Phase 2 Study of Glycomacropeptide vs. Amino Acid Diet for the Management of PKU

描述(由申请人提供)： PKU患者缺乏代谢必需氨基酸苯丙氨酸(Phe)所需的苯丙氨酸羟基酶。当吃正常饮食时，他们的血液中苯丙氨酸水平升高，这对大脑有害。为了预防脑损伤和认知障碍，PKU患者必须遵循终身低Phe饮食，这种饮食仅限于天然食物，需要摄入不含Phe的氨基酸(AA)配方。大多数患有PKU的青少年和成年人发现AA配方令人不快，并停止饮食，导致血液Phe水平升高和神经心理恶化。患有PKU的孕妇的风险和潜在的医疗费用尤其高，当其婴儿暴露在母亲血液Phe水平升高时，即母亲的PKU时，其婴儿表现出先天异常。糖巨肽(GMP)是一种在奶酪制作过程中产生的完整蛋白质，特别适合低Phe饮食，因为它是唯一已知的含有最低Phe的饮食蛋白质。用GMP制成的食品和饮料是AA配方奶粉的可口替代品。长期目标是评估GMP用于北京大学营养管理的安全性、有效性和可接受性。具体目的是进行一项随机、两阶段、11周(Wk)的交叉试验，比较GMP饮食和AA饮食，其中30名PKU=12岁的受试者从出生起就接受低Phe AA饮食治疗。这些网站是：威斯康星大学麦迪逊分校，韦斯曼中心(小学)和哈佛大学，波士顿儿童医院。受试者将被招募并随机开始研究的第一个3-wk，其中大部分膳食蛋白质由GMP或AA医疗食品提供的低Phe饮食开始，然后，在3-wk与他们通常的饮食摄入后，开始第二个3-wk的饮食。饮食教育将在每种饮食开始前1周的基准期内提供。主要终点是喂食GMP饮食3-wk的PKU受试者血浆Phe浓度的变化与喂食AA饮食3-wk时血浆Phe浓度的变化(配对t检验，受试者配对)。次要结果变量包括通过食物记录评估的依从性，通过问卷评估的可接受性，以及通过神经心理测试评估的认知功能。研究人员预计，与通常的AA饮食相比，GMP饮食将降低血浆Phe水平，并由于改善饮食依从性和Phe利用率而改善认知功能。为了加强对低骨量的病因的了解，低骨量是PKU患者常见的长期并发症，将获得探索性数据，以评估20名12-20岁的PKU受试者的骨转换标志。

DESCRIPTION (provided by applicant): Individuals with PKU lack the enzyme phenylalanine hydroxylase that is needed to metabolize the essential amino acid phenylalanine (phe). When eating a normal diet they show an elevated level of phe in blood that is toxic to the brain. In order to prevent brain damage and cognitive impairment, individuals with PKU must follow a lifelong, low-phe diet that is restricted in natural foods and requires ingestion of a phe-free amino acid (AA) formula. Most adolescents and adults with PKU find the AA formula unpalatable and go off the diet resulting in elevated blood phe levels and neuropsychological deterioration. The risk and potential health care costs are especially high for pregnant women with PKU whose infants show congenital anomalies when exposed to elevated maternal blood phe levels, i.e., maternal PKU. Glycomacropeptide (GMP), an intact protein produced during cheese making, is uniquely suited to a low-phe diet because it is the only known dietary protein that contains minimal phe. Foods and beverages made with GMP are a palatable alternative to AA formula. The long-term goal is to assess the safety, efficacy and acceptability of GMP for the nutritional management of PKU. The specific aim is to conduct a randomized, two-stage, 11-week (wk), crossover trial comparing the GMP diet with the AA diet in 30 subjects with PKU =12 years of age treated since birth with a low-phe AA diet. The sites are: University of Wisconsin- Madison, Waisman Center (primary) and Harvard University, Children's Hospital Boston. Subjects will be recruited and randomized to begin the first 3-wk of the study with either a low phe diet in which the majority of dietary protein is provided by GMP or AA medical foods and then, after a 3-wk washout with intake of their usual diet, begin the second diet for 3-wk. Dietary education will be provided in a 1-wk base period preceding initiation of each diet. The primary endpoint is change in the plasma phe concentration of PKU subjects fed the GMP diet for 3-wk compared with change in the plasma phe concentration when fed the AA diet for 3-wk (paired t-test, pairing on subject). Secondary outcome variables include compliance assessed by food records, acceptability assessed by questionnaires, and cognitive function assessed by neuropsychological tests. The investigators expect that compared to the usual AA diet, the GMP diet will reduce plasma phe levels and improve cognitive function due to improved dietary compliance and phe utilization. To enhance understanding of the etiology of low bone mass, a common long-term complication in those with PKU, exploratory data will be obtained to assess markers of bone turnover in a subset of 20 PKU subjects, 12-20 years of age.