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

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ClinicalTrials.gov Identifier: NCT01428258
Recruitment Status : Completed
First Posted : September 2, 2011
Results First Posted : March 3, 2017
Last Update Posted : August 24, 2018
Sponsor:
Collaborator:
Boston Children’s Hospital
Information provided by (Responsible Party):
University of Wisconsin, Madison

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Phenylketonuria
Interventions Other: GMP Diet/GMP Medical Foods
Other: AA Diet/AA Medical Foods
Enrollment 32
Recruitment Details  
Pre-assignment Details  
Arm/Group Title GMP Diet-AA Diet AA Diet - GMP Diet
Hide Arm/Group Description

In this randomized crossover study, half of subjects will be assigned to an arm that consists of the the GMP diet followed by the AA diet referred to as the Glycomacropeptide (GMP) diet given first intervention.

Glycomacropeptide (GMP) diet given first: The intervention compares a new low-phenylalanine (phe) dietary therapy for PKU, a diet containing foods and beverages made from GMP using Glytactin provided by Cambrooke Foods LLC, with the usual amino acid (AA) low-phe dietary therapy. PKU subjects in the GMP Diet-AA Diet Arm will follow the GMP diet that will replace all of the dietary protein equivalents provided by AA formula with foods and beverages made from GMP for 3 weeks followed by a 3 wk wash out period. They will then follow the usual AA diet for 3 weeks. Each dietary treatment period will maintain constant intake of total protein and phe and last for 3 weeks in subjects living at home.

In this randomized crossover study, half of subjects will be assigned to an arm that consists of the AA diet followed by the GMP diet referred to as the Amino Acid (AA) Diet given first intervention.

Amino Acid (AA) Diet Given First: The intervention compares the usual amino acid (AA) low-phenylalanine (phe) dietary therapy with a new dietary therapy for PKU, a low-phe diet containing foods and beverages made from glycomacropeptide (GMP). PKU subjects in the AA Diet-GMP Diet Arm will follow their usual AA diet for 3 weeks followed by a 3 wk wash out period. They will then replace all of the protein equivalents provided in their diet by AA formula with foods and beverages made from GMP using Glytactin as provided by Cambrooke Foods, LLC. Each dietary treatment period will maintain constant intake of total protein and phe and last for 3 weeks in subjects living at home.

Period Title: Intervention 1
Started 17 15
Completed 15 15
Not Completed 2 0
Reason Not Completed
Withdrawal by Subject             2             0
Period Title: Intervention 2
Started 15 15
Completed 15 15
Not Completed 0 0
Arm/Group Title GMP Diet-AA Diet AA Diet - GMP Diet Total
Hide Arm/Group Description

In this randomized crossover study, half of subjects will be assigned to an arm that consists of the the GMP diet followed by the AA diet referred to as the Glycomacropeptide (GMP) diet given first intervention.

Glycomacropeptide (GMP) diet given first: The intervention compares a new low-phenylalanine (phe) dietary therapy for PKU, a diet containing foods and beverages made from GMP using Glytactin provided by Cambrooke Foods LLC, with the usual amino acid (AA) low-phe dietary therapy. PKU subjects in the GMP Diet-AA Diet Arm will follow the GMP diet that will replace all of the dietary protein equivalents provided by AA formula with foods and beverages made from GMP for 3 weeks followed by a 3 wk wash out period. They will then follow the usual AA diet for 3 weeks. Each dietary treatment period will maintain constant intake of total protein and phe and last for 3 weeks in subjects living at home.

In this randomized crossover study, half of subjects will be assigned to an arm that consists of the AA diet followed by the GMP diet referred to as the Amino Acid (AA) Diet given first intervention.

Amino Acid (AA) Diet Given First: The intervention compares the usual amino acid (AA) low-phenylalanine (phe) dietary therapy with a new dietary therapy for PKU, a low-phe diet containing foods and beverages made from glycomacropeptide (GMP). PKU subjects in the AA Diet-GMP Diet Arm will follow their usual AA diet for 3 weeks followed by a 3 wk wash out period. They will then replace all of the protein equivalents provided in their diet by AA formula with foods and beverages made from GMP using Glytactin as provided by Cambrooke Foods, LLC. Each dietary treatment period will maintain constant intake of total protein and phe and last for 3 weeks in subjects living at home.

Total of all reporting groups
Overall Number of Baseline Participants 17 15 32
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants 15 participants 32 participants
<=18 years
3
  17.6%
2
  13.3%
5
  15.6%
Between 18 and 65 years
14
  82.4%
13
  86.7%
27
  84.4%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 17 participants 15 participants 32 participants
28
(15 to 56)
28
(15 to 56)
28
(15 to 56)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants 15 participants 32 participants
Female
14
  82.4%
5
  33.3%
19
  59.4%
Male
3
  17.6%
10
  66.7%
13
  40.6%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 17 participants 15 participants 32 participants
17
 100.0%
15
 100.0%
32
 100.0%
1.Primary Outcome
Title Change in the Plasma Phenylalanine Concentration of PKU Subjects Fed the Glycomacropeptide Diet Compared With the Change When Fed the Amino Acid Diet
Hide Description 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.
Time Frame baseline to day 22 on each diet
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description:
All subjects received the Glycomacropeptide (GMP) diet either in the first or second period. The intervention consists of a low-Phe diet in combination with medical foods made from glycomacropeptide, a low-Phe whey protein.
All subjects received the Amino Acid (AA) Diet in either the first or second period. The intervention consists of a low-Phe diet in combination with each subject's usual AA medical formula.
Overall Number of Participants Analyzed 30 30
Mean (Standard Error)
Unit of Measure: micro moles per liter plasma
62  (40) -85  (40)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GMP Diet/GMP Medical Foods, AA Diet/AA Medical Foods
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -147
Parameter Dispersion
Type: Standard Error of the Mean
Value: 39
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection GMP Diet/GMP Medical Foods
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.136
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection AA Diet/AA Medical Foods
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.044
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
2.Secondary Outcome
Title Dietary Compliance
Hide Description 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.
Time Frame 3 week dietary treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title GMP Diet AA Diet/AA Medical Foods
Hide Arm/Group Description:
All subjects received the Glycomacropeptide (GMP) diet either in the first or second period. The intervention consists of a low-Phe diet in combination with medical foods made from glycomacropeptide, a low-Phe whey protein.
All subjects received the Amino Acid (AA) Diet in either the first or second period. The intervention consists of a low-Phe diet in combination with each subject's usual AA medical formula.
Overall Number of Participants Analyzed 30 30
Mean (Standard Error)
Unit of Measure: g protein from MF/kg/day
0.74  (0.04) 0.76  (0.05)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GMP Diet, AA Diet/AA Medical Foods
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.576
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
3.Secondary Outcome
Title Executive Function Assessed by BRIEF
Hide Description 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.
Time Frame day 22 of each dietary treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description:
The intervention followed as the first or second treatment consists of a low-Phe diet in combination with medical foods made from glycomacropeptide .
The intervention followed as the first or second treatment consists of a low-Phe diet in combination with each subjects usual AA medical foods.
Overall Number of Participants Analyzed 30 30
Mean (Standard Error)
Unit of Measure: T score
49.0  (1.8) 48.8  (2.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GMP Diet/GMP Medical Foods, AA Diet/AA Medical Foods
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.902
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
4.Secondary Outcome
Title Vitamin D (25-OH) Plasma Concentration at Day 22
Hide Description 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.
Time Frame day 22 of each dietary treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description:
All subjects received the Glycomacropeptide (GMP) diet either in the first or second period. The intervention consists of a low-Phe diet in combination with medical foods made from glycomacropeptide, a low-Phe whey protein.
All subjects received the Amino Acid (AA) Diet in either the first or second period. The intervention consists of a low-Phe diet in combination with each subject's usual AA medical formula.
Overall Number of Participants Analyzed 30 30
Mean (Standard Error)
Unit of Measure: ng per ml
33.8  (1.70) 33.6  (1.52)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GMP Diet/GMP Medical Foods, AA Diet/AA Medical Foods
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.797
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
5.Secondary Outcome
Title Comparison of Phe Concentrations in Plasma With Concentrations in Dried Blood Spots
Hide Description 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.
Time Frame 4 times total, 2 per treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis of sample pairs is required to determine the discrepancy in Phe levels with the 2 methods. Each subject should have had 4 sample pairs, 29 x 4 = 116, but we ended up with only 110 sample pairs. The explanation for the difference is that several subjects did not provide dried blood spots because research staff forgot to obtain them.
Arm/Group Title Phe Concentration in Plasma, Ion Exchange Chromatography Phe Concentration in Dried Blood Spots, Tandem Mass Spec
Hide Arm/Group Description:
Blood was collected by venipuncture at 3 to 4 time points, plasma was isolated and the concentration of Phe was determined by ion exchange chromatography.
Subjects spotted their blood on filter paper at the same time as plasma was obtained at 3 or 4 time periods, dried blood spots were obtained, and analyzed for Phe concentration using tandem mass spectrometry.
Overall Number of Participants Analyzed 29 29
Mean (Standard Error)
Unit of Measure: micro moles per liter
731  (32) 514  (23)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phe Concentration in Plasma, Ion Exchange Chromatography, Phe Concentration in Dried Blood Spots, Tandem Mass Spec
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
6.Secondary Outcome
Title Bone-specific Alkaline Phosphatase (BSAP) Plasma Concentration at Day 22
Hide Description Plasma concentration of BSAP was determined as a measure of bone turnover.
Time Frame day 22 of each dietary treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Samples were not obtained from 4 subjects due to a collection error by research staff. Thus the sample size is reduced from 30 to 26.
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description:
The intervention followed as the first or second treatment consists of a low-Phe diet in combination with medical foods made with glycomacropeptide.
The intervention followed as the first or second treatment consists of a low-Phe diet in combination with each subjects usual AA medical foods.
Overall Number of Participants Analyzed 26 26
Mean (Standard Error)
Unit of Measure: micro gram per liter
17.0  (2.1) 17.0  (2.2)
7.Secondary Outcome
Title N-terminal Telopeptide (NTX) Plasma Concentration at Day 22
Hide Description Plasma concentration of NTX was determined as a measure of bone resorption; higher levels indicate greater bone breakdown
Time Frame day 22 of each dietary treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Samples were not obtained from 3 subjects due to a collection error by research staff. Thus the sample size is reduced from 30 to 27.
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description:
The intervention administered as the first or second dietary treatment consists of a low-Phe diet in combination with medical foods made with glycomacropeptide.
The intervention administered as the first or second dietary treatment consists of a low-Phe diet in combination with each subjects usual AA medical foods.
Overall Number of Participants Analyzed 27 27
Mean (Standard Error)
Unit of Measure: nmol per liter bone collagen equivalents
17.5  (0.66) 17.1  (0.65)
8.Other Pre-specified Outcome
Title Bone Mineral Density Determined by Dual-energy X-ray Absorptiometry (DXA) Scan
Hide Description Subjects will have a single DXA test to assess bone mineral density of the lumbar spine and total body during the first dietary treatment that they are randomly assigned to start with.
Time Frame once during first 3 week dietary treatment
Outcome Measure Data Not Reported
Time Frame For each subject, adverse events were monitored for each of the 3-wk treatment periods for each diet.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Hide Arm/Group Description All subjects received the Glycomacropeptide (GMP) diet either in the first or second period. The intervention consists of a low-Phe diet in combination with medical foods made from glycomacropeptide, a low-Phe whey protein. All subjects received the Amino Acid (AA) Diet in either the first or second period. The intervention consists of a low-Phe diet in combination with each subject's usual AA medical formula.
All-Cause Mortality
GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Affected / at Risk (%) Affected / at Risk (%)
Total   0/32 (0.00%)   0/30 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
GMP Diet/GMP Medical Foods AA Diet/AA Medical Foods
Affected / at Risk (%) Affected / at Risk (%)
Total   0/32 (0.00%)   0/30 (0.00%) 
The trial was completed as planned with an adequate number of subjects and there were no limitations.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Denise M Ney
Organization: University of Wisconsin-Madison
Phone: 608-262-4386
Publications of Results:
Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT01428258     History of Changes
Other Study ID Numbers: H-2010-0165
1R01FD003711-01A1 ( U.S. FDA Grant/Contract )
First Submitted: August 31, 2011
First Posted: September 2, 2011
Results First Submitted: October 11, 2016
Results First Posted: March 3, 2017
Last Update Posted: August 24, 2018