Effect of Henagliflozin on Myocardial Fibrosis in Non-Obstructive HCM: A Randomized, Double-Blind, Placebo-Controlled Trial Using 68Ga/18F-FAPI PET/CMR

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Effect of Henagliflozin on Myocardial Fibrosis Burden in Patients With Non-Obstructive Hypertrophic Cardiomyopathy Using 68Ga/18F-FAPI PET/CMR

his is a single-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of Henagliflozin (an SGLT2 inhibitor) on myocardial fibrosis burden in patients with non-obstructive hypertrophic cardiomyopathy (nHCM). The study will use 68 68 Ga/ 18 18 F-FAPI PET/CMR imaging to quantitatively assess changes in active fibroblast activity after 6 months of treatment. A total of 150 eligible adult patients with nHCM (FAPI-positive at baseline, NYHA class I-III) will be enrolled and randomized in a 1:1 ratio to either the Henagliflozin group (10 mg once daily) or the placebo group for a 6-month treatment period. The primary endpoint is the change in myocardial FAPI target-to-background ratio (ΔTBR) at 6 months. Secondary endpoints include changes in FAPI SUVmax, FAPI burden percentage (FAV%), cardiac structure and function parameters, 6-minute walk distance, NYHA classification, NT-proBNP levels, and quality-of-life scores. Exploratory analyses will assess clinical events over 12 months, such as heart failure hospitalization, atrial fibrillation, ventricular arrhythmias, and cardiovascular death. The study employs stratified block randomization based on baseline FAPI burden, central randomization and blinding via IWRS, independent core laboratory imaging evaluation, and an intention-to-treat analytical approach. It aims to provide early evidence for the anti-fibrotic effect of Henagliflozin in nHCM and to validate FAPI-PET/CMR as an imaging biomarker for fibrosis activity.

This is a single-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of Henagliflozin, an SGLT2 inhibitor, on myocardial fibrosis burden in patients with non-obstructive hypertrophic cardiomyopathy. The study will utilize integrated Gallium-68 or Fluorine-18 labeled FAPI PET/CMR imaging to quantitatively assess changes in active fibroblast activity following six months of treatment. A total of 150 eligible adult patients with non-obstructive hypertrophic cardiomyopathy, who are FAPI-positive at baseline and classified as NYHA functional class I to III, will be enrolled. Participants will be randomized in a one-to-one ratio to receive either Henagliflozin 10 mg once daily or a matching placebo for a treatment period of six months.

The primary endpoint of the study is the change in myocardial FAPI target-to-background ratio from baseline to six months. Secondary endpoints include changes in other FAPI parameters such as SUVmax and FAPI-active volume percentage, as well as changes in cardiac structure and function parameters assessed by CMR, six-minute walk distance, NYHA functional class, NT-proBNP levels, and quality of life scores. Furthermore, exploratory analyses will assess clinical events over a 12-month period, including heart failure hospitalization, atrial fibrillation, ventricular arrhythmias, and cardiovascular death.

The trial employs a stratified block randomization method based on baseline FAPI burden, with central randomization and blinding maintained through an interactive web response system. All imaging data will be evaluated by an independent core laboratory to ensure objectivity, and statistical analyses will adhere to the intention-to-treat principle. This study aims to generate early evidence regarding the potential anti-fibrotic effect of Henagliflozin in non-obstructive hypertrophic cardiomyopathy and to validate FAPI-PET/CMR as a promising imaging biomarker for monitoring myocardial fibrosis activity.

Inclusion Criteria:

1. Aged 18 years or older, regardless of gender.

2. Meets the diagnostic criteria for non-obstructive hypertrophic cardiomyopathy (HCM):

   • Confirmed diagnosis of HCM by cardiac magnetic resonance (CMR) or echocardiography (left ventricular wall thickness ≥15 mm, or ≥13 mm in the presence of a family history of HCM).
   • Exclusion of patients in whom left ventricular hypertrophy is primarily attributable to hypertensive heart disease, as assessed by a cardiology specialist based on clinical and imaging evidence.
   • Exclusion of other identifiable causes of secondary myocardial hypertrophy (e.g., valvular heart disease, storage cardiomyopathies).
   • Left ventricular outflow tract (LVOT) gradient <30 mmHg at rest or under provocation, as assessed by echocardiography or CMR.

3. Willing to undergo FAPI PET/CMR examination and complete imaging evaluations.

4. Baseline FAPI PET/CMR scan shows positive FAPI uptake: myocardial FAPI target-to-background ratio (TBR) ≥1.3, using the ascending aorta blood pool as the background reference.

5. Capable of understanding and signing the informed consent form, and agrees to participate in the study, accept randomization, and comply with follow-up visits.

6. New York Heart Association (NYHA) functional class I-III.

Exclusion Criteria:

1. Significant left ventricular outflow tract obstruction (resting or provoked LVOT pressure gradient ≥30 mmHg).

2. Coexistence of other identifiable causes of myocardial hypertrophy, including:

   • Predominant or persistent hypertensive heart disease;
   • Severe aortic stenosis or other significant valvular heart disease;
   • Infiltrative or storage cardiomyopathies (e.g., Fabry disease, amyloidosis);
   • Ischemic heart disease (e.g., severe coronary artery disease).

3. Overt decompensated heart failure or NYHA functional class IV.

4. Unstable, serious arrhythmias (e.g., sustained ventricular tachycardia, recent cardioversion for atrial fibrillation).

5. Recent (within 3 months) cardiac surgery or interventional procedure.

6. ALT or AST >3 times the upper limit of normal (ULN), OR total bilirubin (Tbil) >2 times ULN, OR ketonuria/ketonemia, OR eGFR <30 mL/min/1.73m², OR creatine kinase (CK) >3 times ULN.

7. Concurrent other severe systemic disease with a life expectancy of less than 1 year.

8. Pregnant or breastfeeding women.

9. History of allergy to the study drug or any contraindication to its use.

10. Any other condition deemed by the investigator to make the subject unsuitable for participation.