Clinical Research Directory

Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia

The purpose of this study is to test the safety and preliminary efficacy of AAVrh.10hFXN to treat the cardiomyopathy associated with Friedreich's ataxia (FA). AAVrh.10hFXN is a serotype rh.10 adeno-associated virus gene transfer vector coding for Frataxin (FXN). The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 25 participants.

Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction

Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

IMPRoving Cardiovascular RiSk Stratification Using T1 Mapping in General populatION

Magnetic properties of myocardial tissue change in the presence of disease. This is detectable in the change of rate of magnetic relaxation, and measurable by T1 and T2 mapping using cardiovascular magnetic resonance (CMR). These markers provide novel quantifiable imaging measures for myocardial tissue characterisation. Despite similar principles, the measurements differ considerably between different sequences, vendors and field strengths, yielding a necessity to establish robust sequence-specific normal ranges, diagnostic accuracy, relationships with clinical characteristics, cardiovascular risk factors, routine cardiac imaging parameters, and prognosis. A further unknown relates to separation between healthy myocardium and subclinical disease in subgroups of patients with suspected cardiac involvement. Examples include patients with possible inflammation, such as in patients with a recent COVID-19 infection or vaccination. Anticipated recruitment of a total of 3000 subjects, with 1500 subjects per field strength (1.5 and 3.0 Tesla).

⁶⁸Ga-FAPI PET/CT for Cardiac Fibrosis in Heart Failure

Heart failure (HF) is a clinical syndrome with increasing incidence and prevalence, associated with high morbidity, mortality, and economic impact, despite therapeutic advances. Myocardial fibrosis is a common feature across different pathophysiological processes and plays a key role in HF development, with growing research interest specifically in non-ischemic dilated cardiomyopathy (HFrEF phenotype) and hypertrophic cardiomyopathy (HFpEF phenotype). Given its potential reversibility with certain drugs, fibrosis is an attractive therapeutic target, requiring non-invasive methods to monitor fibrogenesis and treatment efficacy. Cardiac magnetic resonance imaging (CMR) is the gold standard for detecting fibrosis but cannot distinguish between active and inactive fibrosis or detect early stages, limitations that may be addressed by gallium-68-labeled fibroblast activation protein inhibitor positron emission tomography/computed tomography (68Ga-FAPI PET/CT). This single-center, prospective, observational pilot study aims primarily to assess myocardial fibrosis in patients with HFrEF (non-ischemic dilated cardiomyopathy) and a subtype of HFpEF (hypertrophic cardiomyopathy) using 68Ga-FAPI PET/CT compared to CMR. Secondary objectives include developing 68Ga-FAPI uptake assessment methodologies for future anti-fibrotic therapy studies and correlating fibrosis with serum cardiac biomarkers and cardiovascular events.

Ultrahypofractionation and Normal Tissue Toxicity

This research is being done to see if proton beam radiation therapy (PBT) results in fewer changes to a participant's heart measured with MRI-imaging than conventional or "photon" radiation therapy (XRT) for participants with non-metastatic left sided breast cancer. The names of the two study groups in this research study are: * Proton Radiation Therapy (PBT) * Conventional or "Photon" Radiation Therapy (XRT)

High Relaxivity Contrast Agent for Cardiac MR in the Myocardial Scar Assessment

Elucirem (Gadopiclenol) is a new macrocyclic gadolinium-based contrast agent (GBCA) with high relaxivity indicated for use in adults and children aged 2 years and older for contrast-enhanced magnetic resonance imaging. The product was approved in 2022 by FDA to be used to detect and visualize lesions with abnormal vascularity in the central nervous system (brain, spine and associated tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system). However, given its at least twofold higher relaxivity than other GBCAs, the performance of Elucirem in cardiac MR (CMR) has yet to be demonstrated. The hypothesis for the study: Half dose (0.05mmol/kg) Elucirem is not inferior to double dose (0.2 mmol/kg) Dotarem in the myocardial scar assessment. All participants will be selected from the investigators previous CMR study cohort with double-dose Dotarem T1 mapping and LGE images. Ten participants without scars will be recruited for the Phase I dose evaluation. Five for 0.05 mmol/kg and five for 0.075 mmol/kg. The investigators have identified 15 participants with LGE findings from double-dose Dotarem CMR acquired in the years 2021, 2022, or earlier years. This study was performed in August 2022. The same protocol will be used for single-dose Elucirem.

Quantification of Myocardial Fibrosis in Aortis Stenosis

This study is a long term follow-up of patients that were included as part of a previous study (NCT03422770), where patients with aortic stenosis and healthy controls went through echocardiography, cardiac MRI, long-term ECG-recording, blood tests and quality of life assessment. Echocardiography included high frame ultrasound for detection of natural mechanical waves, and the measured speed of these waves were used as a marker of the extent of myocardial fibrosis. Up to five years have now passed since inclusion at baseline, and a proportion of the patients in the cohort have undergone aortic valve replacement at some point. In this study, the investigators will repeat the cardiac imaging (echocardiography and cardiac MRI), ECG and blood test, to assess long-term changes in myocardial fibrosis in aortic stenosis patients.

Fibrosis Assessment in Myocardial Infarction-associated Ventricular Aneurysm

The study will use 18F-FAPI PET/CT to study myocardial fibrosis in patients diagnosed with myocardial infarction-associated ventricular aneurysm (MI-VA). Participants will receive the PET/CT scan during hospital stay, as well as serial echocardiography and telephonic follow-ups. Analysed will focus on the characterization of myocardial fibrosis and its correlations with the clinical prognosis in the patients.

Effect of Dapagliflozin in Myocardial Fibrosis and Ventricular Function in Patients With a ST-segment Elevation Myocardial Infarction

The DAPA-STEMI trial investigates whether dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), reduces heart muscle scarring (fibrosis) and improves heart function after a ST-segment elevation myocardial infarction (STEMI). The trial will use cardiac MRI to measure changes in heart structure and function over six months. Patients aged 30-85 who have had a recent STEMI will receive either dapagliflozin or a placebo. The study aims to provide mechanistic insights into heart failure prevention after heart attacks.

Triple Combination Therapy (ARNI, SGLT2i, MRA) in Advanced HFpEF

Patients with advanced heart failure with preserved ejection fraction (HFpEF) will be randomly assigned in open-label multicenter study to receive triple combination therapy with \[angiotensin receptor/neprilysin inhibitor \[ARNI\] + sodium-glucose cotransporter 2 inhibitor \[SGLTi\] + mineralocorticoid receptor antagonist \[MRA\]) or with individualized medical therapy \[SGLTi + renin-angiotensin system inhibitor \[RASi\] \[angiotensin receptor blocker \[ARB\] or angiotensin-converting enzyme inhibitor \[ACE-I\]), and will be treated for 52 weeks

Response of the Myocardium to Hypertrophic Conditions in the Adult Population

Hypertension and aortic stenosis are the two leading conditions that cause thickening of the heart muscles (left ventricular hypertrophy). Left ventricular hypertrophy is initially adaptive to maintain optimal heart function. Ultimately, heart failure occurs as a result of progressive muscle cell death and scarring (myocardial fibrosis). Dedicated techniques using cardiovascular magnetic resonance imaging (MRI) and novel high-sensitivity cardiac troponin blood assays are potential markers to detect myocardial fibrosis. Although hypertension-related heart disease is very common in Singapore, the significance of myocardial fibrosis is not well understood. In this study, the significance of myocardial fibrosis in 2000 patients with hypertension would be investigated. This will be the largest study using state-of-the-art MRI to examine the importance of myocardial fibrosis in hypertensive heart disease. 1000 participants, with at least 1 year follow-up, will be invited for a repeat assessment.