- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03416270
ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure (ERADICATE-HF)
ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: "ERADICATE-HF"
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Ontario
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Toronto, Ontario, Canada, M5G2N2
- Toronto General Hospital
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-
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Groningen, Netherlands
- University Medical Center Groningen
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De Boelelaan
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Amsterdam, De Boelelaan, Netherlands, 1117
- Vanderbilt University Medical Centre
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female subjects diagnosed with T2D ≥12 months prior to informed consent;
- eGFR ≥30 ml/min/1.73m2;
- Age >18 years;
- HbA1c 6.5%-10.5%;
- Body Mass Index (BMI) 18.5-45.0 kg/m2;
- Blood pressure ≤160/110 and ≥90/60 at screening,
- Heart failure with New York Heart Association (NYHA) class 2-3 symptoms and ejection fraction ≥20%
- Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days
- Stable diuretic dose for at least 30 days at the time of baseline physiological assessment
- BNP levels at baseline ≥100 pg/ml (no atrial fibrillation), ≥200 pg/ml if in atrial fibrillation
Exclusion Criteria:
- Type 1 Diabetes;
- Leukocyte and/or nitrite positive urinalysis that is untreated;
- Severe hypoglycaemia within 2 months prior to screening;
- History of brittle diabetes or hypoglycaemia unawareness based on investigator judgement;
- Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months;
- Clinically significant valvular disease;
- Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction;
- Uncontrolled systemic hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >110) or systemic hypotension (systolic blood pressure < 90/60 mmHg);
- Bariatric surgery or other surgeries that induce chronic malabsorption;
- Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
- Treatment with systemic corticosteroids;
- Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells;
- Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control;
- Participation in another trial with an investigational drug within 30 days of informed consent;
- 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;
- Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening;
- Active malignancy at the time of screening;
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Ertuglifozin Treatment Arm
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks
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Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks
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Placebo Comparator: Placebo Arm
Placebo Matching Ertugliflozin Tablet for 12 weeks
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Placebo once daily for 12 weeks
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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Outcome will be measured at 2 time points: acute (1 week) and chronic (12 weeks)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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Glomerular Filtration Rate (GFR, based on plasma inulin clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks)
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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)
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The difference in ERPF with ertugliflozin vs. placebo
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Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks)
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Systolic blood pressure (SBP)
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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The difference in SBP with ertugliflozin vs. placebo
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2 time points: acute (1 week) and chronic (12 weeks)
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Diastolic blood pressure (DBP)
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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The difference in DBP with ertugliflozin vs. placebo
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2 time points: acute (1 week) and chronic (12 weeks)
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Heart rate (HR)
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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The difference in HR with ertugliflozin vs. placebo
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2 time points: acute (1 week) and chronic (12 weeks)
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Echocardiography for markers of systolic and diastolic function, cardiac output
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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2 time points: acute (1 week) and chronic (12 weeks)
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Arterial stiffness
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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2 time points: acute (1 week) and chronic (12 weeks)
|
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Plasma volume
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution)
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2 time points: acute (1 week) and chronic (12 weeks)
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Extracellular water
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Extracellular water will be measured non-invasively using bioimpedence spectroscopy
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2 time points: acute (1 week) and chronic (12 weeks)
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Cardiac output
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)
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2 time points: acute (1 week) and chronic (12 weeks)
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Systemic vascular resistance
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM)
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2 time points: acute (1 week) and chronic (12 weeks)
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RAAS hormones
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Neurohormones/biomarkers
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2 time points: acute (1 week) and chronic (12 weeks)
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Natriuretic peptides
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Neurohormones/biomarkers
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2 time points: acute (1 week) and chronic (12 weeks)
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Sympathetic nervous system markers
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Neurohormones/biomarkers
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2 time points: acute (1 week) and chronic (12 weeks)
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Urinary adenosine
Time Frame: 2 time points: acute (1 week) and chronic (12 weeks)
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Neurohormones/biomarkers
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2 time points: acute (1 week) and chronic (12 weeks)
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: David ZI Cherney, MD PhD, University Health Network, Toronto General Hospital
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Heart Failure
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Sodium-Glucose Transporter 2 Inhibitors
- Ertugliflozin
Other Study ID Numbers
- 17-5627
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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