Sidenafil Impacts Exercise Performance in Adolescent Survivors of the Fontan

Sidenafil 影响 Fontan 青少年幸存者的运动表现

• 批准号: 8851656
• 负责人: JAMES WILLIAM GAYNOR
• 金额: $ 50.25万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851656
• 关键词: Address; Admission activity; Adolescence; Adolescent; Adolescent and Young Adult; Aerobic; Aerobic Exercise; Affect; Age; Aging; Anaerobic Threshold; Beds; Blood Circulation; Bronchitis; Carbon Dioxide; Cardiac Death; Cardiopulmonary; Cessation of life; Child; Childhood; Common Ventricle; Consent; Control Groups; Data; Double-Blind Method; Eligibility Determination; Environmental air flow; Equipoise; Exercise; Exercise Tolerance; Expressed Sequence Tags; Face; Failure; Fontan Procedure; Gender; Health; Heart; Heart Transplantation; Heart failure; Hospitalization; Hospitals; Individual; Infant; Intention; Life; Long-Term Effects; Longitudinal Studies; Lung; Measures; Oral; Oxygen Consumption; Performance; Phase III Clinical Trials; Physical Function; Physiology; Placebo Control; Placebos; Plastics; Population; Prevalence; Prevention; Principal Investigator; Protein-Losing Enteropathies; Quality of life; Questionnaires; Randomized; Research; Risk; Severities; Stress Tests; Survivors; Symptoms; Target Populations; Testing; Time; Transplantation; Vasodilator Agents; adolescent patient; base; falls; functional status; improved; mortality; novel; predictive marker; pressure; prevent; primary outcome; programs; prospective; psychosocial; randomized placebo controlled trial; respiratory; screening; secondary outcome; sildenafil; targeted treatment; treatment strategy

DESCRIPTION (provided by applicant): There is a progressive decline in measured aerobic exercise capacity during adolescence in survivors of the Fontan operation. Adolescent survivors of the Fontan operation face an anticipated decline of approximately 2.6 % of predicted aerobic capacity per year during the second decade of life. When aerobic exercise capacity falls below a threshold of approximately 45% of predicted for age and gender; the risk of cardiopulmonary failure, death, or need for heart transplantation increases significantly. A therapy which reduces this observed decline in exercise capacity might forestall the onset of heart failure and prolong transplant-free survival. The Fontan aerobic exercise capacity is limited by the inability to maintain adequate preload to the systemic ventricle. The underlying pathophysiologic mechanisms are limited pulmonary vasodilatory reserve and absence of a sub-pulmonary ventricle to generate an adequate trans-pulmonary pressure gradient. No current therapy for the failing Fontan circulation specifically addresses this problem. The primary aim of this study is to determine if long-term treatment with oral sildenafil will prevent or ameliorate this decline in aerobic exercise performance in adolescents following the Fontan operation. Sildenafil is a selective pulmonary vasodilator that in short term studies increases Fontan aerobic capacity. Its long term effects are unknown. This will be a three-year double-blinded, placebo-controlled, intention to treat, phase 3 clinical trial utilizing sildenafil as a pulmonary vasodilator in adolescent survivors of the Fontan operation. Previous research indicates that submaximal aerobic capacity will be most affected by this treatment strategy. Therefore, oxygen consumption at the ventilatory anaerobic threshold (VAT) will serve as the primary measure of aerobic performance. The rate of decline (trajectory) in VAT measured within the sildenafil and control groups will be compared over the 3 year study period as the primary endpoint. It is hypothesized that the short term effects of sidenafil on aerobic capacity will be sustained and result in a 50% decrease in the rate of decline (trajectory) in the aerobic capacity to 1.3% per year in the adolescent Fontan population in the sildenafil treatment group with a greater decline (2.6% per year) in the placebo group. RELEVANCE: The Fontan operation results in long term survival of infants with single ventricle hearts, but results in significant symptoms with aging which are reflected in a steadily decreasing exercise tolerance. This study will test if the long term use of sidenafil, which improves exercise in these children with short term use, will result in sustained improvement in exercise and hopefully delay the onset of these symptoms and mortality.

描述（由申请人提供）： 丰丹运营幸存者在青春期期间测得的有氧运动能力的逐渐下降。预计在生命的第二个十年中，方坦行动的青春期幸存者预计每年约有2.6％的有氧运动能力下降。当有氧运动能力低于年龄和性别预测的大约45％的阈值时；心肺衰竭，死亡或需要心脏移植的风险显着增加。一种降低这种运动能力下降的疗法可能会阻止心力衰竭发作和延长无移植生存。 Fontan有氧运动能力受到无法维持足够的全身性心室的限制。潜在的病理生理机制是有限的肺血管舒张储备和缺乏肺部心室以产生适当的反肺压力梯度。目前没有针对Fontan循环的疗法专门解决此问题。 这项研究的主要目的是确定口服西地那非的长期治疗是否会预防或改善Fontan操作后青少年的有氧运动表现下降。西地那非是一种选择性的肺血管扩张剂，在短期研究中会增加Fontan有氧能力。它的长期影响未知。这将是一个三年的双盲，安慰剂对照的意图，以治疗3阶段的临床试验，利用西地那非作为丰丹运营的青少年幸存者中的肺血管扩张剂。先前的研究表明，次最大的有氧运动能力将受到这种治疗策略的影响。因此，通风性厌氧阈值（VAT）处的氧气消耗将是有氧性能的主要度量。在西地那非和对照组内测得的增值税的下降速率（轨迹）将在3年的研究期间比较为主要终点。假设，西多纳芬对有氧运动能力的短期影响将持续，并导致在西地那非治疗组的青少年fontan人群中，有氧运动能力下降率下降了50％（轨迹）每年1.3％的下降（每年下降2.6％）。 相关性：Fontan操作导致具有单个心室心脏的婴儿的长期存活，但导致衰老的显着症状反映在稳步降低运动耐受性中。这项研究将测试Sidenafil的长期使用（这些短期使用儿童的运动）是否会持续改善运动，并希望延迟这些症状和死亡率的发作。