2025-524783-38-00招募中3 期
Spironolactone and SGLT2 inhibitor to Address Fontan circulatory failure and Enhance Resilience: The SAFER-Fontan trial
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- UZ Leuven
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- The primary efficacy assessment of the SAFER-Fontan trial is structured hierarchically to evaluate treatment effects on the principal hemodynamic domains of the Fontan circulation, while maintaining control of the overall type I error rate. 1. Primary Endpoint: PVP at rest and peak exercise, reflecting systemic venous congestion. 2. Key Secondary Endpoint: PCWP at rest and peak exercise, reflecting ventricular filling pressures.
研究概览
简要总结
To determine whether combination therapy with spironolactone and dapagliflozin improves hemodynamic status in adults with a Fontan circulation and elevated filling pressures, operationalized as improvements in:
- Systemic venous congestion, assessed by peripheral venous pressure (PVP) at rest and during peak exercise; and
- Ventricular filling pressures, assessed by pulmonary capillary wedge pressure (PCWP) at rest and during peak exercise; compared with placebo.
入排标准
- 年龄范围
- 18 years 至 64 years（18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Status post Fontan operation for univentricular heart disease.
- •Signs of elevated filling pressures on recent clinical evaluation, defined as resting PVP ≥15mmHg, peak exercise PVP >25mmHg, PVP/CO slope >3mmHg/(L/min), or requiring maintenance therapy with diuretics.
- •Clinically stable condition for ≥3 months prior to enrolment (ie., no hospitalizations for Fontan failure, arrhythmia, or decompensated heart failure).
- •Stable background medication, including heart failure therapy and anticoagulation, for at least 8 weeks prior to screening and expected to remain stable during the trial (except for protocol-mandated adjustments).
- •Ability and willingness to comply with all scheduled study visits, procedures (including preload modulation, blood sampling, and CMR), and trial medication intake.
- •Voluntary written informed consent of the participant has been obtained prior to any trial-related procedures.
- •At least 18 years of age at the time of signing the Informed Consent Form (ICF).
- •For women of childbearing potential (WOCBP): willingness and ability to comply with the contraceptive and pregnancy-testing requirements specified in Section 3.2 of the Trial Protocol.
排除标准
- •History of heart transplantation, mechanical circulatory support, or currently listed for transplantation.
- •Hemodynamic instability or decompensated Fontan circulation within 1 month prior to enrolment, defined as hospitalization for heart failure, arrhythmia requiring intervention, or acute deterioration of end-organ function.
- •Current or imminent hospitalization for management of Fontan circulatory failure.
- •Organ dysfunction, defined as: serum potassium >5.0 mmol/L; eGFR <30 mL/min/1.73 m² or anuria; or hepatic transaminases or bilirubin >2x upper limit of normal (ULN).
- •Symptomatic hypotension or systemic systolic blood pressure of <80mmHg.
- •Unresolved acute illness (e.g., acute appendicitis, COVID-19, gastroenteritis).
- •History of ketoacidosis or living with type 1 diabetes mellitus.
- •Current or recent (≤8 weeks) therapy with spironolactone, eplerenone, or SGLT2 inhibitors that cannot be discontinued. However, if therapy can be temporarily discontinued in a safe manner prior to the trial, patients are still eligible for inclusion.
- •Addison’s disease or other clinically relevant adrenal insufficiency.
- •Inability to understand the nature, significance, implications and risks of the Trial or otherwise to provide valid informed consent personally.
- •Excellent functional capacity defined as a peak VO2 ≥35 mL/kg/min on cardiopulmonary exercise testing, suggesting absence of significant Fontan-related circulatory limitation.
- •Known hypersensitivity or contraindication to trial drugs or their excipients.
- •CMR-incompatible or life supporting electronic devices such as pacemakers or ICDs, or any other contra-indications for CMR (including patient rejection).
- •Difficulty with upper extremity intravenous placement in the past, or known obstruction anywhere within the venous circulation including at the level of the Glenn or Fontan anastomosis or within the pulmonary vasculature.
- •Female participant who is pregnant, breastfeeding, intends to become pregnant during the trial or within 7 days after the final dose of oral IMP, or is a woman of childbearing potential (WOCBP) who is unwilling or unable to comply with the protocol-specified contraceptive and pregnancy-testing requirements. For more details on definitions, see Section 3.2 of the Trial Protocol.
- •Participation in an interventional Trial with an investigational medicinal product (IMP) or device.
- •Any medical, psychiatric, or social condition that, in the Investigator’s judgment, may compromise participant safety, compliance, or data integrity
- •Admission for interventional cardiological or cardiac surgical procedure within 30 days prior to screening, or consideration for any cardiac surgical or interventional cardiological procedure during trial participation.
研究组 & 干预措施
Forxiga 10 mg film-coated tablets
Test
干预措施: Forxiga 10 mg film-coated tablets (Drug)
Placebo 500mg Fagron tablets
Placebo
干预措施: Placebo 500mg Fagron tablets (Drug)
Spironolactone EG 25 mg tabletten
Test
干预措施: Spironolactone EG 25 mg tabletten (Drug)
结局指标
主要结局
The primary efficacy assessment of the SAFER-Fontan trial is structured hierarchically to evaluate treatment effects on the principal hemodynamic domains of the Fontan circulation, while maintaining control of the overall type I error rate. 1. Primary Endpoint: PVP at rest and peak exercise, reflecting systemic venous congestion. 2. Key Secondary Endpoint: PCWP at rest and peak exercise, reflecting ventricular filling pressures.
The primary efficacy assessment of the SAFER-Fontan trial is structured hierarchically to evaluate treatment effects on the principal hemodynamic domains of the Fontan circulation, while maintaining control of the overall type I error rate. 1. Primary Endpoint: PVP at rest and peak exercise, reflecting systemic venous congestion. 2. Key Secondary Endpoint: PCWP at rest and peak exercise, reflecting ventricular filling pressures.
次要结局
- Ventricular active relaxation endpoints a. Isovolumic relaxation time (IVRT). b. τ-Doppler (PCWP- and IVRT-based estimation of relaxation constant τ).
- Clinical and functional outcomes a. NYHA functional class. b. 6 minute walk distance (6MWD). c. CPET outcomes: peak oxygen uptake (VO2), metabolic equivalents (METs), heart rate and blood pressure response, oxygen saturation during exercise, VO2 at anaerobic threshold, ventilatory efficiency (VE/VCO2 slope), arterio-venous oxygen difference. d. Composite clinical worsening events. e. Patient-reported outcomes: quality of life assessed by KCCQ-12 and ACHD-PRO.
- Congestion outcomes a. Loop diuretic dose (furosemide-equivalent). b. Fontan Outpatient Congestion Score (FOCS), a score developed for this trial. c. Venous Excess Ultrasound (VExUS) grade.
- Ventricular compliance endpoints a. PVP- and PCWP-derived end-diastolic pressure-volume relationship (EDPVR): operating stiffness (dP/dV), stiffness constant β, end-diastolic volume at 15 mmHg (V15), and volume-axis intercept V0. b. Shear wave elastography (SWE).
- Echocardiography endpoints a. Pulmonary vein flow: S/D ratio, A-wave reversal duration, pulmonary venous A-wave reversal duration minus mitral inflow A-wave duration. b. Atrioventricular valve inflow: E, E deceleration time, E/A, S/D ratio. c. Ventricular inflow propagation velocity (Vp). d. Tissue Doppler velocities, including E/e’. e. Ventricular diastolic strain rate and dyssynchrony. f. Atrial function and strain.
- Fibrosis endpoints a. CMR tissue characterization, including native T1, ECV, and LGE. b. Standardized uptake value (SUVmean/SUVmax) of fibroblast activation within myocardium and liver parenchyma on FAPI-PET (only in subset of patients with myocardial fibrosis on pre-trial CMR).
- Vascular and circulation endpoints a. Cardiac output (CO). b. Systemic vascular resistance (SVR). c. Total arterial compliance (TAC). d. Effective arterial elastance (Ea). e. Ventriculo-arterial coupling (Ea/Ees ratio). f. Mean systemic filling pressure (MSFP). g. Venous compliance and capacitance. h. Total plasma volume (TPV), total blood volume (TBV), stressed blood volume (SBV), and unstressed blood volume (UBV).
- Circulating biomarkers a. RAAS activation markers: renin, angiotensin II, and aldosterone. b. Collagen turnover markers: PICP, PIIINP, PINP, CITP, and CITP/MMP-1 ratio. c. Other fibrotic and inflammatory mediators: galectin-3, soluble ST2 (sST2), and GDF-15. d. Congestion biomarkers: NT-proBNP and CA125.
- Extracardiac endpoints a. Hepatic function, assessed by MELD-XI score and liver elastography. b. Renal function, assessed by urinary albumin–creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR).
- Safety endpoints a. Serum potassium. b. Serum creatinine and cystatin C. c. Incidence, severity and causality of adverse and serious adverse events (AEs/SAEs) during study drug exposure.
- Clinical and functional outcomes a. NYHA functional class. b. CPET outcomes: peak oxygen uptake (VO2), metabolic equivalents (METs), heart rate and blood pressure response, oxygen saturation during exercise, VO2 at anaerobic threshold, ventilatory efficiency (VE/VCO2 slope), arterio-venous oxygen difference. c. Composite clinical worsening events. d. Patient-reported outcomes: quality of life assessed by KCCQ-12 and ACHD-PRO.
研究者
Clinical Studies Secretariat Cardiology
Scientific
UZ Leuven
研究点 (1)
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