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

NCT01428258 | Completed Results DMC

• 2 other identifiers: H-2010-01651R01FD003711-01A1
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

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.

Conditions

Phenylketonuria

Keywords

Diet therapy; Low phenylalanine diet; Attention; Executive function

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Dietary Compliance

  3 week dietary treatment

• Executive Function Assessed by BRIEF

  day 22 of each dietary treatment

• Vitamin D (25-OH) Plasma Concentration at Day 22

  day 22 of each dietary treatment

• Comparison of Phe Concentrations in Plasma With Concentrations in Dried Blood Spots

  4 times total, 2 per treatment

• Bone-specific Alkaline Phosphatase (BSAP) Plasma Concentration at Day 22

  day 22 of each dietary treatment

Other Outcomes (1)

• Bone Mineral Density Determined by Dual-energy X-ray Absorptiometry (DXA) Scan

  once during first 3 week dietary treatment

Study Arms (2)

GMP Diet/GMP Medical Foods

EXPERIMENTAL

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

AA Diet/AA Medical Foods

ACTIVE COMPARATOR

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

Interventions

GMP Diet/GMP Medical Foods OTHER

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.

Also known as: GMP Medical Foods, Glytactin trademark of Cambrooke Therapeutics,LLC

AA Diet/AA Medical Foods

AA Diet/AA Medical Foods OTHER

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.

Also known as: AA Medical Foods

GMP Diet/GMP Medical Foods

Eligibility Criteria

• Age: 12 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• Boston Children's Hospital: collaborator

Study Sites (2)

Children's Hospital of Boston

Boston, Massachusetts, 02115, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53706, United States

Location

Related Publications (13)

• 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.

  PMID: 19244369 BACKGROUND

• 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.

  PMID: 18956251 BACKGROUND

• 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.

  PMID: 18203898 BACKGROUND

• 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.

  PMID: 20466571 BACKGROUND

• 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.

  PMID: 19490325 BACKGROUND

• 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.

  PMID: 27413125 RESULT

• 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.

  PMID: 27014575 RESULT

• 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.

  PMID: 28400091 RESULT

• 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.

  PMID: 28664173 RESULT

• 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.

  PMID: 28546877 RESULT

• 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.

  PMID: 29464117 RESULT

• 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.

  PMID: 29490096 RESULT

• 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.

  PMID: 30023287 RESULT

Related Links

• National PKU Alliance

MeSH Terms

Conditions

Phenylketonurias

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

The trial was completed as planned with an adequate number of subjects and there were no limitations.

Results Point of Contact

• Title: Dr. Denise M Ney
• Organization: University of Wisconsin-Madison

ney@nutrisci.wisc.edu

608-262-4386

Study Officials

• Denise M Ney, PhD, RD

  Professor of Nutritional Sciences, University of Wisconsin-Madison

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 31, 2011
• First Posted: September 2, 2011
• Study Start: September 1, 2011
• Primary Completion: November 1, 2015
• Study Completion: May 1, 2016
• Last Updated: August 24, 2018
• Results First Posted: March 3, 2017

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)