Androgen effect on motor/cognitive outcome in Klinefelter syndrome

雄激素对克兰费尔特综合征运动/认知结果的影响

• 批准号: 7217906
• 负责人: Judith L Ross
• 金额: $ 56.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217906
• 关键词: Adolescence; Adolescent; Adult; Age; Androgen Analogues; Androgens; Attention; Behavioral; Birth; Caring; Characteristics; Child; Childhood; Chromosomes; Clinical Management; Clinical Trials; Cognition; Cognitive; Complex; Controlled Clinical Trials; Development; Disease; Dose; Early treatment; Failure; Genetic; Goals; Hereditary Disease; Hormones; Impairment; Intervention; Karyotype; Klinefelter' s Syndrome; Language; Learning; Life; Medical; Memory; Modeling; Motor; Movement; Muscle; Neuraxis; Neurocognitive; Neurodevelopmental Deficit; Outcome; Oxandrolone; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Population; Principal Investigator; Publishing; Randomized; Randomized Clinical Trials; Replacement Therapy; Reporting; Research; Research Personnel; Safety; Self Perception; Serious Adverse Event; Shyness; Speed; Standards of Weights and Measures; Statistically Significant; Testing; Testis; Therapeutic Intervention; X Chromosome; base; boys; cognitive function; design; early childhood; improved; innovation; male; muscle strength; novel; penis; programs; randomized placebo controlled trial; response

DESCRIPTION (provided by applicant): Klinefelter syndrome (KS), a genetic disorder that occurs in 1/1000 males, is defined by the abnormal chromosome karyotype 47.XXY (extra X chromosome), and has characteristic physical and cognitive phenotypes evident in childhood. The KS physical phenotype includes testicular failure (androgen deficiency) and tall stature. The KS neurocognitive phenotype includes diminished motor function and language-based learning difficulties. The KS behavioral phenotype involves poor self-image and shyness. The neurodevelopmental deficits associated with KS likely reflect the influence of both androgen deficiency and genetic factors on development and represent a major impediment for living a normal life with KS. It is the goal of this clinical trial to determine whether this burden can be reduced by treatment early in childhood with androgen replacement. Androgen replacement is standard in adolescent and adult KS males but has not been used in younger, prepubertal KS boys. The Phase I study will establish that the androgen oxandrolone, an FDA-approved medication for children, is also safe in prepubertal KS boys. The Phase II study is the randomized clinical trial, in which we plan to study the effects of childhood androgen replacement on motor and cognitive aspects of the KS phenotype that may result from childhood androgen deficiency. This randomized, placebo-controlled study tests a novel intervention in this population: low-dose androgen (oxandrolone) treatment for two years in KS boys (n=120), ages of 4-12 years. We predict that KS boys treated with androgen for 24 months will have improved muscle strength, compared to the placebo-treated KS boys. Second, we predict that KS boys treated with androgen for 24 months will have improved aspects of motor function including response speed, simple repetitive movement, and complex nonrepetitive motor action, compared to the placebo-treated KS boys. Third, we predict that KS boys treated with androgen (oxandrolone) for 24 months will have improved aspects of language, including verbal memory and verbal fluency and fourth, we predict that KS boys treated with androgen for 24 months will have improved aspects of simple and complex attention, compared to the placebo-treated KS boys. RELEVANCE OF THIS RESEARCH: KS is well suited for interventional studies because testicular failure is nearly universal in this disorder. Early androgen replacement is a reasonable, appropriate, and safe research treatment option in this androgen-deficient population. Therapeutic interventions for this relatively common disorder have not been forthcoming, and this proposal represents a unique opportunity to replace a missing hormone and potentially improve motor function and cognition. If successful, androgen replacement in the clinical management of KS would commence early in childhood rather than adolescence or adulthood.

描述（由申请人提供）：克兰费尔特综合征 (KS) 是一种遗传性疾病，发生于 1/1000 的男性，由异常染色体核型 47.XXY（额外 X 染色体）定义，并具有童年时期明显的特征性身体和认知表型。 KS 身体表型包括睾丸衰竭（雄激素缺乏）和身材高大。 KS 神经认知表型包括运动功能减弱和基于语言的学习困难。 KS 行为表型包括自我形象不佳和害羞。与 KS 相关的神经发育缺陷可能反映了雄激素缺乏和遗传因素对发育的影响，并且是 KS 正常生活的主要障碍。这项临床试验的目的是确定是否可以通过在儿童早期进行雄激素替代治疗来减轻这种负担。雄激素替代疗法是青少年和成年 KS 男性的标准治疗，但尚未用于年轻的青春期前 KS 男孩。第一阶段研究将确定雄激素氧雄龙（FDA 批准的儿童药物）对于青春期前的 KS 男孩也是安全的。 II 期研究是随机临床试验，我们计划研究儿童雄激素替代对可能因儿童雄激素缺乏而导致的 KS 表型运动和认知方面的影响。这项随机、安慰剂对照研究测试了针对该人群的一种新颖干预措施：对 4-12 岁的 KS 男孩 (n=120) 进行为期两年的低剂量雄激素（氧雄龙）治疗。我们预测，与接受安慰剂治疗的 KS 男孩相比，接受雄激素治疗 24 个月的 KS 男孩的肌肉力量会有所改善。其次，我们预测，与接受安慰剂治疗的 KS 男孩相比，接受雄激素治疗 24 个月的 KS 男孩运动功能方面将有所改善，包括反应速度、简单的重复运动和复杂的非重复运动动作。第三，我们预测接受雄激素（氧雄龙）治疗 24 个月的 KS 男孩将在语言方面有所改善，包括言语记忆和言语流畅性；第四，我们预测接受雄激素治疗 24 个月的 KS 男孩将在简单和语言方面有所改善。与接受安慰剂治疗的 KS 男孩相比，复杂的注意力。本研究的相关性：KS 非常适合介入研究，因为睾丸衰竭在这种疾病中几乎是普遍存在的。对于雄激素缺乏人群来说，早期雄激素替代是一种合理、适当且安全的研究治疗选择。针对这种相对常见疾病的治疗干预措施尚未出现，该提议代表了一个独特的机会来替代缺失的激素并有可能改善运动功能和认知。如果成功，KS 临床治疗中的雄激素替代将在儿童早期而不是青春期或成年期开始。