SGLT2 Inhibitors in Transthyretin Amyloid Cardiomyopathy

Transthyretin Amyloid Cardiomyopathy Clinical Trial

Official title:

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in Transthyretin Amyloid (ATTR) Cardiomyopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05233163
• Other study ID #: AAAT9709
• Status: Completed
• Phase: Phase 4
• Start date: March 14, 2022
• Est. completion date: May 1, 2023

Study information

• Verified date: May 2023
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: May 1, 2023
• Est. primary completion date: May 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyloidosis
• Cardiomyopathies
• Transthyretin Amyloid Cardiomyopathy

Intervention

Drug:
• Empagliflozin
Empagliflozin 10 mg oral daily for 12 weeks

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center / NewYork-Presbyterian Hospital	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serious Adverse Event (SAE) Rate	Calculated from occurrence of observed SAEs	12 weeks
Secondary	Mean Change in Daily Diuretic Dose	Calculated in mg/kg of furosemide equivalence	Baseline, 6 weeks and 12 weeks
Secondary	Mean Change in Body Weight (kg)	Change in body weight (kg) at trial end compared to trial start	Baseline, 6 weeks and 12 weeks
Secondary	Mean Change in Total Water Content (kg)	Change in total water content (kg) as assessed by bioimpedance analysis and quantitative magnetic resonance techniques at trial end compared to trial start	Baseline, 6 weeks and 12 weeks
Secondary	Mean Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure the patient's perception of their health status, which includes heart failure symptoms, impact on physical and social function, and how their heart failure impacts their quality of life (QOL) within a 2-week recall period. KCCQ scores are scaled from 0 to 100 and frequently summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent (better outcome).	Baseline, 6 weeks and 12 weeks
Secondary	Mean Change in Short Physical Performance Battery Score	The Short Physical Performance Battery (SPPB) is an objective assessment tool for evaluating lower extremity functioning in older persons. Each test is scored on a 0 to 4 scale using previously validated norms and summed for an overall score range of 0 to 12, with 0 indicating the lowest physical performance, and scores of 12 indicating the highest performance (better outcome).	Baseline, 6 weeks and 12 weeks