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

Heart Failure Clinical Trial

— ERADICATE-HF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03416270
• Other study ID #: 17-5627
• Status: Completed
• Phase: Phase 2
• Start date: June 28, 2018
• Est. completion date: April 14, 2021

Study information

• Verified date: May 2023
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: April 14, 2021
• Est. primary completion date: April 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Heart Failure
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Ertugliflozin
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks
• Placebo
Placebo once daily for 12 weeks

Locations

Country	Name	City	State
Canada	Toronto General Hospital	Toronto	Ontario
Netherlands	Vanderbilt University Medical Centre	Amsterdam	De Boelelaan
Netherlands	University Medical Center Groningen	Groningen

Sponsors (5)

Lead Sponsor	Collaborator
University Health Network, Toronto	Merck Sharp & Dohme LLC, Toronto General Hospital, University Medical Center Groningen, University of Toronto

Countries where clinical trial is conducted

Canada,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	Systolic blood pressure (SBP)	The difference in SBP with ertugliflozin vs. placebo	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Diastolic blood pressure (DBP)	The difference in DBP with ertugliflozin vs. placebo	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Heart rate (HR)	The difference in HR with ertugliflozin vs. placebo	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Echocardiography for markers of systolic and diastolic function, cardiac output		2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Arterial stiffness		2 time points: acute (1 week) and chronic (12 weeks)
Secondary	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)
Secondary	Extracellular water	Extracellular water will be measured non-invasively using bioimpedence spectroscopy	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Cardiac output	Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	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)
Secondary	RAAS hormones	Neurohormones/biomarkers	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Natriuretic peptides	Neurohormones/biomarkers	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Sympathetic nervous system markers	Neurohormones/biomarkers	2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Urinary adenosine	Neurohormones/biomarkers	2 time points: acute (1 week) and chronic (12 weeks)