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

NCT03416270 | Completed Phase 2 Results

• 1 other identifier: 17-5627
• Study Type: interventional
• Target: 34
• Locations: 2 countries
• Sites: 3

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).

Conditions

Type 2 Diabetes Mellitus; Heart Failure

Keywords

SGLT2 inhibtion; Ertugliflozin; Type 2 Diabetes; Heart Failure

Outcome Measures

Primary Outcomes (3)

• Fractional Excretion of Lithium (FELi)

  The difference in fractional excretion of lithium (FELi) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before lithium excretion was measured in urine and blood.

  Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)

• Fractional Excretion of Sodium (FENa)

  The difference in fractional excretion of sodium (FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.

  Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)

• Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa)

  The difference in fractional excretion of lithium and fractional excretion of sodium (calculated by the difference between FELi and FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.

  Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)

Secondary Outcomes (15)

• Glomerular Filtration Rate (GFR)

  Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks

• Effective Renal Plasma Flow (ERPF)

  Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks

• Systolic Blood Pressure (SBP)

  chronic (12 weeks)

• Diastolic Blood Pressure (DBP)

  chronic (12 weeks)

• Heart Rate (HR)

  chronic (12 weeks)

Study Arms (2)

Ertuglifozin Treatment Arm

EXPERIMENTAL

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

Drug: Ertugliflozin

Placebo Arm

PLACEBO COMPARATOR

Placebo Matching Ertugliflozin Tablet for 12 weeks

Drug: Placebo

Interventions

Ertugliflozin DRUG

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

Ertuglifozin Treatment Arm

Placebo DRUG

Placebo once daily for 12 weeks

Placebo Arm

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• University Health Network, Toronto: lead
• University Medical Center Groningen: collaborator
• Merck Sharp & Dohme LLC: collaborator
• University of Toronto: collaborator
• Toronto General Hospital: collaborator

Study Sites (3)

Toronto General Hospital

Toronto, Ontario, M5G2N2, Canada

Location

Vanderbilt University Medical Centre

Amsterdam, De Boelelaan, 1117, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Heart Failure

Interventions

ertugliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Heart Diseases; Cardiovascular Diseases

Limitations and Caveats

There are limitations to the present analysis. Due to increasing use of SGLT2 inhibition for the clinical indication of HF and challenges posed by the COVID-19 pandemic, we were unable to meet the participant recruitment target for this trial. Therefore, our study was potentially underpowered to detect a difference between ertugliflozin and placebo groups in the primary outcome of FELi.

Results Point of Contact

• Title: Dr. David Cherney
• Organization: University Health Network

david.cherney@uhn.ca

416.340.4151

Study Officials

• David ZI Cherney, MD PhD

  University Health Network, Toronto General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind study
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine, Clinician Scientist

Model Details: Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.

Study Record Dates

• First Submitted: January 15, 2018
• First Posted: January 31, 2018
• Study Start: June 28, 2018
• Primary Completion: April 14, 2021
• Study Completion: April 14, 2021
• Last Updated: May 6, 2025
• Results First Posted: May 6, 2025

Record last verified: 2025-04

Locations

NL (2); CA (1)