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

基本信息

批准号：
8486484
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
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8486484
关键词：
Address Admission activity Adolescence Adolescent 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 Patients 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 base falls functional status improved mortality novel pressure prevent primary outcome programs prospective psychosocial randomized placebo controlled trial respiratory screening secondary outcome sildenafil treatment strategy young adult

项目摘要

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）：丰坦手术幸存者在青春期期间测量的有氧运动能力逐渐下降。 Fontan 手术的青少年幸存者在生命的第二个十年期间，预计每年将面临约 2.6% 的有氧能力下降。当有氧运动能力低于年龄和性别预测值的约 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。减少这种观察到的运动能力下降的疗法可能会预防心力衰竭的发生并延长无移植生存期。 Fontan 有氧运动能力因无法维持全身心室足够的前负荷而受到限制。潜在的病理生理机制是肺血管舒张储备有限和缺乏肺下心室来产生足够的跨肺压力梯度。目前还没有针对 Fontan 循环衰竭的治疗方法专门解决这个问题。本研究的主要目的是确定口服西地那非的长期治疗是否可以预防或改善 Fontan 手术后青少年有氧运动表现的下降。西地那非是一种选择性肺血管扩张剂，短期研究可增加 Fontan 有氧能力。其长期影响尚不清楚。这将是一项为期三年的双盲、安慰剂对照、意向治疗 3 期临床试验，利用西地那非作为 Fontan 手术青少年幸存者的肺血管扩张剂。先前的研究表明，次最大有氧能力受这种治疗策略的影响最大。因此，通气无氧阈值 (VAT) 下的耗氧量将作为有氧性能的主要衡量标准。将在 3 年研究期间比较西地那非组和对照组内测得的增值税下降率（轨迹），作为主要终点。据推测，西地那非对有氧能力的短期影响将持续，并导致西地那非治疗组青少年 Fontan 人群的有氧能力下降率（轨迹）降低 50%，每年下降 1.3%安慰剂组的下降幅度更大（每年 2.6%）。相关性：Fontan 手术可以使单心室心脏婴儿长期存活，但随着年龄的增长会出现明显的症状，这反映在运动耐量的稳步下降上。这项研究将测试长期使用西那非（短期使用可改善这些儿童的运动能力）是否会导致运动能力持续改善，并有望延缓这些症状的出现和死亡率。