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Effects of Kuvan on Melatonin Secretion

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01617070
First Posted: June 12, 2012
Last Update Posted: November 18, 2016
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.
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Shoji Yano, University of Southern California
  Purpose
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.

Condition Intervention Phase
Phenylketonuria (PKU) Drug: Kuvan Dietary Supplement: Large Neutral Amino Acid Therapy Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study to Evaluate Melatonin Secretion as a Marker of Decreased Serotonin in Individuals With PKU: Evaluation of the CNS Effects of Tetrahydrobiopterin

Resource links provided by NLM:


Further study details as provided by Shoji Yano, University of Southern California:

Primary Outcome Measures:
  • Serum Melatonin at the End of 4 Weeks [ Time Frame: measured every 4 weeks up to 16 weeks ]
    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)

  • Urine 6-sulfatoxymelatonin at the End of 4 Weeks [ Time Frame: measured every 4 weeks up to 16 weeks ]
    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)

  • Urine Dopamine at the End of 4 Weeks [ Time Frame: measured every 4 weeks up to 16 weeks ]
    Evaluated for each subject under 4 conditions (washout, LNAA only, Kuvan only and LNAA+Kuvan)


Enrollment: 10
Study Start Date: May 2012
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LNAA, washout, Kuvan, and LNAA+Kuvan
One group of 12 subjects, each under 4 conditions (each phase is 4 weeks)
Drug: Kuvan
Dosed at 20 mg/kg; PO; Phase 3, Phase 4
Other Name: Tetrahydrobiopterin
Dietary Supplement: Large Neutral Amino Acid Therapy
Dosed by weight: weight x .5 = total tablets per day; PO; Phase 1, Phase 4; taken with food
Other Name: LNAA

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01617070


Locations
United States, California
Keck School of Medicine, Clinical Trials Unit at Keck Medical Center of USC
Los Angeles, California, United States, 90033
Sponsors and Collaborators
University of Southern California
BioMarin Pharmaceutical
Investigators
Principal Investigator: Shoji Yano, M.D., Ph.D. USC Keck School of Medicine, Dept. of Pediatrics, Genetics Division
  More Information

Publications:
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.
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.
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. Epub 2007 Mar 23.
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.
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.
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.
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.

Responsible Party: Shoji Yano, M.D., Ph.D, University of Southern California
ClinicalTrials.gov Identifier: NCT01617070     History of Changes
Other Study ID Numbers: USC Kuvan Melatonin
First Submitted: June 8, 2012
First Posted: June 12, 2012
Results First Submitted: November 8, 2016
Results First Posted: November 18, 2016
Last Update Posted: November 18, 2016
Last Verified: November 2016

Keywords provided by Shoji Yano, University of Southern California:
Tetrahydrobiopterin
Kuvan
Phenylketonuria (PKU)
Large Neutral Amino Acids
Serotonin
Dopamine
Melatonin

Additional relevant MeSH terms:
Phenylketonurias
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
Metabolic Diseases
Melatonin
Serotonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents


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