Clinical trial NCT03416270: ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure
Official title: ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: "ERADICATE-HF"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Heart Failure
Keywords: SGLT2 inhibtion
Ertugliflozin
Type 2 Diabetes
Heart Failure
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: University Medical Center Groningen
name: Merck Sharp & Dohme LLC
name: University of Toronto
name: Toronto General Hospital
First posted: 2018-01-31
Enrollment: 34
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.
Primary purpose: TREATMENT

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.

Eligibility 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;

Primary outcomes:
measure: Fractional Excretion of Lithium (FELi)
timeFrame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
measure: Fractional Excretion of Sodium (FENa)
timeFrame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
measure: Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa)
timeFrame: Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)
Secondary outcomes:
measure: Glomerular Filtration Rate (GFR)
timeFrame: Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks
measure: Effective Renal Plasma Flow (ERPF)
timeFrame: Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks
measure: Systolic Blood Pressure (SBP)
timeFrame: chronic (12 weeks)
measure: Diastolic Blood Pressure (DBP)
timeFrame: chronic (12 weeks)
measure: Heart Rate (HR)
timeFrame: chronic (12 weeks)
measure: LV Ejection Fraction
timeFrame: chronic (12 weeks)
measure: Carotid-femoral Pulse Wave Velocity
timeFrame: chronic (12 weeks)
measure: Plasma Volume
timeFrame: chronic (12 weeks)
measure: Extracellular Water
timeFrame: chronic (12 weeks)
measure: Cardiac Output
timeFrame: chronic (12 weeks)
measure: Systemic Vascular Resistance
timeFrame: chronic (12 weeks)
measure: Blood Angiotensin II
timeFrame: chronic (12 weeks)
measure: BNP
timeFrame: chronic (12 weeks)
measure: Norepinephrine
timeFrame: chronic (12 weeks)
measure: Urinary Adenosine
timeFrame: chronic (12 weeks)
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Amsterdam
country: Netherlands
facility: Vanderbilt University Medical Centre
state: De Boelelaan
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Health Network, Toronto General Hospital
name: David ZI Cherney, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: