Planning a Multi-center Trial of Subclinical Hypothyroidism in Older Adults

描述（由申请人提供）：显性甲状腺功能减退被定义为垂体促甲状腺激素（TSH）升高和相应的甲状腺激素水平低，而更常见的亚临床甲状腺功能减退（SCH）被定义为TSH升高但甲状腺激素水平正常。SCH在50岁以上的人群中尤为常见，并可能与不良的心血管和神经精神预后有关。最近的研究表明，亚临床甲状腺功能减退与临床充血性心力衰竭的两倍增加和缺血性心脏病的风险增加20-50%有关。甲状腺激素替代的小型试验报道了对替代心血管结果的积极影响，如脂蛋白、心功能和内膜-中膜厚度。然而，尚无大型临床试验评估降低亚临床甲状腺功能减退相关发病率和改善临床结果的有效治疗方法。由于缺乏确凿的证据，临床实践中出现了广泛的差异，一些临床医生积极筛查和治疗亚临床甲状腺功能减退症，而另一些则没有。2004年，美国预防服务工作组注意到缺乏关于亚临床甲状腺疾病治疗的数据，并得出结论，没有足够的证据来推荐或反对甲状腺功能障碍筛查。该提案将支持一项大型双盲、多中心试验的计划活动，该试验通过基于人群的筛查招募50-85岁的持续性亚临床甲状腺功能减退患者，并随机分配到甲状腺素替代以使TSH正常化或匹配安慰剂。主要终点将是临床心血管结局，特别是心力衰竭、缺血性心脏病或心血管死亡，伴有继发性神经精神、肌肉骨骼和功能结局。该试验的计划过程将包括一个广泛的研究人员联盟，他们在甲状腺功能障碍、心血管和神经精神预后以及临床试验方法方面具有专业知识。这一计划过程的产物将是向NIH提交的全面临床试验申请，包括详细的方案和组织结构、完整的操作手册、关于甲状腺功能异常人群筛查的可行性数据以及研究人员、临床中心和旧金山协调中心拟议活动的全面描述。

DESCRIPTION (provided by applicant): Overt hypothyroid is defined as an elevated pituitary thyrotropin (TSH) and corresponding low thyroid hormone levels, while the much more common entity, subclinical hypothyroidism (SCH), is defined as an elevated TSH but normal thyroid hormone levels. SCH is particularly common among individuals over age 50 and may be associated with adverse cardiovascular and neuropsychiatric outcomes. Recent studies suggest that subclinical hypothyroidism is associated with a two-fold increase in clinical congestive heart failure and a 20-50% increased risk of ischemic heart disease. Small trials of thyroid hormone replacement have reported positive effects on surrogate cardiovascular outcomes, such as lipoproteins, cardiac function, and intima-media thickness. However, no large clinical trials have evaluated effective treatment to reduce the morbidity associated with subclinical hypothyroidism and improve clinical outcomes. Lacking conclusive evidence, wide variations in clinical practice have emerged, with some clinicians actively screening for and treating subclinical hypothyroidism, while others do neither. In 2004 the US Preventive Services Task Force noted the paucity of data regarding treatment of subclinical thyroid disorders and concluded that there was insufficient evidence to recommend for or against screening for thyroid dysfunction. This proposal will support planning activities for a large double-blind, multi-center trial of men and women 50-85 years old with persistent subclinical hypothyroidism recruited by population-based screening and randomized to either thyroxine replacement to normalize TSH, or matching placebo. The primary endpoints will be clinical cardiovascular outcomes, specifically heart failure, ischemic heart disease, or cardiovascular death, with secondary neuropsychiatric, musculoskeletal, and functional outcomes. The planning process for this trial will include a broad coalition of investigators with expertise in thyroid dysfunction, cardiovascular and neuropsychiatric outcomes, and clinical trial methodology. The product of this planning process will be a full-scale clinical trial application to the NIH, including a detailed protocol and organization structure, complete manual of operations, feasibility data regarding population-screening for abnormal thyroid function and a comprehensive description of the proposed activities of the investigators, clinical centers, and San Francisco Coordinating Center. PUBLIC HEALTH RELEVANCE: Subclinical hypothyroidism, sometimes called mild thyroid failure, is particularly common in older individuals and may be associated with adverse cardiovascular, neuropsychiatric, and neuromuscular outcomes. In this multi-center planning grant we request support to design a large randomized, placebo-controlled trial to determine if, compared to placebo, treatment of subclinical hypothyroidism with thyroid hormone replacement is associated with improved cardiovascular and neuropsychiatric outcomes. This trial will provide high quality evidence on the utility of screening for and treating subclinical hypothyroidism in older individuals.