ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure

Study Overview
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Brief Summary
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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
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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.

Official Title
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ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: ERADICATE-HF

Conditions
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Type 2 Diabetes Mellitus, Heart Failure

Intervention / Treatment
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* Drug: Ertugliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertuglifozin Treatment Arm<br>Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks | Drug: Ertugliflozin<br>* Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks<br>|
| Placebo Comparator: Placebo Arm<br>Placebo Matching Ertugliflozin Tablet for 12 weeks | Drug: Placebo<br>* Placebo once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proximal sodium reabsorption (FENa) | The difference in proximal sodium reabsorption FENa (measured using FELi) with ertugliflozin vs. placebo | 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) | The difference in GFR with ertugliflozin vs. placebo | Glomerular Filtration Rate (GFR, based on plasma inulin clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Effective Renal Plasma Flow (ERPF) | The difference in ERPF with ertugliflozin vs. placebo | Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Systolic blood pressure (SBP) | The difference in SBP with ertugliflozin vs. placebo | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Diastolic blood pressure (DBP) | The difference in DBP with ertugliflozin vs. placebo | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Heart rate (HR) | The difference in HR with ertugliflozin vs. placebo | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Echocardiography for markers of systolic and diastolic function, cardiac output |  | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Arterial stiffness |  | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Plasma volume | Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution) | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Extracellular water | Extracellular water will be measured non-invasively using bioimpedence spectroscopy | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Cardiac output | Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM) | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Systemic vascular resistance | Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM) | 2 time points: acute (1 week) and chronic (12 weeks) | 
| RAAS hormones | Neurohormones/biomarkers | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Natriuretic peptides | Neurohormones/biomarkers | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Sympathetic nervous system markers | Neurohormones/biomarkers | 2 time points: acute (1 week) and chronic (12 weeks) | 
| Urinary adenosine | Neurohormones/biomarkers | 2 time points: acute (1 week) and chronic (12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT2 inhibtion, Ertugliflozin, Type 2 Diabetes, Heart Failure