Clinical trial NCT05233163
Conditions: Transthyretin Amyloid Cardiomyopathy
Keywords: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) Empagliflozin Cardiomyopathy
Sponsor: Columbia University
Start date: 2022-03-14; Completion date: 2023-05-01
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: Subjects will take empagliflozin 10 mg oral daily for 12 weeks.
Interventions: intervention 1: Empagliflozin
Intervention descriptions: intervention 1: Empagliflozin 10 mg oral daily for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Sodium-glucose Cotransporter 2 Inhibitors 
in Transthyretin Amyloid Cardiomyopathy
NCT05233163
July 11, 2022
Protocol Version: 
5 
Protocol Date: 
July 11, 2022 
Sponsor: 
Columbia University Irving Medical Center 
Clinical Cardiovascular Research Laboratory for the Elderly 
(CCRLE) 
21 Audubon Ave. SB-0180 
New York, NY 10032, USA 
Sponsor-Investigator: 
Mathew Maurer, MD 
Principal Investigator 
212-932-4537
Collaborating Investigators: Jonathan Barasch, MD PhD 
Division of Nephrology 
Columbia University Irving Medical Center 
Elissa Driggin, MD 
Division of Cardiology 
Columbia University Irving Medical Center 
Dympna Gallagher, EdD 
Division of Endocrinology & Institute of Human Nutrition 
Columbia University Irving Medical Center 
Helene Maltz, PharmD 
Department of Pharmacy 
Columbia University Irving Medical Center 
Ani Nalbandian, MD 
Division of Cardiology 
Columbia University Irving Medical Center 
Utpal Pajvani, MD 
Division of Endocrinology 
Columbia University Irving Medical Center 
Jai Radhakrishnan, MD 


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Division of Nephrology 
Columbia University Irving Medical Center 
Yuichi Shimada, MD 
Division of Cardiology 
Columbia University Irving Medical Center 
Hirad Yarmohammadi, MD, MPH 
Division of Cardiology 
Columbia University Irving Medical Center 
STUDY SYNOPSIS 
Protocol Title 
SGLT2 Inhibitors in Cardiac Amyloidosis 
Protocol Number 
3 
Design 
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), 
an age-related infiltrative cardiomyopathy that causes heart failure and death. 
The target population for enrollment will be subjects with ATTR-CM and either 
non-insulin dependent diabetes mellitus (DM) or chronic kidney disease (CKD). 
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. In addition, we will evaluate a number of secondary outcomes, 
including differences in daily diuretic dose, patient important outcomes using 
the Kansas City Cardiomyopathy Questionnaire (a validated health status 
measure for heart failure) and the Short Physical Performance Battery (a 
functional assessment), and potential mechanistic effects by evaluating changes 
in body composition, echocardiographic features, and cytokine and cardiorenal 
syndrome biomarker levels.  
The accrual target is 15 subjects for this single arm pilot study assessing safety 
and tolerability of the study drug as the primary outcome. 
Consented eligible patients will be evaluated for safety and tolerability of study 
drug, empagliflozin 10 mg oral daily, over a period of 3 months. During this 
time, subjects will undergo a total of 6 study visits: 3 in-person and 3 telephone 
follow-ups. 
Study Sites 
This study is to be conducted at 3 locations at Columbia University Irving 
Medical Center: screening, recruitment, and in-person visits at the Center for 
Advanced Cardiac Care, Heart Center 4th Floor; in-person visits, laboratory 
specimen collection, and echocardiography at the Clinical Cardiovascular 
Research Laboratory for the Elderly (CCRLE) at 21 Audubon Avenue, SB-
0180; body composition analysis (including bioimpedance analysis and 
quantitative magnetic resonance) at the Body Composition Unit of NY Nutrition 
Obesity Research Center, located at 21 Audubon Avenue, Suite SB-0134. 


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Time on Study 
The duration of patient participation in this study is approximately 4 months. 
Primary Objective 
To assess safety and tolerability of the SGLT2i empagliflozin in patients with 
ATTR-CM. 
Sample Size 
15 subjects 
Inclusion 
and 
Exclusion Criteria 
Every participant must meet all of the following inclusion criteria to be eligible 
for enrollment in ALL parts of 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 FDA-approved indications below for
an SGLT2i, and meet package-insert criteria for drug initiation
a.
Non-insulin dependent diabetes mellitus with hemoglobin A1c
ranging from 6.5-9.9
OR 
b.
Chronic kidney disease (defined as an estimated glomerular
filtration rate of 20-75 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
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.
Current or anticipated ventricular assist device 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


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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 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. 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 pyelonephritis
22. Systolic blood pressure < 90 mmHg and symptomatic hypotension
23. Systolic blood pressure ≥ 180 mmg Hg
24. Severe chronic obstructive pulmonary disease thought to be a primary
contributor to dyspnea
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
*Subjects with exclusion criteria 6 or 7 may be enrolled in a study subset
that entails all study procedures EXCEPT the body composition analysis,
which would necessarily be excluded.
**In addition, all subjects will be offered the opportunity of opting out of 
the body composition analysis if they meet eligibility criteria (e.g. if a 
subject has a compatible pacemaker / defibrillator but does not want to 
undergo device adjustments, a physical limitation or claustrophobia 
making it difficult to lay in the scanner, they may opt OUT of the body 
composition analysis scans).  
Aims 
The specific aims of this investigation include: 
1.
To evaluate the safety and tolerability of SGLT2i therapy in patients
with ATTR-CM and DM or CKD on oral loop diuretic therapy
2.
To evaluate the change in oral loop diuretic daily dose in patients with
ATTR-CM and DM or CKD on an SGLT2i.


 
 
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3. To evaluate the effect of SGLT2i therapy on body composition in 
patients with ATTR-CM and DM or CKD. 
4. To evaluate the effect of SGLT2i therapy on echocardiographic features 
of volume status in patients with ATTR-CM and DM or CKD. 
We will explore the following: 
1. The effect of SGLT2i therapy on urinary PAPPA2, a potential urinary 
biomarker of volume status by measuring differences in urinary 
PAPPA2 before and after SGLT2i therapy. 
2. The effect of SGLT2i therapy on markers of systemic inflammation and 
uricosuria in patients with ATTR-CM and DM or CKD by measuring 
differences in cytokine and cardiorenal syndrome biomarker levels 
before and after SGLT2i therapy utilizing proteomics. 
 
 
The safety of study participants will be evaluated by: 
1. Assessment of adverse events (AEs), including serious adverse events 
(SAEs). 
2. Clinical laboratory safety tests (serum chemistry). 
3. Vital sign measurements (blood pressure, pulse rate, and respiratory 
rate). 
4. 12-Lead electrocardiogram (ECG). 
5. Physical examinations 
6. Scheduled phone follow-ups to screen for signs and symptoms related 
to study drug 
7. Review of subjects’ available medical records, including for urgent care 
or emergency room visits, hospitalizations, and office visits 
 
 


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SCHEDULE OF ACTIVITIES 
The following table summarizes the activities to be performed at each of the designated study visits. Details of the 
different procedures can be found in subsequent section of this protocol. For every study visit, a checklist will be used to 
help ensure completion of all the study procedures. 
Procedure 
Screening 
(within 30 days 
of baseline 
visit) 
Baseline 
(day 1) 
Week 1 
(7 ± 2 days) 
Week 4 
(28± 3 days) 
Week 6 
(42± 4 days) 
Week 8 
(56± 5 days) 
Week 12 
(84± 7 days) 
Site 
Clinic 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Clinic 
Informed Consent 
X 
Inclusion and Exclusion Criteria 
X 
Baseline History 
X 
Vitals Signs, Clinical Exam 
X 
X 
X 
Medications 
X 
X 
X 
X 
X 
X 
Adverse Events Review 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
X 
Laboratory Analysis‡ 
X 
Xò
X 
X 
Transthoracic Echocardiogram 
X 
X 
KCCQ 
X 
X 
X 
SPPB 
X 
X 
X 
Body Composition Analysis* 
X 
X 
X 
‡ Includes: NT-proBNP, troponin-t, basic metabolic panel, hepatic function panel, complete blood count, hemoglobin A1c (at baseline and week 12), 
uric acid, cystatin C, beta-hydroxybutyrate, erythrocyte sedimentation rate, c-reactive protein; urinalysis, urine albumin, urine uric acid, urine 
creatinine. 
*Body composition analysis includes bioimpedance and quantitative magnetic resonance measurements. As described in Inclusions and Exclusion
Criteria section, a subset of study subjects may not be eligible for, OR may opt out of body composition analysis.
ò Laboratory analysis includes a single test, basic metabolic panel, to be drawn 7-10 days after study drug initiation to assess for significant flucations 
in renal function and ensure subjects’ safety. Lab draw may be performed at CUIMC or locally to reduce subject burden. 


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Description of Study Procedures 
*All study procedures will take place at Center for Advanced Cardiac Care, Heart Center 4th floor, or the Clinical
Cardiovascular Research Laboratory for the Elderly (CCRLE) at 21 Audubon Avenue, unless otherwise noted.
I. Analysis of existing data and/or prospective record review
Study personnel will screen charts of patients seen in the Center for Advanced Cardiac Care for study eligibility. Medical
records will be screened for assessment of cardiac function, renal function, inclusion and exclusion criteria.
II. Biological specimens (collection or use of)
Study participants will have fasted blood samples obtained via routine phlebotomy during each of 3 in-person clinic visits,
each 6 weeks apart. Blood samples obtained will consist of routine bloodwork for clinical care, in addition to specific lab
tests for study purposes; 15 cc of blood (plasma and serum) sample will also be collected and stored in the CUIMC biobank
for future research, which may include analysis of cytokines, biomarkers of cardiorenal syndrome, and proteomics. Study
participants will also be asked to provide a urine specimen during each in-person clinic visit, 10 cc of which will be stored
in the CUIMC biobank for future research, including analysis of biomarkers of cardiorenal syndrome. See table for
specification of blood and urine laboratory measures to be made at each time interval. Laboratory analysis at the 1 week
timepoint (which consists of a single lab test, a basic metabolic panel) may be performed at CUIMC or locally to reduce
subject burden.
III. Drugs or Biologics
As part of this trial, study participants will be asked to take 1 tablet of empagliflozin 10 mg oral daily for 3 months.
Empagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) approved by the U.S. Food and Drug Administration
(FDA) for treatment of diabetes mellitus (type 2), chronic kidney disease, and heart failure with reduced ejection fraction.
Subjects who are enrolled in this study will have either diabetes mellitus or chronic kidney disease, consistent with FDA
approved indications for this drug.
IV. Future use of data and/or specimens
Biobanked blood and urine specimens may be analyzed in the future for cytokine expression profiles, biomarkers of
cardiorenal syndrome, and proteomics. Data collected during this pilot trial may be used for design and development of
future larger trials of SGLT2i in subjects with ATTR-CM.
V. Transthoracic Echocardiogram
Study participants will have a transthoracic echocardiogram (TTE) performed at trial start and 12 weeks during the in-
person clinic visits. TTE will be performed by certified echocardiographer and CCRLE lab manager, Steve Helmke.
Estimated time for TTE: 40 minutes.
VI. Survey/interview/questionnaire
Study participants will be administered the Kansas City Cardiomyopathy Questionnaire (KCCQ) at trial start, 6 weeks, and
12 weeks during 3 in-person clinic visits. Questionnaire data will be collected and recorded in a secure manner as previously
described. See attached PDF entitled "KCCQ" for questionnaire (English and Spanish versions provided).
VII. Non-invasive physical measurements*
a. At each of 3 in-person visits, subjects will first arrive to the Body Composition Unit of NY Nutrition Obesity
Research Center, located at 21 Audubon Avenue, basement level in Suite SB-0134, where they will undergo body
composition analysis. Subjects will be asked to change into a hospital gown, void, and undergo body weight
measurement on a certified scale, and height measurement.
b. Body composition analysis will be performed using 2 techniques: bioimpedance analysis (BIA) and quantitative
magnetic resonance (QMR). Subjects with a pacemaker or implantable cardioverter defibrillator device will require
an additional 20 minutes for interrogation and adjustment of their device settings before and after BIA and QMR
scan to ensure no cardiac device interference and normal device functioning, a procedure which is consistent with
standard of care for patients with cardiac electrophysiologic devices. Device adjustment and interrogation will be
performed by Dr. Ani Nalbandian, fellow in cardiovascular disease, under the supervision of Dr. Hirad
Yarmohammadi, electrophysiology cardiology attending.


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c. Bioelectrical impedance analysis (BIA) is a commonly used method to measure body composition, specifically
fat, fat-free mass, and water in the whole body in healthy adults. We will assess how well the seca BIA instrument 
(seca gmbh & co. kg, Hamburg, Germany) measures the amount of water, fat and fat-free mass in the body 
compared to quantitative magnetic resonance, another established approach. There are several BIA devices on the 
market approved for use by the Federal Drug Administration. The accuracy of the BIA approach for use in patients 
with HF, where edema is common, needs to be determined. BIA offers a rapid and practical approach for estimating 
body composition in patients, however, both cross-sectional and longitudinal validation studies are needed to 
confirm whether the method is valid and reliable using an established reference method, such as that proposed here 
with quantitative magnetic resonance technology. This study will collect BIA measurements when standing. The 
results from this BIA measure will be compared to the corresponding total body water, fat, fat-free mass values 
from quantitative magnetic resonance, as described below. This study will help physicians, scientists, and health 
professionals to interpret the accuracy of the results from this BIA device. Bioimpedance analysis measurements 
will take approximately 15 minutes. 
d. Subjects will undergo quantitative magnetic resonance scan (QMR). Subject set-up and QMR scan will require
a total of 6 minutes. The QMR system offers the potential of a safe, rapid, practical, accurate, precise and affordable
means of quantifying fat, lean tissue mass, and body water.
e. After completion of the body composition analysis, subjects will proceed next door to the CCRLE where the
remaining study procedures will be performed. This will include the Short Physical Performance Battery, a
functional assessment tool which includes gait speed, chair stand and balance tests.
*As described in Inclusion and Exclusion Criteria: subjects with exclusion criteria 6 or 7, OR who opt out
of body composition analysis will not undergo study procedures VIIb, VIIc, VIId.
Statistical Procedures:
The primary endpoint for this pilot trial will be a serious adverse event rate greater than 30%, which is an acceptable 
rate, based on prior clinical trial data with sodium-glucose cotransporter 2 inhibitors in subjects with heart failure over 
a 3 month period. Secondary endpoints will include mean change in daily diuretic dose (mg/kg of furosemide 
equivalence), mean change in body weight (kg) and total water content (kg), and mean change in Kansas City 
Cardiomyopathy Questionnaire (KCCQ) score and Short Physical Performance Battery (SPPB) score. In preliminary 
analyses, we will describe the baseline characteristics of subjects. In particular, we will present summary measures on 
patient age, sex, diabetes status, renal function, NT-proBNP level, KCCQ score, SPPB score, daily diuretic dose, 
echocardiographic features, and body composition analysis (including body weight and total water content). 
Continuous variable distributions will be assessed for normality and skewness, and log transform applied when 
appropriate. A matched-paired t-test will be used to test for a significant difference in the means of measured 
secondary endpoints pre- and post-treatment with empagliflozin 10 mg oral daily for 3 months.
Power calculations:
Primary endpoint: A power calculation for our primary endpoint is not applicable in this pilot safety and tolerability 
trial.
Sample secondary (daily diuretic dose) endpoint power calculation: Based on prior literature, an estimated mean daily 
diuretic dose of 0.6 mg/kg with an effect size of 0.5 mg/kg, and a sample size of 15 total accrued subjects, will have 
75% power to detect a difference in mean daily diuretic dose before and after study drug treatment using a two-
sample t-test at the 5% level of significance.