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

NCT ID: NCT03416270

Last Updated: 2025-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-28
• Study Completion Date: 2021-04-14

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.

Conditions

Type 2 Diabetes Mellitus; Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ertuglifozin Treatment Arm

Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks

Group Type: EXPERIMENTAL

Ertugliflozin

Intervention Type: DRUG

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

Placebo Arm

Placebo Matching Ertugliflozin Tablet for 12 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo once daily for 12 weeks

Interventions

Ertugliflozin

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

Intervention Type: DRUG

Placebo

Placebo once daily for 12 weeks

Intervention Type: DRUG

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;

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Medical Center Groningen

OTHER

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Toronto

OTHER

Sponsor Role: collaborator

Toronto General Hospital

OTHER

Sponsor Role: collaborator

University Health Network, Toronto

OTHER

Sponsor Role: lead

Responsible Party

David Z.I. Cherney

Associate Professor of Medicine, Clinician Scientist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David ZI Cherney, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University Health Network, Toronto General Hospital

Locations

Toronto General Hospital

Toronto, Ontario, Canada

Vanderbilt University Medical Centre

Amsterdam, De Boelelaan, Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Countries

Canada; Netherlands

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

17-5627

Identifier Type: -

Identifier Source: org_study_id