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    Summary
    EudraCT Number:2017-001840-37
    Sponsor's Protocol Code Number:2017-001840-37
    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:2018-06-22
    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 number2017-001840-37
    A.3Full title of the trial
    ERtugliflozin triAl in DIabetes with preserved or reduced ejeCtion FrAcTion
    mEchanistic evaluation in Heart Failure: "ERADICATE-HF"
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The cardiovascular effects of ertugliflozin in patients with type 2 diabetes
    and heart failure.
    A.3.2Name or abbreviated title of the trial where available
    ERADICATE-HF
    A.4.1Sponsor's protocol code number2017-001840-37
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03416270
    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 SponsorVU University Medical Center
    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 supportMSD
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University Medical Center
    B.5.2Functional name of contact pointDaniel van Raalte
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081 HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031 0204440534
    B.5.6E-maild.vanraalte@vumc.nl
    D. IMP Identification
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diabetes Mellitus Type 2 and Heart failure
    E.1.1.1Medical condition in easily understood language
    Diabetes and heart failure
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    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
    To elucidate the mechanisms whereby the SGLT2i ertugliflozin modifies cardiorenal interactions that regulate fluid volume and neurohormonal
    activation in patients with T2D and HF (T2D-HF). Our primary goal is to determine if SGLT2i causes a persistent proximal renal tubular
    natriuretic effect. We will capture acute (1 week) and chronic (12 weeks) responses, since physiological effects of SGLT2i agents may
    change over time. As an extension of our primary aim, we will assess whether ertugliflozin-related effects on proximal tubule natriuresis lead to a reduction in plasma volume and extracellular body water.
    E.2.2Secondary objectives of the trial
    1. We will determine if volume contraction leads to a decline in hormones that are activated in HF patients such as B‐type natriuretic
    peptides (BNP), without activating the SNS;
    2. We will determine the impact of ertugliflozin on: renal hemodynamic function (GFRiohexol) measured at 1 week2,3,5 and 12 weeks as a
    measure of safety;
    3. Blood pressure, echocardiographic measures of cardiac output (and derived systemic vascular resistance) arterial stiffness and systemic
    vascular resistance to better understand the blood pressure lowering effect in this patient population;
    4. Heart rate and heart rate variability, to assess effects on SNS activation;
    5. Urinary natriuretic modulators, such as angiotensin converting enzyme and adenosine;
    6. To characterize the safety of ertugliflozin vs. placebo by determining the number of hypoglycemic episodes between groups, and serious
    adverse events.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects diagnosed with T2D ≥12 months prior to
    informed consent;
    2. eGFR ≥30 ml/min/1.73m2;
    3. Age >18 years;
    4. HbA1c 6.5%-10.5%;
    5. Body Mass Index (BMI) 18.5-45.0 kg/m2;
    6. Blood pressure < 160/110 and > 90/60 at screening,
    7. Heart failure with New York Heart Association (NYHA) class 2-3 symptoms and ejection fraction > 20%
    8. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days
    9. Stable diuretic dose for at least 30 days at the time of baseline physiological assessment
    10. BNP levels at baseline > 100 pg/ml (no atrial fibrillation), > 200 pg/ml if in atrial fibrillation (if NT-pro-BNP is used then baseline should be >300 ng/L (no atrial fibrillation), or >600 ng/L (in atrial fibrillation)
    E.4Principal exclusion criteria
    1. Type 1 Diabetes;
    2. Leukocyte and/or nitrite positive urinalysis that is untreated;
    3. Severe hypoglycaemia within 2 months prior to screening;
    4. History of brittle diabetes or hypoglycaemia unawareness based on investigator judgement;
    5. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months;
    6. Clinically significant valvular disease;
    7. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction;
    8. Uncontrolled systemic hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure >110) or systemic hypotension
    (systolic blood pressure < 90/60 mmHg);
    9. Bariatric surgery or other surgeries that induce chronic malabsorption;
    10. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
    11. Treatment with systemic corticosteroids;
    12. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells;
    13. Pre-menopausal women who are nursing, pregnant, or of childbearing potential and not practicing an acceptable method of birth
    control;
    14. Participation in another trial with an investigational drug within 30 days of informed consent;
    15. Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical
    condition that would jeopardize subject safety or study compliance based on investigator judgement;
    16. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of
    normal as determined during screening;
    17. Active malignancy at the time of screening;
    18. Allergy to iodine-based substances if receiving iohexol for GFR measures
    E.5 End points
    E.5.1Primary end point(s)
    Fractional excretion of sodium, using lithium clearance as a surrogate for
    proximal tubular sodium handling
    E.5.1.1Timepoint(s) of evaluation of this end point
    Fractional excretion of sodium, using lithium clearance as a surrogate for proximal tubular sodium handling, will be measured at baseline, 1 week after start treatment/placebo and 12 weeks after start treatment/placebo.
    E.5.2Secondary end point(s)
    • Glomerular Filtration Rate and Renal plasma flow measured with iohexol and PAH, as well as derived renal hemodynamic parameters as
    described elsewhere. Iohexol will be used, provided that there is no history of allergy to iodine based substances.
    • Systolic/diastolic blood pressure, heart rate
    • Echocardiography for markers of systolic and diastolic function, cardiac output
    • Arterial stiffness
    • Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution) to assess changes in plasma volume in
    response to SGLT2i.
    • Extracellular water, will be measured non-invasively using bioimpedence spectroscopy, as described elsewhere.
    • Cardiac output and systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM). This non-invasive
    technique is a form of bioelectrical impedance ("bioreatance") to measure thoracic fluid content with electrocardiogram electrode
    stickers. Beat-to-beat changes in fluid content can be used to derive cardiac output. Then, using measured mean arterial pressure, systemic
    vascular resistance can be calculated. This entire measurement process takes approximately 15 minutes.
    • Neurohormones/biomarkers: Hormones of the RAAS (renin, aldosterone in plasma and urine), Natriuretic Peptides, Sympathetic
    nervous system markers, Urinary adenosine
    E.5.2.1Timepoint(s) of evaluation of this end point
    These secondary end points will be measured at baseline, 1 week after start treatment/placebo and 12 weeks after start treatment/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 No
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    Canada
    Netherlands
    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 years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    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: 6
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 No
    F.3.3Specific vulnerable populations Yes
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Diabetes Type 2 and Heart Failure NYHA class 2-2, ejection fraction > 20%
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 36
    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)
    No different treatment is expected after completion of the study.
    Participants will return to their own physician
    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 Decision2018-06-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-15
    P. End of Trial
    P.End of Trial StatusOngoing
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