Heart Failure With Reduced Ejection FractionPhase 4ERTU-SODIUMNCT05152940
ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF
A Phase 4 study testing Ertugliflozin in people with Heart Failure With Reduced Ejection Fraction and Congestion, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Reduced Ejection Fraction, Congestion
- 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
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Feb 2023to 27 Oct 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Icahn School of Medicine at Mount Sinai
New York, New York, 10029
About this study
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)
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).
Read the 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
- Being tested
- Ertugliflozin, Placebo
- Keywords
- SGLT2 inhibitors, heart failure with reduced ejection fraction, congestion, sodium
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErtugliflozinDrug
Treatment with Ertugliflozin 5 mg oral once per day for one month
PlaceboDrug
Treatment with matching placebo to ertugliflozin administered orally once daily for a period of one month
| Study group | Role | What they receive |
|---|---|---|
| Ertugliflozin then Placebo | Active comparator | Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month Receives: Drug: Ertugliflozin; Drug: Placebo |
| Placebo | Active comparator | Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month Receives: Drug: Ertugliflozin; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Baseline and One month
Secondary outcomes (10)
Change in skin sodium content
Skin sodium content will be measured by flame spectrophotometry after dry ashing
Measured: Baseline and One month
Change in interstitial Fluid
Interstitial Fluid to measure tissue congestion and will be calculated as Extracellular Volume minus Plasma Volume
Measured: Baseline and One month
Change in pulmonary fluid
Pulmonary fluid content to measure tissue congestion and is quantified using remote dielectric sensing with ReDS Vest
Measured: Baseline and One month
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
Measured: Baseline and One month
Change in the plasma volume
Plasma volume to measure vascular congestion.
Measured: Baseline and One month
Change in vascular congestion
Vascular congestion will be evaluated using VExUS (Volume Evaluation by UltraSound)
Measured: Baseline and One month
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)
Measured: Baseline and One month
Change in plasma concentrations of catecholamines
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of catecholamines.
Measured: Baseline and One month
Change in plasma concentrations of aldosterone
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of aldosterone.
Measured: Baseline and One month
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
Measured: Baseline and One month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2021
- Study start2 Feb 2023
- Primary completion27 Oct 2023
- Study completion27 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
- More trials run by Icahn School of Medicine at Mount SinaiThe 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Icahn School of Medicine at Mount Sinai
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Carlos Santos-Gallego, Icahn School of Medicine at Mount Sinai
- Investigators
- Carlos G Santos-Gallego, MD, Principal investigator, Icanh School of Medicine at Mount Sinai
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05152940
- Sponsor's protocol ID
- PD21-12423
- Acronym
- ERTU-SODIUM
- Status last verified
- Oct 2025
- First submitted
- 29 Nov 2021
- Last updated
- 11 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT05152940
- Acronym / sponsor ID
- ERTU-SODIUM / PD21-12423
- Keywords
- SGLT2 inhibitors, heart failure with reduced ejection fraction, congestion, sodium
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Icahn School of Medicine at Mount SinaiUniversity, hospital or other
- Study start
- 2 Feb 2023 (actual)
- Primary completion
- 27 Oct 2023 (actual)
- Study completion
- 27 Oct 2023 (actual)
- First posted
- 10 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ertugliflozin then Placebo | Active comparator | Drug: Ertugliflozin, Drug: PlaceboTreatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month |
| Placebo | Active comparator | Drug: Ertugliflozin, Drug: PlaceboTreatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (8 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ErtugliflozinTreatment with Ertugliflozin 5 mg oral once per day for one month | Drug | Ertugliflozin then Placebo, Placebo |
| PlaceboTreatment with matching placebo to ertugliflozin administered orally once daily for a period of one month | Drug | Ertugliflozin then Placebo, Placebo |
Primary outcome
Change in the skin water content
Time frame: Baseline and One month
Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight
10 secondary outcomes
Change in skin sodium content
Time frame: Baseline and One month
Change in interstitial Fluid
Time frame: Baseline and One month
Change in pulmonary fluid
Time frame: Baseline and One month
Change in the number of pulmonary Kerley's B-lines
Time frame: Baseline and One month
Change in the plasma volume
Time frame: Baseline and One month
Change in vascular congestion
Time frame: Baseline and One month
Change in left ventricular filling pressures
Time frame: Baseline and One month
Change in plasma concentrations of catecholamines
Time frame: Baseline and One month
Change in plasma concentrations of aldosterone
Time frame: Baseline and One month
Change in plasma concentrations of plasma renin activity
Time frame: Baseline and One month
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2026.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carlos G Santos-Gallego, MD principal investigator
Icanh School of Medicine at Mount Sinai
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ertugliflozin in people with Heart Failure With Reduced Ejection Fraction and Congestion, run by Icahn School of Medicine at Mount Sinai at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in the skin water content (time frame: Baseline and One month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2026.