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

Phenylketonuria Clinical Trial

— PKU  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01428258
• Other study ID #: H-2010-0165
• Secondary ID: 1R01FD003711-01A
• Status: Completed
• Phase: N/A
• Start date: September 2011
• Est. completion date: May 2016

Study information

• Verified date: July 2018
• Source: University of Wisconsin, Madison
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: May 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Children's Hospital of Boston	Boston	Massachusetts
United States	University of Wisconsin-Madison	Madison	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	Boston Children’s Hospital

Country where clinical trial is conducted

United States, 

References & Publications (13)

Laclair CE, Ney DM, MacLeod EL, Etzel MR. Purification and use of glycomacropeptide for nutritional management of phenylketonuria. J Food Sci. 2009 May-Jul;74(4):E199-206. doi: 10.1111/j.1750-3841.2009.01134.x. — View Citation

MacLeod EL, Clayton MK, van Calcar SC, Ney DM. Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Mol Genet Metab. 2010 Aug;100(4):303-8. doi: 10.1016/j.ymgme.2010.04.003. Epub 2010 Apr 14. — View Citation

Ney DM, Gleason ST, van Calcar SC, MacLeod EL, Nelson KL, Etzel MR, Rice GM, Wolff JA. Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis. 2009 Feb;32(1):32-9. doi: 10.1007/s10545-008-0952-4. Epub 2008 Oct 29. Review. — View Citation

Ney DM, Hull AK, van Calcar SC, Liu X, Etzel MR. Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria. J Nutr. 2008 Feb;138(2):316-22. — View Citation

Ney DM, Murali SG, Stroup BM, Nair N, Sawin EA, Rohr F, Levy HL. Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Mol Ge — View Citation

Ney DM, Stroup BM, Clayton MK, Murali SG, Rice GM, Rohr F, Levy HL. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr. 2016 Aug;104(2):334-45. doi: 10.3945/ajcn.116.135293. Epub 2016 — View Citation

Stroup BM, Hansen KE, Krueger D, Binkley N, Ney DM. Sex differences in body composition and bone mineral density in phenylketonuria: A cross-sectional study. Mol Genet Metab Rep. 2018 Feb 3;15:30-35. doi: 10.1016/j.ymgmr.2018.01.004. eCollection 2018 Jun. — View Citation

Stroup BM, Held PK, Williams P, Clayton MK, Murali SG, Rice GM, Ney DM. Clinical relevance of the discrepancy in phenylalanine concentrations analyzed using tandem mass spectrometry compared with ion-exchange chromatography in phenylketonuria. Mol Genet M — View Citation

Stroup BM, Murali SG, Nair N, Sawin EA, Rohr F, Levy HL, Ney DM. Dietary amino acid intakes associated with a low-phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects wit — View Citation

Stroup BM, Nair N, Murali SG, Broniowska K, Rohr F, Levy HL, Ney DM. Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria. J Nutr. 2018 Feb 1;148(2):194-201. doi: 10.1093/jn/nxx — View Citation

Stroup BM, Ney DM, Murali SG, Rohr F, Gleason ST, van Calcar SC, Levy HL. Metabolomic Insights into the Nutritional Status of Adults and Adolescents with Phenylketonuria Consuming a Low-Phenylalanine Diet in Combination with Amino Acid and Glycomacropepti — View Citation

Stroup BM, Sawin EA, Murali SG, Binkley N, Hansen KE, Ney DM. Amino Acid Medical Foods Provide a High Dietary Acid Load and Increase Urinary Excretion of Renal Net Acid, Calcium, and Magnesium Compared with Glycomacropeptide Medical Foods in Phenylketonur — View Citation

van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA, Ney DM. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. Am J Clin Nutr. 2009 Apr;89(4):1068-77. doi: 10.3945/ajcn.2008.27280. Epub 2009 Feb 25. Erratum in: Am J Clin Nutr. 2010 Apr;91(4):1072. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Bone Mineral Density Determined by Dual-energy X-ray Absorptiometry (DXA) Scan	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.	once during first 3 week dietary treatment
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Am J Clin Nutri open access article pdf
•   Dept Health and Human Services FDA Orphan Products Development (OPD) Grant Program
•   National PKU Alliance