States
    B.5.6E-mailEU_Lilly_Clinical_Trials@lilly.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 nameLY3540378 (Relaxin-LA)
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSolution for injection (Noncurrent)
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLY3540378
    D.3.9.2Current sponsor codeLY3540378
    D.3.9.3Other descriptive name7-(((S)-1-(4-((S)-1-(4-acryloylpiperazin-1-yl)-2-cyclopropylethyl)phenyl)ethyl)amino)-1-ethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one
    D.3.9.4EV Substance CodeSUB216590
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HFpEF (heart failure with preserved ejection fraction)
    E.1.1.1Medical condition in easily understood language
    Heart failure with preserved ejection fraction
    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 LLT
    E.1.2Classification code 10008908
    E.1.2Term Chronic heart failure
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10076396
    E.1.2Term Heart failure with preserved ejection fraction
    E.1.2System Organ Class 100000004849
    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 that LY3540378 administered SC QW is superior to placebo for improving atrial myopathy in participants with worsening chronic HFpEF.
    E.2.2Secondary objectives of the trial
    To compare the effect of LY3540378 administered SC QW on participants with worsening chronic HFpEF
    To assess safety and tolerability of LY3540378 administered SC QW
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participants must be at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the informed consent.
    2. Prior chronic treatment, or prescription, with a loop diuretic (for example, furosemide, torsemide, bumetanide) for ≥30 days prior to the index event. Index event is defined as a recent hospitalization for HF requiring at least 2 doses of intravenous diuretics or an out- of- hospital encounter (for example, Emergency Room, clinic visit, infusion clinic, etc.) for HF requiring at least 2 doses of intravenous diuretics.
    3. Chronic HF diagnosed for at least 3 months before V1 (screening).
    4. Documented LVEF of ≥50% within 6 months prior to V1 (screening); as measured by echocardiography, radionuclide ventriculography, invasive angiography, MRI, or CT.
    5. Have NYHA Class II-IV symptomatology as assessed at V1 (screening).
    6. Had evidence of clinical HF syndrome consisting of
    A. Hospitalization for HF within the past 2 weeks from randomization, for WHF with intravascular volume overload (the index event), as determined by the investigator, based on appropriate supportive documentation at randomization, and defined by ≥2 of the following:
    • dyspnea
    • jugular venous distention
    • pitting edema in lower extremities (>1+)
    • ascites
    • pulmonary congestion on chest X-ray
    • pulmonary rales AND patient received treatment with IV diuretics.
    OR
    B. Treatment for an urgent visit outside of being hospitalized with WHF and intravascular volume overload (the index visit) requiring treatment with IV diuretics (defined as ≥2 IV doses) such as in the outpatient setting/emergency room/observation unit/infusion clinic with a clinical
    response within the past 2 weeks prior to randomization. Urgent visit is defined as an unplanned visit for HF defined by ≥2 of the following:
    • dyspnea
    • jugular venous distention
    • pitting edema in lower extremities (>1+)
    • ascites
    • pulmonary rales on lung examination.
    7. NT-proBNP (>300 [sinus rhythm] or 900 pg/mL [atrial fibrillation or atrial flutter] OR BNP (>100 [sinus rhythm] or 300 pg/mL [atrial fibrillation or atrial flutter]) at screening (Visit 1, determined by local laboratory)
    Note: The presence or absence of atrial fibrillation or atrial flutter to determine the appropriate cut-off for a given BNP or NT-proBNP sample should be evaluated using the ECG performed at V1 (screening) prior to the collection of the BNP or NT-proBNP sample.
    8. eGFR of >30 and <75 ml/min/1.73 m2 at V1 (screening; determined by local laboratory), derived from serum creatinine values, age, and sex based on the CKD-EPI equation (Inker et al. 2021).
    9. Diuretic doses transitioned to oral loop diuretic (defined as: IV diuretic has been discontinued, AND chronic oral diuretic has been prescribed and/or administered) AFTER index event. Note: Do not need to be at a stable dose.
    10. Males and females will be eligible for this study.
    a. Women not of childbearing potential may participate in this trial. (WOCBP are excluded from the trial.) See Appendix 10.4 for definitions.
    b. Males who agree to use highly effective or effective methods of contraception may participate in this trial. See Appendix 10.4 for definitions.
    Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in
    clinical studies. For the contraception requirements of this protocol, see Appendix 10.4.
    11. Are capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Other inclusions
    12. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures, such as
    • self-inject intervention, and
    •store and take provided study interventions as directed.
    Note: Persons with physical limitations or unable to perform the injections must have the assistance of an individual trained to inject the intervention or come onsite for weekly injection.
    E.4Principal exclusion criteria
    1. Prior documentation of LVEF ≤45% in the past 12 months.
    2. Have had acute coronary syndrome or percutaneous coronary intervention, coronary artery bypass graft, cardiac mechanical support implantation, within 3 months prior to V2 (randomization), or any other cardiac surgery planned during the study.
    3. Have had LVAD or cardiac transplantation or have cardiac transplantation planned during the study.
    4. Have hypertrophic cardiomyopathy (obstructive or nonobstructive), restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac sarcoidosis, known amyloid cardiomyopathy, or inherited cardiomyopathy.
    5. Have uncontrolled arrhythmias other than permanent or persistent atrial fibrillation or atrial flutter.
    6. Have a history of an uncorrected cyanotic cardiac disease affecting LV function.
    7. Have a severe valvular disease.
    8. The index admission or index visit for worsening chronic HF triggered primarily by
    • pulmonary embolism
    • cerebrovascular accident, or
    • acute myocardial infarction.
    9. The index event for chronic worsening HF was not caused primarily by intravascular volume overload. For example, index event triggered by
    • significant arrhythmia, e.g., sustained ventricular tachycardia, or atrial fibrillation or flutter with sustained ventricular response >130 bpm, or
    bradycardia with sustained ventricular arrhythmia <45 bpm
    • infection
    • severe anemia, or
    • exacerbation of COPD.
    10. Hospitalization for the index event lasting more than 2 weeks.
    11. Are hospitalized for worsening HF event or received treatment for an urgent visit outside of being hospitalized with WHF, after V1 (screening) and before V2 (randomization)
    12. Have severe COPD as defined by chronic oxygen dependence. Night-time oxygen is not exclusionary.
    13. Uncorrected thyroid disease.
    14. Documented hemoglobin <10 g/dL at V1 (screening).
    15. Patients with uncorrected acute kidney injury at screening and/or on dialysis at screening
    16. Have, within 3 years prior to screening, a history of an active or untreated malignancy or are in remission from a clinically significant malignancy. Exceptions: basal or squamous cell skin cancer.
    17. Participants with personal or family history (first-degree relatives) of breast cancer.
    18. Women with a history of a mammography with clinically significant abnormal findings.
    19. Women with a history of clinically significant abnormal pap smear.
    20. Patients have any history of platelet dysfunction, hemophilia, von Willebrand disease, coagulation disorder causing a bleeding diathesis, other bleeding diathesis, or significant, nontraumatic bleeding episodes, such as from a gastrointestinal source.
    21. Symptomatic hypotension or a seated systolic BP <100 mmHg at the Screening Visit and on the day of V2 (randomization).
    22. SBP ≥180 mmHg at V2 (randomization).
    23. Have a history of or current significant psychiatric disorders considered clinically significant in the opinion of the investigator.
    24. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes them an unreliable trial participant or unlikely to complete the trial.
    25. Any other clinical condition that would jeopardize the participant’s safety while participating in this trial or may prevent the participant from adhering to the trial protocol.
    Diagnostic assessments
    26. Have laboratory values, in relation to the reference range ALT or AST >3.0x ULN or ALP >1.5x ULN or TBL >1.5x ULN, except for participants diagnosed with Gilbert’s syndrome
    27. Have a suboptimal ECHO image quality assessed by a central imaging laboratory at screening.
    Prior/concomitant therapy
    28. Have received IV inotropic therapy within 30 days before the Screening Visit
    Exception: renally dosed (≤3 μg/kg/min) IV dopamine is permitted.
    29. Are currently treated with hormone replacement therapy at the time of screening, including but not limited to testosterone, estrogen, and DHEA.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 26 in LARS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 26
    E.5.2Secondary end point(s)
    Change from baseline to Weeks 12 and 26 in
    • NT-proBNP
    • LAEDVI
    • LAESVI
    • eGFR (calculated by creatinine and cystatin-C)
    • serum creatinine, and
    • cystatin-C
    • AE overall
    • safety topics of special interest
    • laboratory parameters
    • ECG
    • vital signs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12 and week 26
    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 Yes
    E.6.7Pharmacodynamic Yes
    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 No
    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 trial4
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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
    Argentina
    Brazil
    Canada
    Japan
    Puerto Rico
    United States
    Poland
    Spain
    Hungary
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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 years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days6
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days6
    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: 108
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 324
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 152
    F.4.2.2In the whole clinical trial 432
    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 Decision2022-11-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-24
    P. End of Trial
    P.End of Trial StatusOngoing
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