The Effect of Additive On-Demand Sildenafil vs. Dextrose Candy on Maximum Exercise Capacity in Pulmonary Arterial Hypertension: A Randomized, Cross-Over Trial.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Maximum workload (Wmax)
研究概览
简要总结
The goal of this clinical study is to investigate whether the additional intake of sildenafil 20mg on top of standard medical treatment results in a benefit on maximum exercise workload (Wmax) in patients with pulmonary arterial hypertension (PAH).
详细描述
This study is a prospective, randomized, cross-over trial evaluating the effects of additive 20 mg sildenafil versus placebo/sham dextrose candy on exercise capacity in patients with previously diagnosed pulmonary arterial hypertension (PAH).
PAH is a progressive and debilitating disease characterized by increased mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), leading to right ventricular overload, and ultimately right heart failure. Despite advancements in pharmacological therapy, treatment options remain limited and optimizing individualized approaches to improve exercise capacity and manage symptom burden remains a challenge.
Phosphodiesterase type 5 inhibitors, such as sildenafil, are cornerstones of PAH treatment, enhancing pulmonary vasodilation and improving haemodynamics. While three times daily dosing is standard with three time 20-80mg daily. On-demand additive sildenafil use before exercise has not been studied, but as recent trials have shown that dosing up to three times 80mg is as safe as 20mg, there is a potential that additive therapy may be beneficial. Given sildenafil's rapid onset of action with peak effects after 30-120 minutes, it may offer acute functional benefits regarding maximum workload (Wmax) when administered shortly beforehand, in the terms of a "pill-in-the pocket" intake.
After providing informed consent, eligible participants (aged 18 - 80 years, with PAH diagnosed according to the ESC/ERS 2022/2019 guidelines) will be randomly assigned to receive either 20 mg sildenafil or dextrose candy (Dextro Energy). 45 minutes post-intake, they will undergo incremental spiroergometry (10-20 W increases) and right heart focused stress-echocardiography on a cycle ergometer until exhaustion. After a rest phase of 30 minutes, patients will perform CWRET at 75% of achieved Wmax until exhaustion. Then, after a washout period of minimum 24 hours up to 12 weeks, participants will cross over to the opposite treatment, repeating the same protocol.
In case of a beneficial result, our study could support the use of an additive pill-in-the-pocket therapy strategy which may allow treatment to be tailored to the individual activity demands of patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed Informed consent
- •Age 18 - 80 years (both sexes)
- •Pulmonary hypertension (PH) class I (PAH) previously diagnosed according to ESC/ERS 2022/2019 guidelines (mPAP ≥ 20 mmHg, PVR ≥ 2 WU, PAWP ≤ 15 mmHg) during diagnostic right-heart catheterization.
- •Stable condition, on the same PH-medication for >4 weeks
排除标准
- •Severe resting hypoxia (PaO2 <7.3 kPa)
- •Moderate-to-severe chronic obstructive or restrictive pulmonary disease (FEV1 ≤ 60% predicted, FVC ≤ 60% predicted)
- •Women with known pregnancy or breast feeding
- •Other clinically significant concomitant disease states (e.g., severe renal or hepatic disease, unstable cardiovascular disease, etc.)
- •Concurrent medication with:
- •Nitric oxide donors (molsidomine, nicrorandil, etc.)
- •Soluble guanylate cyclase stimulators (riociguat)
- •Potent CYP3A4 inhibitors (azoles, clarithromycin, protease inhibitors)
- •History of anterior ischemic optic neuropathy or hereditary retinal disease
- •Participation in another study with investigational drug with potential influence the study data within the 30 days preceding and during the present study.
- •Known allergies or hypersensitivity to sildenafil 20mg (Revatio 20mg) or dextrose candy (Dextroenergy) including any of its components
研究组 & 干预措施
Intervention Order A
Group A will receive the active comparator first (Sildenafil 20mg) in accordance with the Cross-Over trial design.
干预措施: Sildenafil 20mg (Drug)
Intervention Order B
Group B will receive the placebo comparator first (Dextrose Candy) in accordance with the Cross-Over trial design.
干预措施: Sildenafil 20mg (Drug)
Intervention Order A
Group A will receive the active comparator first (Sildenafil 20mg) in accordance with the Cross-Over trial design.
干预措施: Dextrose (Drug)
Intervention Order B
Group B will receive the placebo comparator first (Dextrose Candy) in accordance with the Cross-Over trial design.
干预措施: Dextrose (Drug)
结局指标
主要结局
Maximum workload (Wmax)
时间窗: Within 1 - 90 days
The difference in maximum workload (Wmax) attained during maximum spiroergometry 45 minutes after treatment with Sildenafil 20mg (Revatio 20mg) versus dextrose candy (Dextro Energy).
次要结局
- Time to Exhaustion (Tmax)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET, CWRET): Oxygen Saturation (SpO2)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Stroke Volume (SV)(Within 1 - 90 days)
- Arterial blood gases: Arterial Partial Pressure of Oxygen (PaO2)(Within 1 - 90 days)
- Borg CR10 (Borg Category-Ratio 10 Scale)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Tricuspid Regurgitation Pressure Gradient (TRPG)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Blood Pressure (BP)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Heart Rate (HR)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Rate Pressure Product (RPP)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Maximum Uptake of Oxygen (V'O2max)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Maximum Carbon Dioxide Production (V'CO2max)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Maximum Minute Ventilation (V'Emax)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Maximum Ventilatory Equivalent for Oxygen (V'E/VO2)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Maximum Ventilatory Equivalent for Carbon Dioxide (V'E/VCO2)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Breathing Frequency (BF)(Within 1 - 90 days)
- Cardiometabolic parameters (CPET / CWRET): Breathing Reserve (BR)(Within 1 - 90 days)
- Arterial blood gases: Arterial Partial Pressure of Carbon Dioxide (PaCO2)(Within 1 - 90 days)
- Arterial blood gases: Bicarbonate (HCO3-)(Within 1 - 90 days)
- Arterial blood gases: Arterial Oxygen Saturation (SaO2)(Within 1 - 90 days)
- Arterial blood gases: Base Excess (BE)(Within 1 - 90 days)
- Arterial blood gases: Lactate (lac)(Within 1 - 90 days)
- Arterial blood gases: Hemoglobin (Hb)(Within 1 - 90 days)
- Arterial blood gases: Hematocrit (Hct)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Tricuspid Regurgitation Velocity (TRV)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Right Atrial Pressure (RAP)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Systolic Pulmonary Arterial Pressure (sPAP)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Fractional Area Change (FAC)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Tricuspid Annular Plane Systolic Excursion (TAPSE)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Ratio of Tricuspid Regurgitation Pressure Gradient to Cardiac Output (TRPG/CO)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Cardiac Output (CO)(Within 1 - 90 days)
- Focused Stress-Echocardiography (Right Heart): Pulmonary Vascular Resistance (PVR)(Within 1 - 90 days)
研究者
Silvia Ulrich
Prof. Dr. med.
University of Zurich