Ertugliflozin in Chronic Heart Failure

Ertugliflozin in Chronic Heart Failure: Cardio-renal and Diuretic Effects

The purpose of this study is to determine the effects on heart failure signs and symptoms of the use of either ertugliflozin, metolazone or placebo, in conjunction with intravenous loop diuretic use in acute settings and chronic oral loop diuretic therapy.

There are two general purposes for this study. The proposed study is both larger and more rigorous than essentially all PK/PD studies that form the basis of current practice with loop diuretics as well as all studies looking at add-on thiazide therapy (current guideline-recommended adjuvant). The second is to generate a mechanistic understanding of the pleotropic cardio-renal factors with chronic therapy that differentiate ertugliflozin from traditional diuretics particularly in how they maintain reduced blood volume without the complication of over-diuresis and volume depletion.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Ertugliflozin; Drug: Metolazone; Drug: Placebo

Detailed Description

This is a randomized placebo controlled mechanistic study to understand the utility of ertugliflozin in acute and post-acute hospitalized heart failure patients with or without diabetes, compared to both placebo and the active control metolazone. The broad study design will be designed around evaluation of change in gold standard determined body fluid spaces (blood volume, extracellular fluid, total body water), administering a sodium chloride challenge, and collecting the necessary biospecimens to test our hypotheses. The general study design will randomize to ertugliflozin vs. placebo early during IV diuretic therapy with continuation post discharge for a total therapy of 6 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Katherine Keith, RN; Phone Number: (203) 737-3571; Email: katherine.keith@yale.edu
• Study Contact Backup: Name: Veena Rao, PhD; Phone Number: (203) 785-7917; Email: veena.s.rao@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale School of Medicine
      • Principal Investigator: Jeffrey Testani, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. A clinical diagnosis of ADHF with at least one objective sign of volume overload (rales, edema, elevated JVP, or preadmission weight gain)
2. As judged by the treating physician, a projected need and ability to tolerate treatment with an extended need for IV diuretics with the goal of significant fluid removal (i.e., goal >1L/day net fluid loss)
3. Chronic daily oral loop diuretic dose > or equal to 20mg furosemide equivalents for at least one month prior to admission
4. eGFR 30 mL/min/1.73 m2
5. Signed informed consent

Exclusion Criteria:

1. Current use or plan to initiate renal replacement therapy or ultrafiltration this hospital admission
2. Significant bladder dysfunction or urinary incontinence
3. Inability to comply with the serial urine collection procedures
4. Current use of a thiazide or thiazide like diuretics or use within 5 half-lives of the drug, including metolazone
5. Prior heart transplant, critical stenotic valvular disease or complex congenital heart
6. History of type 1 diabetes, diabetic ketoacidosis, "brittle" diabetes or frequent hypoglycemia or severe hypoglycemic episodes requiring emergent intervention (ER visit or EMS response, glucagon administration or forced oral carbs) in the last 3 months
7. History of or current urosepsis or frequent urinary tract infections
8. Anemia with hemoglobin <8g/dL (due to required phlebotomy for the study)
9. Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ertugliflozin; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo	Drug: Ertugliflozin; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
Experimental: Metolazone; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo	Drug: Metolazone; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
Placebo Comparator: Placebo; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo	Drug: Placebo; Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Natriuretic effect of adjuvant to loop diuretic therapy	The natriuretic effect (urine sodium concentration) of each arm with loop diuretic therapy will be measured by the urine sodium output.	1 day
Change from baseline to day 7 of total body water by add-on to loop diuretic therapy (Chronic)	The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to day 7	7 days
Change from baseline to 6 weeks total body water by add-on to loop diuretic therapy (Chronic)	The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to 6 weeks.	6 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2021
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: June 3, 2020
• First Submitted That Met QC Criteria: June 16, 2020
• First Posted (Actual): June 18, 2020

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 21, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Ertugliflozin; Metolazone
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium-Glucose Transporter 2 Inhibitors; Sodium Chloride Symporter Inhibitors; Ertugliflozin; Metolazone
• Other Study ID Numbers: 2000027951; MISP59625 (Other Grant/Funding Number: Merck Sharp & Dohme)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes