Efficacy and Safety Evaluation of Sotagliflozin in Patients with Symptomatic Obstructive and Non-obstructive Hypertrophic Cardiomyopathy

Trial ID: 2024-513869-39-00
Protocol: LX4211.1-314-HCM
Sponsor: Lexicon Pharmaceuticals Inc.

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Diseases & Conditions

Hypertrophic cardiomyopathy

Objectives

The primary objective of this study is to evaluate the changes in **symptoms** and functional limitations in patients with symptomatic **hypertrophic cardiomyopathy** (HCM) treated with sotagliflozin compared to placebo. This is clinically relevant as it aims to assess the potential of sotagliflozin to improve the quality of life and physical capabilities in individuals suffering from this condition, which is characterized by thickened heart muscle that can lead to heart failure and other complications.

Secondary objectives include:

To determine the safety and tolerability of sotagliflozin as compared with placebo in patients with symptomatic HCM over the 26-week treatment period.

Participants

The clinical trial involves a total of **229 participants** diagnosed with **Hypertrophic Cardiomyopathy** (HCM), including both non-obstructive and obstructive forms. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including a diagnosis consistent with the guidelines of the American College of Cardiology Foundation/American Heart Association and the European Society of Cardiology. The trial includes individuals with a **New York Heart Association (NYHA) functional class** of II or III and a **Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS)** of less than 85. Participants are required to have stable doses of background therapy, such as beta-blockers, calcium channel blockers, and other relevant medications, for at least one month prior to screening. The trial population includes a vulnerable population, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group, multicenter study** to evaluate the efficacy and safety of **sotagliflozin** in patients with symptomatic **hypertrophic cardiomyopathy** (HCM), both obstructive and non-obstructive. The primary objective is to assess changes in symptoms and functional limitations in patients treated with sotagliflozin compared to placebo. The trial is expected to last until November 2025, with recruitment starting in February 2025. The total duration of the trial for each participant is approximately 30 weeks, including a 26-week treatment period and a follow-up period through Week 30.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) of less than 85, and a diagnosis of HCM consistent with established guidelines. The screening will also include assessments of left ventricular outflow tract (LVOT) gradients and left ventricular ejection fraction (LVEF). Following successful screening, participants will be randomized to receive either sotagliflozin or placebo, administered orally in the form of film-coated tablets.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status and treatment response. These visits will include evaluations of the primary endpoint, which is the change from baseline to Week 26 in the KCCQ CSS. Secondary endpoints include the proportion of patients with an improvement in New York Heart Association (NYHA) functional class, changes in KCCQ Total Symptom Score (TSS), and treatment-emergent adverse events (TEAEs). Clinical laboratory results and vital signs will also be monitored through Week 26.

The end-of-study visit will occur at Week 30, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

Treatment

The clinical trial involves the administration of **Sotagliflozin**, an experimental medication, to evaluate its efficacy and safety in patients with symptomatic hypertrophic cardiomyopathy (HCM). **Sotagliflozin** is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 400 mg, with a total maximum dose of 72,800 mg over a treatment period of up to 26 weeks. The active substance in the medication is **Sotagliflozin**, a chemical compound, and the trial aims to assess changes in symptoms and functional limitations in the target patient population.

The study also includes a **placebo** group to serve as a comparator for the experimental treatment. The placebo is designed to mimic the appearance and administration route of the **Sotagliflozin** tablets, ensuring the study remains double-blind. Participants in the placebo group will receive the placebo tablets orally, following the same dosing schedule as the experimental group. This design allows for a controlled comparison of the effects of **Sotagliflozin** against no active treatment, thereby providing a robust assessment of the drug's efficacy and safety.

Efficacy

The efficacy of sotagliflozin in patients with symptomatic hypertrophic cardiomyopathy (HCM) will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline to Week 26 in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS). Secondary endpoints include the proportion of patients at Week 26 with an improvement of at least one category in the New York Heart Association (NYHA) functional class, change from baseline to Week 26 in KCCQ Total Symptom Score (TSS), and changes in left ventricular outflow tract (LVOT) gradient at rest and with Valsalva maneuver as measured by echocardiogram at Week 4 and Week 26.

Additional assessments will include treatment-emergent adverse events (TEAEs) reported during the double-blind treatment period and through Week 30, as well as clinical laboratory results, including serum creatinine and estimated glomerular filtration rate (eGFR), and vital signs through Week 26. These efficacy parameters will be collected and analyzed at specified timepoints to evaluate the impact of sotagliflozin compared to placebo in improving symptoms and functional limitations in patients with HCM.

Inclusion and Exclusion Criteria

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Inclusion Criteria

KCCQ CSS < 85.
NYHA functional class II or III
A diagnosis of HCM consistent with the current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guideline definition: unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease with maximal LV wall thickness ≥ 15 millimeters (mm), or ≥ 13 mm with positive family history of HCM.
For obstructive hypertrophic cardiomyopathy (oHCM), left ventricular outflow tract (LVOT) peak gradient ≥ 30 millimetre of mercury (mm Hg) during screening as assessed by echocardiography at rest or during a valsalva maneuver.
For nonobstructive hypertrophic cardiomyopathy (nHCM), LVOT peak gradient < 30 mm Hg during screening as assessed by echocardiography at rest and < 30 mm Hg during a valsalva maneuver.
Screening left ventricular ejection fraction (LVEF) ≥ 50%, except for those on a cardiac myosin inhibitor (screening LVEF ≥ 55%).
For participants on a cardiac myosin inhibitor, the dose must be stable at least 3 months prior to screening. Participants on cardiac myosin inhibitor should not be scheduled for up-titration during the trial.
Stable doses of background therapy (ie, β-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, diuretics) for at least 1 month prior to screening.

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Exclusion Criteria

Received therapy with a sodium glucose co-transporter 2 (SGLT2) inhibitor within the past 8 weeks prior to screening.
Previous intolerance to an SGLT2 inhibitor.
Any previous treatment with sotagliflozin.
Current use of thiazolidinediones or digoxin.
Current/planned participation in another interventional clinical trial or prior participation in any interventional trial with an investigational agent within 45 days of screening.
Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy.
History of unexplained syncope within 6 months prior to screening.
History of sustained ventricular tachyarrhythmia (> 30 seconds) or appropriate ICD (implantable cardioverter defibrillator) discharge within the 6 months prior to Screening.
Has paroxysmal, persistent, or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to screening and/or not adequately rate controlled within 3 months of screening.
Septal reduction therapy planned during the study period. For participants who had septal reduction therapy, the procedure should have been completed more than 3 months prior to screening.
Cardiac surgery (eg, coronary artery bypass graft, valvular repair/replacement), percutaneous coronary intervention, or implantation of cardiac device (pacemaker or implantable cardioverter defibrillator) within 3 months prior to screening or planned during the study period.
Presence of a cardiac resynchronization therapy device.
Acute coronary syndrome within 2 months prior to screening.
History of stroke or myocardial infarction within 6 months prior to screening.
Hospitalization for heart failure or arrhythmia within 4 weeks prior to screening.
Has known moderate or severe (as per investigator's judgment) aortic valve stenosis at screening.
Current angina or clinically significant ischemia due to unstable epicardial coronary disease, as per investigator judgment.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	03 Feb 2025	16
Bulgaria	Recruiting	03 Feb 2025	16
Croatia	Recruiting	03 Feb 2025	28
Czechia	Recruiting	03 Feb 2025	12
France	Recruiting	03 Feb 2025	28
Germany	Recruiting	03 Feb 2025	22
Hungary	Recruiting	03 Feb 2025	12
Italy	Recruiting	03 Feb 2025	23
Poland	Recruiting	03 Feb 2025	24
Portugal	Recruiting	03 Feb 2025	26