A Phase II Trial of Levodopa in Angelman Syndrome

左旋多巴治疗 Angelman 综合征的 II 期试验

• 批准号: 8118054
• 负责人: Wen-Hann Tan
• 金额: $ 36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118054
• 关键词: Phase; II; Trial; Levodopa; Angelman

DESCRIPTION (provided by applicant): This study will investigate the efficacy of levodopa in improving the neurodevelopment and movement disorders in children with Angelman Syndrome (AS), a rare neurodevelopmental disorder with a prevalence of approximately 1 in 10,000 to 1 in 20,000 individuals. AS is characterized by mental retardation, limited speech, seizures, abnormal movements such as tremors, and ataxic gait. Currently, there is no cure for AS and treatment is largely supportive. Calcium/calmodulin-dependent kinase type 2 (CaMKII) is an enzyme in post-synaptic neurons that is involved in the formation of memory and learning. Recently, it was shown that excess phosphorylation of CaMKII may be responsible for some of the neurological deficits seen in AS. Levodopa (LD) is a prodrug that "delivers" dopamine to the brain. It is usually given with carbidopa (CD), a peripheral decarboxylase inhibitor, to increase the bioavailability of LD. Animal studies have suggested that LD can reverse the excess phosphorylation of some enzymes involved in synaptic and neuronal function, including CaMKII. More recent data have shown that exogenous LD given to both wild-type and AS mice reduces the phosphorylation of CaMKII in the brain and leads to improvements in the motor learning and performance of the AS mice. Therefore, it is hypothesized that oral LD/CD will lead to an improvement in the neurodevelopment and movement disorder in children with AS. Oral LD/CD has been used in at least 12 AS children between 15 months and 21 years old. However, no controlled studies have been carried out to date to evaluate use of LD/CD in children or adults. The specific aim of this study is to conduct a Phase 2 randomized double-blind placebo-controlled trial of LD/CD in AS children between 4 years and 12 years old. Children with AS will be recruited for this study through parent support groups and professional organizations. One hundred AS children will be randomized equally to receive either placebo or LD/CD and observed on therapy for one year. Outcome measures that will be used in this study include the Bayley Scales of Infant and Toddler Development, the Vineland Adaptive Behavior Scales, the Preschool Language Scale, the Aberrant Behavior Checklist, as well as a modified version of the Unified Parkinson Disease Rating Scale. Upon completion of the first year of the Phase 2 trial, all subjects will be offered the option of continuing on LD/CD for an additional year in an open-label study to obtain longer-term safety, and possibly efficacy data in a larger cohort of subjects.

描述（由申请人提供）： 这项研究将调查左旋多巴在改善Angelman综合征儿童（AS）的神经发育和运动障碍方面的功效，Angelman综合征（AS）是一种罕见的神经发育障碍，患病率约为20,000至20,000人中的10,000至1个。 如心理迟缓，有限的言语，癫痫发作，异常运动（如震颤和共同步态）的特征。 目前，AS尚无治疗方法，并且治疗在很大程度上是支持的。 钙/钙调蛋白依赖性激酶类型2（CAMKII）是后突触后神经元中的一种酶，参与记忆和学习的形成。 最近，结果表明，CAMKII的过量磷酸化可能导致AS中看到的某些神经缺陷。 左旋多巴（LD）是一种“将”多巴胺“递送”到大脑的前药。 通常用外围脱羧酶抑制剂Carbidopa（CD）给出，以增加LD的生物利用度。 动物研究表明，LD可以逆转一些参与突触和神经元功能的酶的过量磷酸化，包括CAMKII。 最近的数据表明，野生型的外源性LD和小鼠降低了Camkii在大脑中的磷酸化，并改善了AS小鼠的运动学习和性能。 因此，假设口服LD/CD将改善AS儿童的神经发育和运动障碍。 口服LD/CD至少在12个月至21岁之间使用了12个。 但是，迄今为止尚未进行对照研究以评估儿童或成人中LD/CD的使用。 这项研究的具体目的是进行2期随机的双盲安慰剂对照试验，对LD/CD的儿童在4至12岁之间进行。 将通过父母支持小组和专业组织招募有AS的孩子。 一百个儿童将被同等地随机接受安慰剂或LD/CD，并在治疗上观察一年。 这项研究中将使用的结果指标包括婴儿和蹒跚学步的发展的Bayley量表，Vineland自适应行为量表，学龄前语言量表，异常行为清单以及统一帕金森氏病评级量表的修改版本。 在第2阶段试验的第一年完成后，将为所有受试者提供在开放标签研究中继续在LD/CD上继续额外的一年的选项，以获得长期安全性，并可能在较大的受试者组中获得疗效数据。