Phase 2 Study of Glycomacropeptide Versus Amino Acid Diet for Management of Phenylketonuria

Study Overview
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Brief Summary
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For individuals with Phenylketonuria (PKU), the investigators hypothesize that glycomacropeptide will provide an acceptable form of low-phenylalanine dietary protein that will improve dietary compliance, blood phenylalanine levels, cognitive function, and ultimately quality of life compared with the usual amino acid based diet. The study is funded by the Food and Drug Administration (FDA) Office of Orphan Products Development Grants Program, R01 FD003711.

Detailed Description
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Individuals with phenylketonuria (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. 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-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.

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

Conditions
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Phenylketonuria

Intervention / Treatment
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* Other: GMP Diet/GMP Medical Foods
* Other: AA Diet/AA Medical Foods


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Identified PKU by newborn screening; started diet treatment before 1 mo age Diagnosis of classical or variant PKU with documented phenylalanine level of greater than 600 umol/L at 7-10d of age Follows or willing to follow PKU diet and consume amino acid medical formula providing more than 50% of protein needs Acceptance of glycomacropeptide foods determined prior to enrollment Exclusion Criteria: Females who are pregnant or planning pregnancy Individuals with mental deficits due to untreated or poorly controlled PKU Individuals with any health condition deemed to interfere with participation

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study is a randomized, two-arm, crossover trial comparing the GMP diet and the AA diet in 30 subjects with PKU > 12 years of age. Subjects were randomized to start with either the GMP diet or the AA diet which they followed for 3-wk at home, followed by a 3-wk washout period when they resumed their usual AA diet, and then 3-wk of either the GMP diet or the AA diet whichever they did not consume first. Each subject served as their own control; there was no control group. We studied medical foods - either AA or GMP medical foods which are not drugs. The FDA did not require that we have an IND.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GMP Diet/GMP Medical Foods<br>The experimental intervention is the GMP diet followed at home for 3-wk. In this randomized crossover study, half of subjects (n=15) were randomized to receive the GMP diet as the first arm, and half of the subjects (n=15) were randomized to receive the GMP diet as the second arm. | Other: AA Diet/AA Medical Foods<br>* The intervention consists of a low-Phe diet in combination with commercial AA medical foods as consumed in each subject's usual diet. A total of 15 different commercial AA medical foods were consumed by subjects in the study. The diet is formulated to provide each subject with their typical daily intake of protein equivalents from AA medical foods. The AA dietary treatment period consists of all subjects following the AA diet for 3-wks at home. The AA Diet comparator intervention is administered in differing orders, GMP Diet/AA Diet or AA diet/GMP Diet.<br>* Other names: AA Medical Foods;|
| Active Comparator: AA Diet/AA Medical Foods<br>The experimental intervention is the AA diet followed at home for 3-wk. In this randomized crossover study, half of subjects (n=15) were randomized to receive the AA diet as the first arm, and half of the subjects (n=15) were randomized to receive the AA diet as the second arm. | Other: GMP Diet/GMP Medical Foods<br>* The intervention consists of a low-phenylalanine (Phe) diet in combination with medical foods made with the peptide GMP supplemented with limiting indispensable amino acids, as provided by Cambrooke Therapeutics, LLC. The diet is formulated to replace the protein equivalents provided by AA medical foods with GMP medical foods, keeping other dietary components constant. The GMP dietary treatment period consists of all subjects following the GMP diet for 3-wks at home. The GMP diet intervention is administered in differing orders, GMP Diet/AA Diet or AA diet/GMP Diet.<br>* Other names: Glytactin trademark of Cambrooke Therapeutics,LLC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Plasma Phenylalanine Concentration of PKU Subjects Fed the Glycomacropeptide Diet Compared With the Change When Fed the Amino Acid Diet | Plasma will be collected at each base week and after 3 weeks on each of the dietary treatments, glycomacropeptide and amino acid, following an overnight fast. Plasma phenylalanine concentration (along with the complete profile of free amino acids) will be determined with an amino acid analyzer in the Wisconsin State Lab of Hygiene. Statistical analysis to determine the significance of the change in plasma phe concentration when comparing the 2 diets will consist of ANCOVA with covariates for baseline Phe and dietary Phe intake. The change in plasma Phe concentration from day 22 (final) to day 1 (baseline) was determined after adjusting for baseline Phe level and dietary Phe intake. | baseline to day 22 on each diet | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dietary Compliance | Compliance with the glycomacropeptide and amino acid dietary treatments will be assessed by comparison of the intake of medical food in grams of protein from medical food per day based on subject completion of 3-day food records prior to the final study visit on day 22. Statistical analysis for a dietary treatment effect will consist of ANOVA. | 3 week dietary treatment | 
| Executive Function Assessed by BRIEF | Completion of a standardized test, the Behavior Rating Inventory of Executive Function (BRIEF), by each subject for the GMP diet and the AA diet. Values are T-scores which have a mean of 50 points and a SD of 10 points. A T score of <50 is considered within the normative range. Data are analyzed with a paired t-test. | day 22 of each dietary treatment | 
| Vitamin D (25-OH) Plasma Concentration at Day 22 | Vitamin D was measured as a measure of the capacity for calcium absorption. Higher levels of plasma vitamin D are consistent with higher calcium absorption. | day 22 of each dietary treatment | 
| Comparison of Phe Concentrations in Plasma With Concentrations in Dried Blood Spots | Concentrations of Phe in plasma and in dried blood spots collected simultaneously by subjects will be compared using 2 methodologies, regardless of intervention. At each of the 4 study visits (baseline and final for each dietary treatment): 1) venipuncture was used to collect blood and plasma was isolated and analyzed for Phe with ion exchange chromatography and 2) subjects were asked right after the venipuncture to spot their blood on filter paper for analysis of Phe with tandem mass spectroscopy (MS/MS). The discrepancy in Phe concentrations with these 2 methods was compared for each sample pair using Bland-Altman statistical analysis. Each subject should have had 4 sample pairs, 29 x 4 = 116, but we ended up with only 110 sample pairs, as explained below. | 4 times total, 2 per treatment | 
| Bone-specific Alkaline Phosphatase (BSAP) Plasma Concentration at Day 22 | Plasma concentration of BSAP was determined as a measure of bone turnover. | day 22 of each dietary treatment | 
| N-terminal Telopeptide (NTX) Plasma Concentration at Day 22 | Plasma concentration of NTX was determined as a measure of bone resorption; higher levels indicate greater bone breakdown | day 22 of each dietary treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diet therapy, Low phenylalanine diet, Attention, Executive function