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    Summary
    EudraCT Number:2022-000655-36
    Sponsor's Protocol Code Number:80684
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-03-31
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2022-000655-36
    A.3Full title of the trial
    Evaluation of GeranylGeranylAcetone in heart failure with preserved ejection fraction
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of GeranylGeranylAcetone in patients with heart failure and preserved heart function
    A.3.2Name or abbreviated title of the trial where available
    GLADIATOR-HFpEF
    A.4.1Sponsor's protocol code number80684
    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 SponsorAmsterdam UMC
    B.1.3.4CountryNetherlands
    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 supportDutch Heart Foundation
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUMCG
    B.5.2Functional name of contact pointClinical trial information
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31625651341
    B.5.6E-mailg.h.d.voordes@umcg.nl
    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 Yes
    D.2.1.1.1Trade name Teprenone
    D.2.1.1.2Name of the Marketing Authorisation holderStichting VUmc
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameGeranylGeranylAcetone
    D.3.4Pharmaceutical form Oral drops, liquid
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 placeboOral liquid
    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
    Heart Failure with preserved ejection fraction.
    E.1.1.1Medical condition in easily understood language
    Heart failure with a preserved ventricule function.
    E.1.1.2Therapeutic area Body processes [G] - Cell Physiological Phenomena [G04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objectives
    To study whether Geranyl-Geranyl Acetone (GGA) reduces left ventricular (LV) diastolic dysfunction in patients with HFpEF compared to placebo (and to assess/confirm its effectiveness and safety in patients with HFpEF)
    E.2.2Secondary objectives of the trial
    Secondary objectives
    • To assess whether GGA improves endothelial function in patients with HFpEF compared to placebo.
    • To assess whether GGA improves renal (hemodynamic) function in patients with HFpEF compared to placebo
    • To assess whether GGA improves self-reported quality of life and exercise tolerance in patients with HFpEF compared to placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible to participate in this study, a subject must meet all of the following criteria:
    1. Age≥ 50 years
    2. Patients with a diagnosis of symptomatic chronic heart failure (New York Heart Association class II or III) AND preserved systolic LV function (LV ejection fraction or LVEF ≥ 50%) documented within the last 6 months AND evidence of diastolic LV dysfunction with at least 1 out of the following 4 criteria:
    - HFA-PEFF score ≥5
    - H2FPEF score ≥6
    - HFpEF according to the 2021 ESC HF Guidelines (NT-proBNP>125 pg/ml AND either LV mass indexed or LVMI >95 g/m2 for women and >115 g/m2 for men OR left atrial volume indexed or LAVI >34 ml/m2 OR mean e; septal/lateral < 9 cm/s) OR E/e’ >13) OR TR velocity at rest > 2.8 m/s.
    - Pulmonary capillary wedge pressure (PCWP) >15 mmHg and/or >25 mmHg during exercise
    E.4Principal exclusion criteria
    1. Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs
    2. Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months
    3. Hemoglobin <9 g/dl at screening
    4. LVEF <40% measured at any time point in the history of the patient
    5. History of mitral valve repair or replacement
    6. Presence of significant valvular disease defined as mitral valve regurgitation defined as grade ≥ 3+ MR; tricuspid valve regurgitation defined as grade ≥ 2+ TR; aortic valve disease defined as ≥ 2+ AR or > moderate AS
    7. Acute myocarditis within 3 months prior to randomization
    8. Infiltrative cardiomyopathy
    9. Genetic cardiomyopathy
    10. Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy
    11. Precapillary pulmonary hypertension
    12. BMI >40 kg/m2
    13. Estimated glomerular filtration rate (GFR) <20 ml/min or >90 ml/min
    14. History of solid organ transplantation including kidney transplantation
    15. Atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm
    16. Not able to undergo the complete study protocol
    17. Doubt about compliance
    18. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control
    19. Chronic absorption problems
    20. Proven allergy for lactose products or cow-milk.
    21. Proven allergy for Iodide-containing contrast, Iohexol or PAH.
    22. Any documented or suspected malignancy or history of malignancy within 1 year prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix
    23. Currently enrolled in another investigational device or drug trial
    24. Estimated life expectancy <1 year
    E.5 End points
    E.5.1Primary end point(s)
    1. Does GGA-treatment improve LV diastolic function in HFpEF, measured by echocardiography derived filling pressures (E/e’)?
    2. Does GGA-treatment improve endothelial function, measured by EndoPAT®-derived reactive hyperemia index (RHI)?
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 13 weeks of treatment with GGA/placebo.
    E.5.2Secondary end point(s)
    Additional echocardiographic measures:
    • Change in echocardiographically determined left atrial (LA) indexed volumes: (LAVImax, LAVImin, LAVIpre-A) and function (LA global strain and LA emptying fractions (reservoir, conduit and booster pump).
    • Change in echocardiographically determined LV global longitudinal strain.
    • Change in echocardiographically determined LV myocardial relaxation (e’).
    • Change in echocardiographically determined LV distensibility, measured by E/e’ and LV end-diastolic volume.
    • Change in echocardiographically determined right ventricular systolic function (TAPSE, RV S’).Change in echocardiographically determined pulmonary artery pressure.

    Patient reported outcomes and exercise capacity:
    • Change in NYHA class between baseline and 13 weeks.
    • Change in the total symptom score of the KCCQ quality of life assessment between baseline and 13 weeks.
    • Change in 6-minute walking distance between baseline and 13 weeks.

    Endothelial function assessment
    • Change in flow-mediated vasodilatation in the finger, determined by applanation tonometry (EndoPAT®)
    • Change in endothelium-dependent and -independent vasodilation in skin, determined by iontophoresis of acetylcholine (miochol) and sodium nitroprusside and measured using laser-Doppler (20)
    • Microvascular and inflammatory biomarkers: Nitrosated hemoglobin (Hb(NO)4), nitrate/nitrite, H2S, CRP, endothelin-1

    Kidney endpoints:
    • Change in iohexol-measured GFR at baseline and 13 weeks of treatment
    • Change in para-aminohippuric acid-measured effective renal plasma flow (ERPF)
    • Change in intrakidney hemodynamic function including renal vascular resistance (RVR), glomerular pressure (Pglo), afferent vascular resistance (Ra) and efferent vascular resistance (Re).
    • Changes in urinary albumin-creatinine ratio (UACR)
    • Change in serum and urinary neutrophil gelatinase associated lipocalin (NGAL)
    • Change in serum and urinary kidney injury molecule (KIM)-1
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 13 weeks of treatment with GGA/placebo.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 Yes
    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 concerned3
    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 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
    The trial ends when the last patient has had his/her last visit.
    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 months
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state40
    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)
    Patients will receive full care/support according to the current therapeutic guidelines during and after the trial.
    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 Decision2023-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-17
    P. End of Trial
    P.End of Trial StatusOngoing
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