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）所需的苯丙氨酸羟化酶。 当他们正常饮食时，血液中的苯丙氨酸水平会升高，这对大脑是有毒的。为了防止脑损伤和认知障碍，PKU患者必须终身遵循低苯丙氨酸饮食，限制天然食物，并需要摄入无苯丙氨酸氨基酸（AA）配方。 大多数青少年和成年PKU发现AA配方不好吃，并停止饮食，导致血液phe水平升高和神经心理恶化。 PKU孕妇的风险和潜在的医疗保健费用特别高，当暴露于升高的母体血液phe水平时，其婴儿显示先天性异常，即，母亲苯丙酮尿症。 糖巨肽（GMP）是一种在奶酪制作过程中产生的完整蛋白质，特别适合于低苯丙氨酸饮食，因为它是唯一已知的含有最少苯丙氨酸的膳食蛋白质。 食品和饮料与GMP是一个可口的替代AA公式。 长期目标是评估GMP用于PKU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、为期11周（wk）的交叉试验，在30例年龄≥ 12岁的PKU受试者中比较GMP饮食与AA饮食，这些受试者自出生起接受低phe AA饮食治疗。这些地点是：威斯康星州-麦迪逊大学、魏斯曼中心（小学）和哈佛大学、波士顿儿童医院。 受试者将被招募并被随机分配至开始研究的前3周，采用低phe饮食，其中大部分膳食蛋白质由GMP或AA医疗食品提供，然后，在摄入其常规饮食的3周洗脱后，开始第二次饮食3周。 将在开始每种饮食前的1周基准期内提供饮食教育。 主要终点是喂食GMP饮食3周的PKU受试者血浆phe浓度的变化，与喂食AA饮食3周时血浆phe浓度的变化相比（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、通过问卷调查评估的可接受性和通过神经心理学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，并改善认知功能，因为改善了饮食依从性和Phe利用率。为了加深对低骨量（PKU患者常见的长期并发症）病因的理解，将获得探索性数据，以评估20例12-20岁PKU受试者亚组的骨转换标志物。

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.