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ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure (ERADICATE-HF)

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ClinicalTrials.gov Identifier: NCT03416270
Recruitment Status : Not yet recruiting
First Posted : January 31, 2018
Last Update Posted : May 2, 2018
Sponsor:
Collaborators:
University Medical Center Groningen
Merck Sharp & Dohme Corp.
University of Toronto
Toronto General Hospital
Information provided by (Responsible Party):
David Z.I. Cherney, University Health Network, Toronto

Brief Summary:
This study aims to elucidate the mechanisms whereby the SGLT2i "ertugliflozin" modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with type 2 diabetes and heart failure (T2D-HF).

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Heart Failure Drug: Ertugliflozin Drug: Placebo Phase 2

Detailed Description:

Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria. SGLT2i also reduce blood pressure and albuminuria in T2D - possibly through natriuresis. Importantly, a landmark trial "EMPA-REG OUTCOME" demonstrated that the SGLT2i "empagliflozin" is the first anti- hyperglycemic agent to reduce mortality and HF risk, and also to decrease the risk of progressive diabetic nephropathy. Similar benefits were also recently reported in the CANVAS Program trial with canagliflozin. Despite the benefits observed in these two pivotal trials, the mechanisms responsible for beneficial effects of SGLT2i in patients with T2D with respect to the development and/or worsening of HF are not currently known.

In light of the results of EMPA-REG OUTCOME, the investigators aim 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). The investigators will test the hypothesis that ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, without inducing significant renal vasoconstriction or activation of the sympathetic nervous system (SNS) (see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of HF will enable the design of rational physiology based strategies to decrease the burden of HF, which could have major clinical and research implications internationally.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind study
Primary Purpose: Treatment
Official Title: ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: "ERADICATE-HF"
Estimated Study Start Date : May 7, 2018
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : March 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Ertuglifozin Treatment Arm
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks
Drug: Ertugliflozin
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks

Placebo Comparator: Placebo Arm
Placebo Matching Ertugliflozin Tablet for 12 weeks
Drug: Placebo
Placebo once daily for 12 weeks




Primary Outcome Measures :
  1. Proximal sodium reabsorption (FENa) [ Time Frame: Outcome will be measured at 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in proximal sodium reabsorption FENa (measured using FELi) with ertugliflozin vs. placebo


Secondary Outcome Measures :
  1. Glomerular Filtration Rate (GFR) [ Time Frame: Glomerular Filtration Rate (GFR, based on plasma inulin clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in GFR with ertugliflozin vs. placebo

  2. Effective Renal Plasma Flow (ERPF) [ Time Frame: Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in ERPF with ertugliflozin vs. placebo

  3. Systolic blood pressure (SBP) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in SBP with ertugliflozin vs. placebo

  4. Diastolic blood pressure (DBP) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in DBP with ertugliflozin vs. placebo

  5. Heart rate (HR) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in HR with ertugliflozin vs. placebo

  6. Echocardiography for markers of systolic and diastolic function, cardiac output [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
  7. Arterial stiffness [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
  8. Plasma volume [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution)

  9. Extracellular water [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Extracellular water will be measured non-invasively using bioimpedence spectroscopy

  10. Cardiac output [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)

  11. Systemic vascular resistance [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM)

  12. RAAS hormones [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers

  13. Natriuretic peptides [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers

  14. Sympathetic nervous system markers [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers

  15. Urinary adenosine [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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 child-bearing 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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03416270


Contacts
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Contact: Vesta Lai, RN 416-340-4800 ext 8508 vesta.lai@uhn.ca
Contact: Yuliya Lytvyn, PhD julia.lytvyn@mail.utoronto.ca

Sponsors and Collaborators
University Health Network, Toronto
University Medical Center Groningen
Merck Sharp & Dohme Corp.
University of Toronto
Toronto General Hospital
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Responsible Party: David Z.I. Cherney, Associate Professor of Medicine, Clinician Scientist, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT03416270    
Other Study ID Numbers: REB# 17-5627.0
First Posted: January 31, 2018    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by David Z.I. Cherney, University Health Network, Toronto:
SGLT2 inhibtion
Ertugliflozin
Type 2 Diabetes
Heart Failure
Additional relevant MeSH terms:
Layout table for MeSH terms
Heart Failure
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-hydroxymethyl-6,8-dioxabicyclo(3.2.1)octane-2,3,4-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs