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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

Tracking Information
First Submitted Date  ICMJE January 15, 2018
First Posted Date  ICMJE January 31, 2018
Last Update Posted Date May 2, 2018
Estimated Study Start Date  ICMJE May 7, 2018
Estimated Primary Completion Date March 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2018)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2018)
  • 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
  • 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
  • Systolic blood pressure (SBP) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in SBP with ertugliflozin vs. placebo
  • Diastolic blood pressure (DBP) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in DBP with ertugliflozin vs. placebo
  • Heart rate (HR) [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    The difference in HR with ertugliflozin vs. placebo
  • Echocardiography for markers of systolic and diastolic function, cardiac output [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
  • Arterial stiffness [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
  • 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)
  • Extracellular water [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Extracellular water will be measured non-invasively using bioimpedence spectroscopy
  • 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)
  • 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)
  • RAAS hormones [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers
  • Natriuretic peptides [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers
  • Sympathetic nervous system markers [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers
  • Urinary adenosine [ Time Frame: 2 time points: acute (1 week) and chronic (12 weeks) ]
    Neurohormones/biomarkers
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure
Official Title  ICMJE ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: "ERADICATE-HF"
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).
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE
  • Type 2 Diabetes Mellitus
  • Heart Failure
Intervention  ICMJE
  • Drug: Ertugliflozin
    Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks
  • Drug: Placebo
    Placebo once daily for 12 weeks
Study Arms  ICMJE
  • Experimental: Ertuglifozin Treatment Arm
    Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks
    Intervention: Drug: Ertugliflozin
  • Placebo Comparator: Placebo Arm
    Placebo Matching Ertugliflozin Tablet for 12 weeks
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 23, 2018)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2021
Estimated Primary Completion Date March 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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;
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Vesta Lai, RN 416-340-4800 ext 8508 vesta.lai@uhn.ca
Contact: Yuliya Lytvyn, PhD julia.lytvyn@mail.utoronto.ca
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03416270
Other Study ID Numbers  ICMJE REB# 17-5627.0
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party David Z.I. Cherney, University Health Network, Toronto
Study Sponsor  ICMJE University Health Network, Toronto
Collaborators  ICMJE
  • University Medical Center Groningen
  • Merck Sharp & Dohme Corp.
  • University of Toronto
  • Toronto General Hospital
Investigators  ICMJE Not Provided
PRS Account University Health Network, Toronto
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP