NCT01617070

Brief Summary

This study examines the effect of tetrahydrobiopterin (Kuvan) and Large Neutral Amino Acid (LNAA) therapy on melatonin and dopamine levels in individuals with Phenylketonuria (PKU). The investigators hypothesize that Kuvan therapy will improve melatonin secretion and urine dopamine levels to some extent. However significantly greater responses in melatonin and dopamine secretions may be observed with combined treatment with Kuvan and supplementation of LNAA.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
10

participants targeted

Target at below P25 for phase_4

Timeline
Completed

Started May 2012

Typical duration for phase_4

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 1, 2012

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

June 8, 2012

Completed
4 days until next milestone

First Posted

Study publicly available on registry

June 12, 2012

Completed
2.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2014

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2014

Completed
2 years until next milestone

Results Posted

Study results publicly available

November 18, 2016

Completed
Last Updated

November 18, 2016

Status Verified

November 1, 2016

Enrollment Period

2.6 years

First QC Date

June 8, 2012

Results QC Date

November 8, 2016

Last Update Submit

November 8, 2016

Conditions

Phenylketonuria (PKU)

Keywords

TetrahydrobiopterinKuvanPhenylketonuria (PKU)Large Neutral Amino AcidsSerotoninDopamineMelatonin

Outcome Measures

Primary Outcomes (3)

  • Serum Melatonin at the End of 4 Weeks

    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)

    measured every 4 weeks up to 16 weeks

  • Urine 6-sulfatoxymelatonin at the End of 4 Weeks

    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)

    measured every 4 weeks up to 16 weeks

  • Urine Dopamine at the End of 4 Weeks

    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)

    measured every 4 weeks up to 16 weeks

Study Arms (1)

LNAA, washout, Kuvan, and LNAA+Kuvan

EXPERIMENTAL

One group of 12 subjects, each under 4 conditions (each phase is 4 weeks)

Drug: KuvanDietary Supplement: Large Neutral Amino Acid Therapy

Interventions

KuvanDRUG

Dosed at 20 mg/kg; PO; Phase 3, Phase 4

Also known as: Tetrahydrobiopterin
LNAA, washout, Kuvan, and LNAA+Kuvan
Large Neutral Amino Acid TherapyDIETARY_SUPPLEMENT

Dosed by weight: weight x .5 = total tablets per day; PO; Phase 1, Phase 4; taken with food

Also known as: LNAA
LNAA, washout, Kuvan, and LNAA+Kuvan

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Adult English-speaking patients who have confirmed PKU, and have tolerated Kuvan therapy at 20 mg/kg/day in the past, and are currently on the LNAA supplements will be considered as candidates for the study.
  • Subjects must be able to stop LNAA therapy for 4 weeks.
  • This will be determined by the subjects themselves, based on their past personal experiences.

You may not qualify if:

  • Individuals who have never taken Kuvan, who have never been on LNAA therapy, who are under the age of 18, or who do not speak English will be excluded.
  • Subjects who cannot stop LNAA therapy for 4 weeks will be excluded.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Keck School of Medicine, Clinical Trials Unit at Keck Medical Center of USC

Los Angeles, California, 90033, United States

Location

Related Publications (7)

  • Kaufman S, Kapatos G, McInnes RR, Schulman JD, Rizzo WB. Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain. Pediatrics. 1982 Sep;70(3):376-80.

    PMID: 7110811BACKGROUND

  • Schindeler S, Ghosh-Jerath S, Thompson S, Rocca A, Joy P, Kemp A, Rae C, Green K, Wilcken B, Christodoulou J. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab. 2007 May;91(1):48-54. doi: 10.1016/j.ymgme.2007.02.002. Epub 2007 Mar 23.

    PMID: 17368065BACKGROUND

  • Lou H. Large doses of tryptophan and tyrosine as potential therapeutic alternative to dietary phenylalanine restriction in phenylketonuria. Lancet. 1985 Jul 20;2(8447):150-1. doi: 10.1016/s0140-6736(85)90250-8. No abstract available.

    PMID: 2862338BACKGROUND

  • Nielsen JB, Lou H, Güttler F. Effects of diet discontinuation and dietary tryptophan supplementation on neurotransmitter metabolism in phenylketonuria. Brain Dysfunction 1:51-56. 1988.

    BACKGROUND

  • Zimmermann RC, McDougle CJ, Schumacher M, Olcese J, Heninger GR, Price LH. Urinary 6-hydroxymelatonin sulfate as a measure of melatonin secretion during acute tryptophan depletion. Psychoneuroendocrinology. 1993;18(8):567-78. doi: 10.1016/0306-4530(93)90034-i.

    PMID: 8127947BACKGROUND

  • Katz I, Lloyd T, Kaufman S. Studies on phenylalanine and tyrosine hydroxylation by rat brain tyrosine hydroxylase. Biochim Biophys Acta. 1976 Oct 11;445(3):567-78. doi: 10.1016/0005-2744(76)90111-x.

    PMID: 9989BACKGROUND

  • Yano S, Moseley K, Fu X, Azen C. Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters. PLoS One. 2016 Aug 11;11(8):e0160892. doi: 10.1371/journal.pone.0160892. eCollection 2016.

    PMID: 27513937RESULT

MeSH Terms

Conditions

Phenylketonurias

Interventions

sapropterin

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, InbornBrain Diseases, MetabolicBrain DiseasesCentral Nervous System DiseasesNervous System DiseasesAmino Acid Metabolism, Inborn ErrorsMetabolism, Inborn ErrorsGenetic Diseases, InbornCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesMetabolic DiseasesNutritional and Metabolic Diseases

Results Point of Contact

Title
Shoji Yano
Organization
USC/Keck School of Medicine
syano@usc.edu
323-226-3816

Study Officials

  • Shoji Yano, M.D., Ph.D.

    USC Keck School of Medicine, Dept. of Pediatrics, Genetics Division

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
Yes

Study Design

Study Type
interventional
Phase
phase 4
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
M.D., Ph.D

Study Record Dates

First Submitted

June 8, 2012

First Posted

June 12, 2012

Study Start

May 1, 2012

Primary Completion

December 1, 2014

Study Completion

December 1, 2014

Last Updated

November 18, 2016

Results First Posted

November 18, 2016

Record last verified: 2016-11

Locations

US(1)