Sodium-Glucose Cotransporter-2 Inhibitor for Acute Cardiorenal Syndrome: A Feasibility Study (SGLT2i in CRS)

The long-term objective of this study is to test whether the addition of SGLT2 inhibitors to usual care during acute heart failure management in patients who develop kidney injury shortens the time to achieving symptomatic improvement and kidney function recovery. The study aims to assess feasibility and acceptability of such a randomized clinical trial.

Study Overview

• Status: Recruiting
• Conditions: Cardiorenal Syndrome
• Intervention / Treatment: Drug: Dapagliflozin

Detailed Description

Acute heart failure is associated with a significant risk of acute kidney injury which is present in up to a third of patients at the time of hospitalization. As adequate kidney function is necessary for self-decongestion, kidney injury makes the treatment of acute heart failure particularly challenging. SGLT2i are drugs consistently shown to reduce hospitalizations in heart failure as well as progression of kidney disease but are frequently discontinued during acute kidney injury. Although they have been included in the armamentarium of heart failure care as guideline directed medical therapy, a concern about the efficacy and safety in patients with kidney dysfunction remains a limitation to their widespread uptake particularly during heart failure exacerbation.

This study aims to enroll adults hospitalized with acute congestive cardiorenal syndrome and develop acute kidney injury in a randomized clinical trial of SGLT2i versus usual care to compare markers of decongestion and biomarkers of kidney injury and health to inform a larger randomized clinical trial. The overall aim is to assess if SGLT2i improve diuretic efficiency in patients with heart failure associated kidney injury. The long-term goal of this study is to promote increased use of SGLT2i by demonstrating their safety and possible benefit in patients who develop heart failure associated kidney injury to avoid interruptions in this setting.

The primary objective of this is study is to test the feasibility and acceptability of randomizing adults hospitalized with acute heart failure complicated by acute kidney injury to SGLT2i or usual care.

The secondary objectives of this study are:

1. To compare changes in biomarkers of kidney injury, repair and tubular function in order to test whether the SGLT2 inhibitor (dapagliflozin) improves response to standard treatment
2. To compare markers of decongestion (weight, urine volume, symptom score, diuretic de-escalation) to test whether the addition of SGLT2i to standard of care improves heart failure symptoms faster.
3. To compare possible adverse events such as: sodium or potassium derangements, metabolic acidosis, urinary tract infections (UTI) or genital mycotic infections in those exposed to the SGLT2i dapagliflozin vs usual care.
4. To compare hospital length of stay, mortality, progression to a higher stage of AKI, and persistent AKI at discharge

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

Contacts and Locations

• Study Contact: Name: Abinet Aklilu; Phone Number: (203) 931-5064; Email: abinet.aklilu@yale.edu
• Study Contact Backup: Name: Perry Wilson; Phone Number: (203) 764-8373; Email: francis.p.wilson@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale New Haven Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged ≥ 18 and ≤ 85 years-old
4. Diagnosed with heart failure of either preserved or reduced left ventricular function
5. NT-proBNP > 300 pg/mL
6. Ability to take an oral medication
7. Willing to adhere to the SGLT2i + usual care regimen

Exclusion Criteria:

1. Current use of SGLT2 inhibitor or use in the past 72 hours
2. Pregnancy or lactation (a pregnancy test will be performed prior to enrollment in women of child-bearing age)
3. Known allergic reactions to components of an SGLT2 inhibitor
4. Treatment with another investigational drug for heart failure different from or in addition to usual care within the 72 hours preceding AKI

5. Any individual who meets any of the following criteria will be excluded from participation in this study:

   • Documented history of ileal conduit (neobladder)
   • No means of collecting urine such as patients with documented incontinence without indwelling or external urinary catheter
   • Advanced kidney disease at baseline defined as baseline eGFR < 25 ml/min/1.73m2
   • Unexplained hypoglycemia in the past 30 days from enrollment
   • History of Fournier's gangrene (pelvic necrotizing fasciitis)
   • History of recurrent urinary tract infection (UTI): defined as documented UTI at least 2x in the past 6 months or 3 x in the past 12 months
   • End-stage kidney disease with dialysis requirement
   • Oliguria: defined as less than 30 ml urine output per hour for more than two consecutive hours or less than 500 ml over the preceding 24 hours
   • Severe acute kidney injury with indications for dialysis
   • Current dialysis receipt for acute kidney injury
   • Comfort measures only
   • Solid organ transplant on immunosuppression

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SGLT2i administration; A 10 mg oral dose of dapagliflozin will be administered daily for three days.	Drug: Dapagliflozin; Receipt of 10mg oral dose of dapagliflozin once daily for three days
No Intervention: Usual Care; Subjects continue with usual care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of eligible versus consented patients	Number of patients deemed eligible after assessment of inclusion and exclusion criteria and number of patients who consent, which serves as a measure of feasibility of enrolling patients with acute cardiorenal syndrome in a randomized clinical trial of SGLT2i.	From study initiation to study close (about 2 years)
Percentage of enrolled patients with completed sample collections	Percentage of enrolled patients who have provided at least two days of urine samples and percentage of enrolled patients who have provided at least two days of blood samples, which serves as a measure of feasibility of enrolling and retaining patients with acute cardiorenal syndrome in a randomized clinical trial of SGLT2i.	From study initiation to study close (about 2 years)
Enrollment rate	Total enrollment into the study over study duration, to serve as a measure of feasibility.	From study initiation to study close (about 2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Slope of creatinine	Comparison between study arms of the slope of the serum biomarker creatinine over five days, as a measure of kidney function	5 days following randomization
Slope of cystatin-C	Comparison between study arms of the slope of the serum biomarker cystatin-C over five days, as a measure of kidney function	5 days following randomization
Slope of NT-proBNP	Comparison between study arms of the slope of the serum biomarker NT-proBNP over five days, as a measure of decongestion.	5 days following randomization
Slope of kidney tubular injury and repair biomarkers	Comparison between study arms of the slopes of the following urinary biomarkers of renal tubular kidney injury, inflammation and repair over five days: molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), uromodulin (UMOD), chitinase-3-like protein (YKL-40).	5 days following randomization
Slope of urine volume	Comparison between study arms of 24 hour urine volume collection as a measure of decongestion	72 hours from randomization
Weight	Weight of subjects at 72 hours post-randomization as a measure of decongestion.	72 hours from randomization
Breathlessness score	Based on the 3 item symptom scale questionnaire given to subjects. Breathlessness scores range from 1-5, with higher scores indicating higher breathlessness. This score serves as a measure of decongestion.	72 hours from randomization
Loop diuretic dose de-escalation	Time from randomization to de-escalation of loop diuretic, serving as a measure of decongestion.	From randomization up to 72 hours from randomization
Mortality	Time to in-hospital death	Assessed from randomization to time of death up to 14 days post-randomization or discharge
Dialysis	Time to in-hospital dialysis	Assessed from point of randomization to the date of first documented dialysis order during index hospitalization, up to 14 days post-randomization or discharge
Rate of rehospitalization with heart failure	Number of patients rehospitalized for heat failure after index hospitalization, wtihin 90 days of discharge	90 days post-index discharge
Time-to-prescription of an SGLT2i	Time to prescription of any SGLT2 by patient's primary provider, up to 90 days post-randomization	90 days post-randomization

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Abinet Aklilu, Yale University; Principal Investigator: Perry Wilson, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 23, 2023
• First Submitted That Met QC Criteria: October 26, 2023
• First Posted (Actual): November 1, 2023

Study Record Updates

• Last Update Posted (Actual): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 29, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Disease; Renal Insufficiency; Heart Failure; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Cardio-Renal Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 2000036118; 000 (Other Identifier: CTGTY)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data for the primary and secondary outcomes will be made available.
• IPD Sharing Time Frame: Upon publication; indefinitely.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

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.: No