Clinical trial NCT05233163: SGLT2 Inhibitors in Transthyretin Amyloid Cardiomyopathy
Official title: Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in Transthyretin Amyloid (ATTR) Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Transthyretin Amyloid Cardiomyopathy
Keywords: Sodium-glucose cotransporter 2 inhibitor (SGLT2i)
Empagliflozin
Cardiomyopathy
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2022-02-10
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single center, single arm, prospective, 12 week open label pilot trial of the sodium-glucose cotransporter 2 inhibitor (SGLT2i), empagliflozin 10 mg oral daily, in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). The target population for enrollment will be subjects with ATTR-CM and either non-insulin dependent diabetes mellitus or chronic kidney disease. The primary aim will be to assess the safety and tolerability of empagliflozin 10 mg oral daily in subjects with heart failure secondary to ATTR, which remain unexplored. The accrual target is 15 subjects. Consented subjects will be evaluated for safety and tolerability of study drug, empagliflozin 10 mg oral daily, over a period of 12 weeks. Subjects will undergo a total of 6 study visits: 3 in-person and 3 telephone follow-ups.

Detailed description: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underrecognized cause of heart failure among older adults, in which misfolded transthyretin (TTR) proteins build up in the muscle tissue of the heart. In 2018, a drug called tafamidis was proven to stabilize the protein and protect people from further damage, and in 2019, it was approved for use in ATTR-CM by the U.S. Food and Drug Administration (FDA). But while people with ATTR-CM are living longer, they continue to suffer from symptoms of heart failure and cardiorenal syndrome as the disease progresses. Sodium glucose co-transporter inhibitors (SGLT2i) are drugs used to treat diabetes mellitus, heart failure, and chronic kidney disease. They may also reduce systemic inflammation, and affect body composition (fat, lean mass, and total water contents) in patients with heart failure, a condition which also has significant overlap with obesity. No one has explored the safety, tolerability, and clinical effects of SGLT2i in patients with heart failure due to ATTR-CM.

Eligibility criteria: Inclusion Criteria:

* Every participant must meet all of the following inclusion criteria to be eligible for enrollment in this study:

  1. Age ≥ 18 years old
  2. Diagnosis of TTR cardiac amyloidosis (wild type or variant), confirmed by the presence of amyloid deposits on analysis of biopsy specimens obtained from cardiac and noncardiac sites (e.g. fat aspirate, gastrointestinal sites, salivary glands, or bone marrow), technetium-99m pyrophosphate cardiac scintigraphy, or mass spectrometry
  3. Normal serum free light chain ratio and the absence of abnormal monoclonal band on serum and urine immunofixation
  4. Subjects will have at least 1 of the indications below for an SGLT2i, and meet package-insert criteria for drug initiation: non-insulin dependent diabetes mellitus with hemoglobin A1c ranging from 6.5-9.9 OR chronic kidney disease (defined as an estimated glomerular filtration rate of 25-75 ml/minute/1.73 m2 of body-surface area)
  5. On stable oral diuretics (defined as no more than a 50% increase from baseline diuretic dose established during a sustained 2 week period) within 2 weeks before enrollment
  6. Able to understand and sign the informed consent document after the nature of the study has been fully explained

Exclusion Criteria:

* The presence of any of the following excludes eligibility for enrollment in this study:

  1. Prior liver or heart transplantation
  2. Active malignancy or non-amyloid disease with expected survival of less than 1 year
  3. Heart failure, in the opinion of the investigator, primarily caused by severe left-sided valve disease. Note: if valve was repaired, subject may be considered as no longer with severe valve disease
  4. Heart failure, in the opinion of the investigator, primarily caused by ischemic heart disease
  5. Ventricular assist device or anticipated within the next 6 months
  6. Pacemaker or implantable cardioverter defibrillator incompatible with magnetic resonance technology
  7. Absolute contraindication for quantitative magnetic resonance (e.g. aneurysmal clips, metal objects)
  8. Impairment from stroke, injury or other medical disorder that precludes participation in the study
  9. Myocardial infarction, cardiovascular surgery, stroke or transient ischemic attack within the prior 90 days
  10. Disabling dementia or other mental or behavioral disease
  11. Enrollment in a clinical trial not approved for co-enrollment
  12. Expected use of continuous intravenous inotropic therapy in the next 6 months
  13. High risk for non-adherence as determined by screening evaluation
  14. Inability or unwillingness to comply with the study requirements
  15. Chronic kidney disease with estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m2 or end-stage renal disease
  16. Current or prior SGLT2i use
  17. Type 1 diabetes mellitus or insulin-dependent diabetes mellitus
  18. N-terminal (NT)-pro hormone BNP (NT-proBNP) \< 300 pg/mL or \< 900 pg/mL if concomitant diagnosis of atrial fibrillation
  19. History of ketoacidosis
  20. History of complex urinary tract or genital infections
  21. History of kidney stone
  22. Systolic blood pressure \< 90 mmHg and symptomatic hypotension
  23. Systolic blood pressure ≥ 180 mmg Hg
  24. Chronic obstructive pulmonary disease
  25. Major surgery in the 90 days before or after screening
  26. Chronic alcohol or drug abuse
  27. Nursing home resident
  28. Other reason that would make the subject inappropriate for entry into this study

Primary outcomes:
measure: Number of Participants Who Experienced a Serious Adverse Event (SAE)
timeFrame: 12 weeks
Secondary outcomes:
measure: Mean Change in Daily Diuretic Dose
timeFrame: Baseline, 12 weeks
measure: Mean Change in Body Weight
timeFrame: Baseline, 6 weeks and 12 weeks
measure: Mean Change in Total Water Content
timeFrame: Baseline, 6 weeks and 12 weeks
measure: Mean Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score
timeFrame: Baseline, 12 weeks
measure: Mean Change in Short Physical Performance Battery Score
timeFrame: Baseline, 12 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center / NewYork-Presbyterian Hospital
state: New York
Study officials:
affiliation: Columbia University
name: Mathew Maurer, MD
role: PRINCIPAL_INVESTIGATOR
References: