Type 2 Diabetes MellitusPhase 2ERADICATE-HFNCT03416270
ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure
A Phase 2 study testing Ertugliflozin in people with Type 2 Diabetes Mellitus and Heart Failure, run by University Health Network, Toronto at 3 sites in 2 countries.
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). Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Type 2 Diabetes Mellitus, Heart Failure
- What is being tested?
- Ertugliflozin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 34 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 28 Jun 2018to 14 Apr 2021
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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,
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- 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
Who cannot join
- 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;
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- 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;
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Netherlands2 sites
Vanderbilt University Medical Centre
Amsterdam, De Boelelaan, 1117
University Medical Center Groningen
Groningen
About this study
Official title: ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure: "ERADICATE-HF"
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).
Read the 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
- Being tested
- Ertugliflozin, Placebo
- Keywords
- SGLT2 inhibtion, Ertugliflozin, Type 2 Diabetes, Heart Failure
- Medical subject headings
- Diabetes Mellitus, Type 2, Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErtugliflozinDrug
Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks
PlaceboDrug
Placebo once daily for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| Ertuglifozin Treatment Arm | Experimental | Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks Receives: Drug: Ertugliflozin |
| Placebo Arm | Placebo comparator | Placebo Matching Ertugliflozin Tablet for 12 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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)
The difference in iohexol-measured GFR with ertugliflozin vs. placebo. 5ml bolus iohexol (Omnipaque 300mg) was infused intravenously over 2 minutes while participants were supine. Iohexol disappearance curve was used to measure GFR over from 2-4 hours after infusion.
Measured: Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks
Effective Renal Plasma Flow (ERPF)
The difference in ERPF with ertugliflozin vs. placebo. Paraaminohippurate (PAH) was intravenously administered to measured ERPF.
Measured: Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks
Systolic Blood Pressure (SBP)
The difference in seated SBP with ertugliflozin vs. placebo
Measured: chronic (12 weeks)
Diastolic Blood Pressure (DBP)
The difference in seated DBP with ertugliflozin vs. placebo
Measured: chronic (12 weeks)
Heart Rate (HR)
The difference in seated HR with ertugliflozin vs. placebo
Measured: chronic (12 weeks)
LV Ejection Fraction
Echocardiography for markers of systolic and diastolic function
Measured: chronic (12 weeks)
Carotid-femoral Pulse Wave Velocity
Arterial Stiffness using SphygmaCor software. Pulse points measured at carotid and femoral arteries.
Measured: chronic (12 weeks)
Plasma Volume
Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution)
Measured: chronic (12 weeks)
Extracellular Water
Extracellular water will be measured non-invasively using bioimpedence spectroscopy
Measured: chronic (12 weeks)
Cardiac Output
Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)
Measured: chronic (12 weeks)
Systemic Vascular Resistance
Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM)
Measured: chronic (12 weeks)
Blood Angiotensin II
Neurohormones/biomarkers
Measured: chronic (12 weeks)
BNP
Neurohormones/biomarkers
Measured: chronic (12 weeks)
Norepinephrine
Neurohormones/biomarkers
Measured: chronic (12 weeks)
Urinary Adenosine
Neurohormones/biomarkers
Measured: chronic (12 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2018
- Study start28 Jun 2018
- Primary completion14 Apr 2021
- Study completion14 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients will be randomized to 15 mg (10mg + 5mg tablets) PO ertugliflozin daily or a matched placebo.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- University Medical Center Groningen, Merck Sharp & Dohme LLC, University of Toronto, Toronto General Hospital
- Responsible party
- Principal investigator, David Z.I. Cherney, University Health Network, Toronto
- Investigators
- David ZI Cherney, MD PhD, Principal investigator, University Health Network, Toronto General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03416270
- Sponsor's protocol ID
- 17-5627
- Acronym
- ERADICATE-HF
- Status last verified
- Apr 2025
- First submitted
- 15 Jan 2018
- Last updated
- 6 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No