Transthyretin Amyloid Cardiomyopathy
Conditions
Keywords
Sodium-glucose cotransporter 2 inhibitor (SGLT2i), Empagliflozin, Cardiomyopathy
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.
Interventions
DRUGEmpagliflozin
Empagliflozin 10 mg oral daily for 12 weeks
Sponsors
Columbia University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants Who Experienced a Serious Adverse Event (SAE) | 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Daily Diuretic Dose | Baseline, 12 weeks | Calculated in mg/kg of furosemide equivalence. This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported. |
| Mean Change in Body Weight | Baseline, 6 weeks and 12 weeks | Change in body weight (kg) at trial end compared to trial start |
| Mean Change in Total Water Content | Baseline, 6 weeks and 12 weeks | Change in total water content (kg) as assessed by bioimpedance analysis and quantitative magnetic resonance techniques at trial end compared to trial start |
| Mean Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | Baseline, 12 weeks | 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). This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported. |
| Mean Change in Short Physical Performance Battery Score | Baseline, 12 weeks | 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). This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin Participants will take empagliflozin 10 mg oral daily for 12 weeks. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Empagliflozin |
|---|---|
| Age, Continuous | 81 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 13 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Number of Participants Who Experienced a Serious Adverse Event (SAE)
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Empagliflozin | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 0 Participants |
Secondary
Mean Change in Body Weight
Change in body weight (kg) at trial end compared to trial start
Time frame: Baseline, 6 weeks and 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Mean Change in Body Weight | -0.97 kg |
Secondary
Mean Change in Daily Diuretic Dose
Calculated in mg/kg of furosemide equivalence. This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Mean Change in Daily Diuretic Dose | -12 mg/kg |
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). This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Mean Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | 4 score on a scale |
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). This outcome was assessed at Baseline, 6 weeks, and 12 weeks; the change from baseline to 12 weeks is reported.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Mean Change in Short Physical Performance Battery Score | -0.7 score on a scale |
Secondary
Mean Change in Total Water Content
Change in total water content (kg) as assessed by bioimpedance analysis and quantitative magnetic resonance techniques at trial end compared to trial start
Time frame: Baseline, 6 weeks and 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Mean Change in Total Water Content | -0.63 kg |