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Response to Phenylketonuria to Tetrahydrobiopterin (BH4)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified January 2009 by FDA Office of Orphan Products Development.
Recruitment status was:  Recruiting
Information provided by:
FDA Office of Orphan Products Development Identifier:
First received: October 25, 2005
Last updated: January 15, 2009
Last verified: January 2009
The purpose of this study is to determine whether tetrahydrobiopterin (BH4)is effective in treating patients with PKU.

Condition Intervention Phase
Drug: tetrahydrobiopterin (BH4)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double Blind (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Response to Phenylketonuria to Tetrahydrobiopterin (BH4)

Resource links provided by NLM:

Further study details as provided by FDA Office of Orphan Products Development:

Primary Outcome Measures:
  • Blood Phe level decrease by 30% [ Time Frame: 9 months ]

Estimated Enrollment: 36
Study Start Date: April 2005
Estimated Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: tetrahydrobiopterin (BH4)
    Either placebo or BH4, 10mg/kg/day will be given for three months. Then the patient will be given three additional months of open label BH4 at the same rate.
Detailed Description:

Phenylketonuria(PKU) is an autosomal recessive disorder caused by a defect in the enzyme phenylalanine hydroxylase(PAH). this incidence of PKU in the US is about 1:15,000 births. The disease is pan ethnic with more prevalence among individuals of European ancestry. Recently, a number of patients with PKU showed a marked decrease in their blood Phe levels when the cofactor for PAH, tetrahydrobiopterin (BH4) was given orally. All these patients had mutations in PAH while the metabolism of BH4 was normal. These observations were confirmed by several centers including a pilot study conducted in our institutions. In the study in our centers, we have identified 21 of 36 patients tested who responded favorably to BH4.

Recognizing the difficulties with phenylalanine restricted diet, an NIH Consensus Conference on PKU held in 1999, encouraged exploring different modalities for treating PKU, and BH4 is among these modalities. This proposal is a three year, double blind placebo control, multi-center study. An oral load of 10 mg/kg BH4 wil be given to patients with PKU to identify those that respond with lowering of blood Phe greater or equal to 30%. Blood Phe, tyrosine and dietary intake will be determined at zero time and 24 hours post load. From this group of BH4 responsive individuals, thirty-six will be enrolled in the double blind study. subjects will be randomized to the treatment of placebo group. Those who enter the trial will have zero time assessments including blood Phe and tyrosine, dietary intake, physical exam, kidney function, liver function and CBC. Phe and tyrosine and diet intakes, two prior to the study and the zero time, will be averaged and used as the baseline measures.

The subjects will be assigned randomly to take either 10mg/kg of BH4 orally or a placebo without BH4. Blood Phe, tyrosine and dietary intake will be obtained every other week throughout the 12 week study period. Liver function and kidney function and CBC's will be obtained monthly. Side effects will be evaluated and noted. Subjects will be instructed to record two day diet diaries prior to blood Phe sampling throughout the study. The NIH Consensus Report suggests maintaining blood Phe< 36 umol/l when less than 12 years of age or up to 900 umol/l after 12 years of age. These levels will be used to determine the efficacy end points of the study. At the end of three months, blood Phe and tyrosine, dietary intake, physical exam, kidney function, liver function and CBC will be performed. At this time efficacy of BH4 will be determined and all subjects will continue in an open label 12 weeks BH4 treatment, (10mg/kg/day), with assessments collected as in the first phase of the study. After the subject has had both phases they will be followed for an additional 3 months. The additional 3 month trial on BH4 will provide long term safety data from 18 subjects who took BH4 in both the first and second phase in a continuous fashion.


Ages Eligible for Study:   10 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Subject and/or parent or guardian must be capable of understanding and providing written informed consent
  • Subjects must have Phenylketonuria (PKU)or hyperphenylalaninemia (HPA), defined as baseline blood Phe levels of >600 umol/L
  • Subjects must be at least 10 years of age, and may be of either gender and any ethnic group
  • Female subjects of childbearing potential must agree to use adequate birth control or refrain from sexual activity throughout study participation

Exclusion Criteria:

  • Female subjects who are pregnant or breastfeeding
  • Subjects who have concurrent diseases or conditions that require medication or treatment
  • Subjects who require concomitant treatment with any drug known to inhibit folate synthesis
  • Subjects who have been treated with any investigational drug within 30 days
  Contacts and Locations
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Please refer to this study by its identifier: NCT00244218

Contact: Reuben Matalon, MD, PhD 409-772-3466
Contact: Earma Robinson 409-772-3466

United States, Texas
University of Texas Medical Branch Recruiting
Galveston, Texas, United States, 77555
Contact: Reuben Matalon, MD, PhD    409-772-3466   
Contact: Earma Robinson    409-772-3466   
Principal Investigator: Reuben Matalon, MD, PHD         
Sponsors and Collaborators
FDA Office of Orphan Products Development
Principal Investigator: Reuben Matalon, MD, PhD University of Texas
  More Information

Responsible Party: Reuben Matalon, MD, PhD, Director, Biochemical/Molecular Genetics; Professor, Pediatrics, Biochemistry and Molecular Biology, University of Texas Medical Branch Identifier: NCT00244218     History of Changes
Other Study ID Numbers: FD-R-002600-01
Study First Received: October 25, 2005
Last Updated: January 15, 2009

Keywords provided by FDA Office of Orphan Products Development:

Additional relevant MeSH terms:
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 processed this record on May 22, 2017