## Protocol Section
### Identification Module
**NCT ID:** NCT06433050

**Acronym:** SOTA-CROSS HCM

**Brief Title:** Sodium Glucose Co-transporter (SGLT) Inhibitors in Nonobstructive Hypertrophic Cardiomyopathy

**Official Title:** Sodium Glucose Co-transporter (SGLT) Inhibitors in Nonobstructive Hypertrophic Cardiomyopathy

#### Organization Study ID Info
**ID:** 855065
#### Organization
**Class:** OTHER
**Full Name:** University of Pennsylvania
#### Secondary ID Infos
**ID:** R61HL164376
**Link:** https://reporter.nih.gov/quickSearch/R61HL164376
**Type:** NIH
### Status Module
#### Completion Date
**Date:** 2027-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-29

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-22

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2027-04

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-09

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-29
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-13
**Study First Submit QC Date:** 2024-05-22
### Sponsor Collaborators Module

#### Collaborators

**Class:** NIH

**Name:** National Heart, Lung, and Blood Institute (NHLBI)

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Pennsylvania

#### Responsible Party

**Investigator Affiliation:** University of Pennsylvania

**Investigator Full Name:** Sharlene Day

**Investigator Title:** Associate Professor of Cardiovascular Medicine

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The goal of this clinical trial is to learn if sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, works to treat symptomatic, nonobstructive hypertrophic cardiomyopathy (noHCM) in adult patients. It will also learn about the safety of sotagliflozin in this patient population. The main questions it aims to answer are:

1. Will sotagliflozin be well tolerated in patients with nonobstructive HCM?
2. Will sotaglifozin improve exercise capacity, diastolic dysfunction and/or physical functioning in patients with nonobstructive HCM?
3. Will sotagliflozin improve circulating markers of cardiac metabolism in patients with nonobstructive HCM?

Researchers will compare sotagliflozin to a placebo (a look-alike substance that contains no drug) to see if sotagliflozin is effective at treating hypertrophic cardiomyopathy (HCM).

Participants will:

Take sotagliflozin or a placebo every day for 12 weeks. They will then cross-over (or switch) to taking placebo or sotagliflozin (whichever one they did not take initially) for an additional 12 weeks.

Visit the clinic once every 4-12 weeks for checkups, surveys, and tests including a stress test and echocardiogram.

### Conditions Module

**Conditions:**

- Hypertrophic Cardiomyopathy Without Obstruction

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** Double-blinded

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 26

**Type:** ESTIMATED

**Phases:**

- EARLY_PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Matching placebo once daily will be administered in the first phase, Sotagliflozin 400 mg once daily will be administered in the second phase

**Intervention Names:**

- Drug: Sotagliflozin

**Label:** Placebo first phase, Sotagliflozin second phase

**Type:** PLACEBO_COMPARATOR

#### Arm Group 2

**Description:** Sotagliflozin 400 mg once daily will be administered in the first phase, matching placebo once daily will be administered in the second phase

**Intervention Names:**

- Drug: Sotagliflozin

**Label:** Sotagliflozin first phase, Placebo second phase

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Placebo first phase, Sotagliflozin second phase

- Sotagliflozin first phase, Placebo second phase

**Description:** Sotagliflozin or placebo will be administered to each participant in a cross over study design. Each participant will receive active drug and placebo with randomization of the order in which they receive them.

**Name:** Sotagliflozin

**Other Names:**

- Inpefa

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Adverse event reporting

**Measure:** Number of participants with treatment-related adverse events

**Time Frame:** Through study completion, 28 weeks

**Description:** Intracavitary left ventricular pressure gradient in mmHg

**Measure:** Intracavitary obstruction

**Time Frame:** Through study completion, 28 weeks

**Description:** New occurrence of cardiac arrhythmia measured by ambulatory monitoring

**Measure:** Cardiac rhythm

**Time Frame:** Through study completion, 28 weeks

**Description:** Peak oxygen consumption in mL/min

**Measure:** Maximal exercise capacity

**Time Frame:** Through study completion, 28 weeks

**Description:** Stroke volume augmentation at exercise steady state in mL/min

**Measure:** Submaximal exercise capacity

**Time Frame:** Through study completion, 28 weeks

#### Secondary Outcomes

**Description:** Left ventricular ejection fraction in % measured by echocardiography

**Measure:** Systolic function

**Time Frame:** Through study completion, 28 weeks

**Description:** Global longitudinal strain in % measured by echocardiography

**Measure:** Contractility

**Time Frame:** Through study completion, 28 weeks

**Description:** E/E' ratio measured by echocardiography

**Measure:** Diastolic function

**Time Frame:** Through study completion, 28 weeks

**Description:** Maximal left ventricular wall thickness in mm by echocardiography

**Measure:** Left ventricular hypertrophy

**Time Frame:** Through study completion, 28 weeks

**Description:** Kansas City Living with Heart Failure (KCCQ) Clinical Summary Score, scale 0-100 with lower scores being worse

**Measure:** Symptom scores

**Time Frame:** Through study completion, 28 weeks

**Description:** Kansas City Living with Heart Failure (KCCQ) Overall Summary Score, score 0-100 with lower scores being worse

**Measure:** Symptom scores and quality of life

**Time Frame:** Through study completion, 28 weeks

**Description:** Serum levels of N-terminal-proBNP

**Measure:** Biomarkers

**Time Frame:** Through study completion, 28 weeks

**Description:** Concentration of serum metabolites

**Measure:** Circulating metabolites

**Time Frame:** Through study completion, 28 weeks

**Description:** Daily step counts by actigraphy

**Measure:** Measurement of periods of activity and rest

**Time Frame:** Through study completion, 28 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Age at least 18 years, both sexes
2. Provision of signed and dated informed consent form
3. Stated willingness to comply with all study procedures and availability for the duration of the study
4. Ability to take oral medication and be willing to adhere to the study intervention.
5. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 2 weeks after the end of administration of study drug.
6. Diagnosis of HCM with NYHA Class II-III functional class or New York Heart Association (NYHA) Class I with peak VO2 \< 90% on cardiopulmonary exercise stress testing performed at Visit 1.
7. Left ventricular outflow tract gradient \< 50 mmHg at rest, with valsalva, and with exercise.

7. Left ventricular ejection fraction \> 50% by echocardiogram or cardiac MRI based on the most recent assessment in the past year prior to screening and confirmed during Visit 1 echocardiogram.

8. Stable medical therapy for at least 1 month prior to study enrollment.

Exclusion Criteria:

1. Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrollment or previous intolerance of an SGLT2 inhibitor
2. Type 1 diabetes mellitus
3. Age \<18 years old
4. Pregnant or lactating women: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
5. Uncontrolled atrial fibrillation, as defined by a resting heart rate \> 100 beats per minute at the time of the baseline assessment
6. Paroxysmal atrial fibrillation (Afib) or flutter with plans to attempt to restore sinus rhythm (with drug therapy, ablation, or DC cardioversion) during the study period.
7. Unable to attain a respiratory exchange ratio of at least 1.05 on cardiopulmonary exercise test (CPET) on the day of screening.
8. Septal reduction therapy within the previous 3 months.
9. Implantable cardio-defibrillator (ICD) implantation planned during the study period.
10. Implantation of a cardiac resynchronization therapy (CRT) device within 12 weeks prior to enrollment or intent to implant a CRT device during the study period
11. Hemoglobin \< 10 g/dL
12. Estimated glomerular filtration rate (eGFR) \< 25 mL/min/1.73m\^2, or unstable or rapidly progressing renal disease at the time of randomization
13. Subject inability/unwillingness to exercise
14. Greater than moderate left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), moderate or greater mitral stenosis, or severe right-sided valvular disease based on baseline echo at the time of enrollment
15. Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
16. Acute coronary syndrome or coronary intervention within the past 2 months
17. Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)
18. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1\<50% predicted), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea.
19. Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)
20. Symptomatic bradycardia or second- or third-degree heart block, in the absence of a pacemaker
21. Significant liver disease impacting synthetic function or volume control (ALT/AST \> 3x ULN, Albumin \< 3.0 g/dL)
22. Severe right ventricular dysfunction on baseline echocardiogram
23. Orthostatic blood pressure response to the transition from supine to standing (\>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
24. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
25. Any condition that, in the opinion of the investigator, will interfere with the completion of the study. This may include comorbid or psychiatric conditions that may impede successful completion of the protocol, or logistical concerns (e.g. inability to travel to the exercise unit).

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** sharlene.day@pennmedicine.upenn.edu

**Name:** Sharlene Day, MD

**Phone:** 734-548-0394

**Role:** CONTACT

**Contact 2:**

**Email:** kimberly.clinton@pennmedicine.upenn.edu

**Name:** Kim Clinton

**Phone:** 215-431-4545

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** University of Pennsylvania

**Name:** Sharlene Day, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Description:** No individual participant data will be available to other researchers

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000020763

- Term: Pathological Conditions, Anatomical

- ID: D000001020

- Term: Aortic Stenosis, Subvalvular

- ID: D000001024

- Term: Aortic Valve Stenosis

- ID: D000082862

- Term: Aortic Valve Disease

- ID: D000006349

- Term: Heart Valve Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M10035

- Name: Hypertrophy

- Relevance: HIGH

- As Found: Hypertrophic

- ID: M12154

- Name: Cardiomyopathies

- Relevance: HIGH

- As Found: Cardiomyopathy

- ID: M5568

- Name: Cardiomyopathy, Hypertrophic

- Relevance: HIGH

- As Found: Hypertrophic Cardiomyopathy

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M22519

- Name: Pathological Conditions, Anatomical

- Relevance: LOW

- As Found: Unknown

- ID: M6475

- Name: Constriction, Pathologic

- Relevance: LOW

- As Found: Unknown

- ID: M4340

- Name: Aortic Valve Stenosis

- Relevance: LOW

- As Found: Unknown

- ID: M2379

- Name: Aortic Valve Disease

- Relevance: LOW

- As Found: Unknown

- ID: M9437

- Name: Heart Valve Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T449

- Name: Aortic Valve Stenosis

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009202

- Term: Cardiomyopathies

- ID: D000002312

- Term: Cardiomyopathy, Hypertrophic

- ID: D000006984

- Term: Hypertrophy

### Intervention Browse Module - Ancestors

- ID: D000077203

- Term: Sodium-Glucose Transporter 2 Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000007004

- Term: Hypoglycemic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M254783

- Name: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

- Relevance: HIGH

- As Found: Approximate

- ID: M1691

- Name: Sodium-Glucose Transporter 2 Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M10054

- Name: Hypoglycemic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000575681

- Term: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

### Misc Info Module

- Version Holder: 2024-05-31
