ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF (ERTU-SODIUM)
Primary Purpose
Heart Failure With Reduced Ejection Fraction, Congestion
Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Ertugliflozin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Heart Failure With Reduced Ejection Fraction focused on measuring SGLT2 inhibitors, heart failure with reduced ejection fraction, congestion, sodium
Eligibility Criteria
Inclusion criteria:
- age >18 years;
- males and females (females of child bearing potential must be using adequate contraceptive precautions)
- diagnosis of heart failure (New York Heart Association [NYHA] functional class II to III);
- Left ventricular ejection fraction <40%;
- stable symptoms and medical therapy within the last month.
- Informed consent has to be given in written form
Exclusion criteria:
- taking SGLT2i in the last month
- acute coronary syndrome or cardiac surgery within the last month;
- estimated glomerular filtration rate <20 ml/kg/min;
- use of continuous parental inotropic agents;
- systolic blood pressure <90 mm Hg;
- LVAD implantation or cardiac transplantation
- pregnant or lactating women; and
- any other medical condition considered unappropriated by a study physician
Sites / Locations
- Icahn School of Medicine at Mount SinaiRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Ertugliflozin then Placebo
Placebo
Arm Description
Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month
Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month
Outcomes
Primary Outcome Measures
Change in the skin water content
Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight
Secondary Outcome Measures
Change in skin sodium content
Skin sodium content will be measured by flame spectrophotometry after dry ashing
Change in interstitial Fluid
Interstitial Fluid to measure tissue congestion and will be calculated as Extracellular Volume minus Plasma Volume
Change in pulmonary fluid
Pulmonary fluid content to measure tissue congestion and is quantified using remote dielectric sensing with ReDS Vest
Change in the number of pulmonary Kerley's B-lines
The number of pulmonary Kerley's B-lines (aka "comets") to measure tissue congestion and will be quantified using lung ultrasound
Change in the plasma volume
Plasma volume to measure vascular congestion.
Change in vascular congestion
Vascular congestion will be evaluated using VExUS (Volume Evaluation by UltraSound)
Change in left ventricular filling pressures
Left ventricular filling pressures to measure vascular and will be evaluated using the echocardiographic parameter E/e' (surrogate of LV filling pressures)
Change in plasma concentrations of catecholamines
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of catecholamines.
Change in plasma concentrations of aldosterone
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of aldosterone.
Change in plasma concentrations of plasma renin activity
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of plasma renin activity
Full Information
NCT ID
NCT05152940
First Posted
November 29, 2021
Last Updated
October 11, 2023
Sponsor
Icahn School of Medicine at Mount Sinai
1. Study Identification
Unique Protocol Identification Number
NCT05152940
Brief Title
ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF
Acronym
ERTU-SODIUM
Official Title
ERTU-SODIUM: Double-blind, Prospective, Randomized, Crossover, Placebo-control Study on the Effects of the SGLT2 Inhibitor Ertugliflozin on the Regulation of Interstitial Volume, Plasma Volume, Subcutaneous Sodium Storage, and the Functionality of the Subcutaneous Glycosaminoglycan Network in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 20, 2023 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Icahn School of Medicine at Mount Sinai
4. Oversight
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.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion).
Detailed Description
The glucosaminoglycan (GAG) network in the subcutaneous interstitium can non-osmotically bind large amounts of sodium. Therefore, the GAG network creates a hypertonic sodium concentration without fluid accumulation. This means that the subcutaneous GAG act as a third compartment that is able to non-osmotically store sodium without inducing congestion, thus serving as buffer in the case of sodium overload.
The researchers hypothesize that the SGLT2 inhibitor Ertugliflozin enhances the functionality of the subcutaneous GAG network. The hypothesis is that Ertugliflozin-induced GAG functionality induces more potent congestion relief (reduction in sodium and water content in the interstitial tissue) with minimal impact on blood volume and organ perfusion.
The research team will perform a randomized clinical trial with a cross-over design. Patients with heart failure with reduced ejection fraction (HFrEF) will be randomized to the SGLT2 inhibitor Ertuglifozin or to placebo. Skin punch biopsy will be performed before treatment and after treatment (one month) to evaluate skin content of water and sodium. At each time point, an oral salt challenge will be performed to investigate the functionality of the GAG network, and whether Ertugliflozin mitigates the degree of tissue and vascular congestion after this oral salt challenge as compared with placebo.
The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion). This overarching hypothesis causes:
in the baseline situation, chronic treatment with Ertugliflozin:
1.1. will reduce skin/tissue congestion as demonstrated by lower skin water content and lower volume of interstitial-extracellular fluid
1.2. will reduce skin sodium content due to a mobilization of sodium from the subcutaneous glucosaminoglycan (GAG) network
1.3. will create a differential regulation of interstitial vs plasmatic volume, with ertugliflozin decreasing tissue congestion (B-lines and dielectric resistance in lungs) better than placebo
1.4. will only cause a mild reduction in plasma volume with no neurohormonal activation
1.5. will ameliorate GAG structure: higher GAG levels, higher sulfated (functional) GAG, less expression of enzymes degrading GAG, less GAG degradation products in plasma
after an oral salt challenge (sodium overload), previous chronic treatment with Ertugliflozin:
2.1. will improve the sodium buffering capacity of the skin GAG network, meaning ertugliflozin will enhance non-osmotic sodium storage in the skin without causing tissue congestion (edema) or vascular congestion (increase in plasma volume and filling pressures).
2.2. will reduce skin/tissue congestion (as mentioned in 2.1): lower skin water content and interstitial-extracellular fluid volume
2.3. will not cause vascular congestion, will not raise plasma volume or LV filling pressures
In summary, Ertugliflozin will protect HFrEF patients from acute decompensations induced by dietary transgressions by enhancing the skin sodium buffering capacity
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure With Reduced Ejection Fraction, Congestion
Keywords
SGLT2 inhibitors, heart failure with reduced ejection fraction, congestion, sodium
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
28 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ertugliflozin then Placebo
Arm Type
Active Comparator
Arm Description
Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month
Arm Title
Placebo
Arm Type
Active Comparator
Arm Description
Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month
Intervention Type
Drug
Intervention Name(s)
Ertugliflozin
Intervention Description
Treatment with Ertugliflozin 5 mg oral once per day for one month
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Treatment with matching placebo to ertugliflozin administered orally once daily for a period of one month
Primary Outcome Measure Information:
Title
Change in the skin water content
Description
Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight
Time Frame
Baseline and One month
Secondary Outcome Measure Information:
Title
Change in skin sodium content
Description
Skin sodium content will be measured by flame spectrophotometry after dry ashing
Time Frame
Baseline and One month
Title
Change in interstitial Fluid
Description
Interstitial Fluid to measure tissue congestion and will be calculated as Extracellular Volume minus Plasma Volume
Time Frame
Baseline and One month
Title
Change in pulmonary fluid
Description
Pulmonary fluid content to measure tissue congestion and is quantified using remote dielectric sensing with ReDS Vest
Time Frame
Baseline and One month
Title
Change in the number of pulmonary Kerley's B-lines
Description
The number of pulmonary Kerley's B-lines (aka "comets") to measure tissue congestion and will be quantified using lung ultrasound
Time Frame
Baseline and One month
Title
Change in the plasma volume
Description
Plasma volume to measure vascular congestion.
Time Frame
Baseline and One month
Title
Change in vascular congestion
Description
Vascular congestion will be evaluated using VExUS (Volume Evaluation by UltraSound)
Time Frame
Baseline and One month
Title
Change in left ventricular filling pressures
Description
Left ventricular filling pressures to measure vascular and will be evaluated using the echocardiographic parameter E/e' (surrogate of LV filling pressures)
Time Frame
Baseline and One month
Title
Change in plasma concentrations of catecholamines
Description
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of catecholamines.
Time Frame
Baseline and One month
Title
Change in plasma concentrations of aldosterone
Description
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of aldosterone.
Time Frame
Baseline and One month
Title
Change in plasma concentrations of plasma renin activity
Description
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of plasma renin activity
Time Frame
Baseline and One month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria:
age >18 years;
males and females (females of child bearing potential must be using adequate contraceptive precautions)
diagnosis of heart failure (New York Heart Association [NYHA] functional class II to III);
Left ventricular ejection fraction <40%;
stable symptoms and medical therapy within the last month.
Informed consent has to be given in written form
Exclusion criteria:
taking SGLT2i in the last month
acute coronary syndrome or cardiac surgery within the last month;
estimated glomerular filtration rate <20 ml/kg/min;
use of continuous parental inotropic agents;
systolic blood pressure <90 mm Hg;
LVAD implantation or cardiac transplantation
pregnant or lactating women; and
any other medical condition considered unappropriated by a study physician
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Carlos G Santos-Gallego, MD
Phone
2122418484
Email
carlos.santos-gallego@mssm.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlos G Santos-Gallego, MD
Organizational Affiliation
Icanh School of Medicine at Mount Sinai
Official's Role
Principal Investigator
Facility Information:
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Individual Site Status
Recruiting
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
IPD Sharing Time Frame
Beginning 9 months and ending 36 months following article publication.
Learn more about this trial
ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF
We'll reach out to this number within 24 hrs