Clinical trial NCT04438213: Ertugliflozin in Chronic Heart Failure
Official title: Ertugliflozin in Chronic Heart Failure: Cardio-renal and Diuretic Effects
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Heart Failure
Keywords: Ertugliflozin
Metolazone
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2020-06-18
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline to day 7 of plasma volume by add-on to loop diuretic therapy
timeFrame: 7 days
measure: Change from baseline to 6 weeks of plasma volume by add-on to loop diuretic therapy
timeFrame: 6 weeks
measure: Change from baseline to day 7 of total body water by add-on to loop diuretic therapy (Chronic)
timeFrame: 7 days
measure: Natriuretic effect of adjuvant to loop diuretic therapy
timeFrame: 1 day
measure: Change from baseline to 6 weeks total body water by add-on to loop diuretic therapy (Chronic)
timeFrame: 6 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
Study officials:
References: