Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE August 31, 2011
First Posted Date  ICMJE September 2, 2011
Results First Submitted Date  ICMJE October 11, 2016
Results First Posted Date  ICMJE March 3, 2017
Last Update Posted Date August 24, 2018
Study Start Date  ICMJE September 2011
Actual Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
Change in the Plasma Phenylalanine Concentration of PKU Subjects Fed the Glycomacropeptide Diet Compared With the Change When Fed the Amino Acid Diet [ Time Frame: baseline to day 22 on each 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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 1, 2011)
Change in the plasma phenylalanine concentration of PKU subjects fed the glycomacropeptide diet compared with the change when fed the amino acid diet. [ Time Frame: 3 week on each 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 a paired t test, pairing on subject.
Change History Complete list of historical versions of study NCT01428258 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2017)
  • Dietary Compliance [ Time Frame: 3 week dietary treatment ]
    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.
  • Executive Function Assessed by BRIEF [ Time Frame: day 22 of each dietary treatment ]
    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.
  • Vitamin D (25-OH) Plasma Concentration at Day 22 [ Time Frame: day 22 of each dietary treatment ]
    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.
  • Comparison of Phe Concentrations in Plasma With Concentrations in Dried Blood Spots [ Time Frame: 4 times total, 2 per treatment ]
    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.
  • Bone-specific Alkaline Phosphatase (BSAP) Plasma Concentration at Day 22 [ Time Frame: day 22 of each dietary treatment ]
    Plasma concentration of BSAP was determined as a measure of bone turnover.
  • N-terminal Telopeptide (NTX) Plasma Concentration at Day 22 [ Time Frame: day 22 of each dietary treatment ]
    Plasma concentration of NTX was determined as a measure of bone resorption; higher levels indicate greater bone breakdown
Original Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2011)
  • Dietary Compliance [ Time Frame: 3 week dietary treatment ]
    Compliance with the glycomacropeptide and amino acid dietary treatments will be assessed by daily protein logs completed throughout the 3 week period and compared with a two-tailed, paired t test.
  • cognitive function assessed by neuropsychological tests [ Time Frame: 3 weeks on each dietary treatment ]
    Each subject will be given neuropsychological tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Delis Kaplan Executive Function System (D-KEFS) to assess specific components of attention and executive function at the end of the glycomacropeptide and amino acid dietary treatments.
Current Other Pre-specified Outcome Measures
 (submitted: February 28, 2017)
Bone Mineral Density Determined by Dual-energy X-ray Absorptiometry (DXA) Scan [ Time Frame: once during first 3 week dietary treatment ]
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Study of Glycomacropeptide Versus Amino Acid Diet for Management of Phenylketonuria
Official Title  ICMJE Phase 2 Study of Glycomacropeptide vs. Amino Acid Diet for the Management of PKU
Brief Summary 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 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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)
Primary Purpose: Treatment
Condition  ICMJE Phenylketonuria
Intervention  ICMJE
  • Other: GMP Diet/GMP Medical Foods
    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.
    Other Names:
    • GMP Medical Foods
    • Glytactin trademark of Cambrooke Therapeutics,LLC
  • Other: AA Diet/AA Medical Foods
    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.
    Other Name: AA Medical Foods
Study Arms  ICMJE
  • Experimental: GMP Diet/GMP Medical Foods
    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.
    Intervention: Other: AA Diet/AA Medical Foods
  • Active Comparator: AA Diet/AA Medical Foods
    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.
    Intervention: Other: GMP Diet/GMP Medical Foods
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 28, 2017)
32
Original Estimated Enrollment  ICMJE
 (submitted: September 1, 2011)
30
Actual Study Completion Date  ICMJE May 2016
Actual Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01428258
Other Study ID Numbers  ICMJE H-2010-0165
1R01FD003711-01A1 ( U.S. FDA Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Wisconsin, Madison
Study Sponsor  ICMJE University of Wisconsin, Madison
Collaborators  ICMJE Boston Children’s Hospital
Investigators  ICMJE
Study Director: Denise M Ney, PhD, RD Professor of Nutritional Sciences, University of Wisconsin-Madison
PRS Account University of Wisconsin, Madison
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP