Clinical trial NCT01428258: Phase 2 Study of Glycomacropeptide Versus Amino Acid Diet for Management of Phenylketonuria
Official title: Phase 2 Study of Glycomacropeptide vs. Amino Acid Diet for the Management of PKU
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Phenylketonuria
Keywords: Diet therapy
Low phenylalanine diet
Attention
Executive function
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: Boston Children's Hospital
First posted: 2011-09-02
Enrollment: 32
Sex: ALL
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in the Plasma Phenylalanine Concentration of PKU Subjects Fed the Glycomacropeptide Diet Compared With the Change When Fed the Amino Acid Diet
timeFrame: baseline to day 22 on each diet
Secondary outcomes:
measure: Dietary Compliance
timeFrame: 3 week dietary treatment
measure: Executive Function Assessed by BRIEF
timeFrame: day 22 of each dietary treatment
measure: Vitamin D (25-OH) Plasma Concentration at Day 22
timeFrame: day 22 of each dietary treatment
measure: Comparison of Phe Concentrations in Plasma With Concentrations in Dried Blood Spots
timeFrame: 4 times total, 2 per treatment
measure: Bone-specific Alkaline Phosphatase (BSAP) Plasma Concentration at Day 22
timeFrame: day 22 of each dietary treatment
measure: N-terminal Telopeptide (NTX) Plasma Concentration at Day 22
timeFrame: day 22 of each dietary treatment
Other outcomes:
measure: Bone Mineral Density Determined by Dual-energy X-ray Absorptiometry (DXA) Scan
timeFrame: once during first 3 week dietary treatment
Locations:
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: Professor of Nutritional Sciences, University of Wisconsin-Madison
name: Denise M Ney, PhD, RD
role: STUDY_DIRECTOR
References:
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.
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.
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. doi: 10.1093/jn/138.2.316.
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.
citation: 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.
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 Jul 13.
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 Metab Rep. 2016 Jan 16;6:21-6. doi: 10.1016/j.ymgmr.2016.01.001. eCollection 2016 Mar.
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 Genet Metab. 2017 Jun;121(2):96-103. doi: 10.1016/j.ymgme.2017.04.003. Epub 2017 Apr 6.
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 with phenylketonuria. Data Brief. 2017 Jun 7;13:377-384. doi: 10.1016/j.dib.2017.06.004. eCollection 2017 Aug.
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 Phenylketonuria. J Nutr Metab. 2017;2017:1909101. doi: 10.1155/2017/1909101. Epub 2017 May 4.
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 Glycomacropeptide Medical Foods. J Nutr Metab. 2017;2017:6859820. doi: 10.1155/2017/6859820. Epub 2017 Dec 31.
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/nxx039.
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.