Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia

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Recruitment Status : Completed
First Posted : June 5, 2013
Last Update Posted : December 11, 2015
McMaster Children's Hospital
Children's Hospital of Eastern Ontario
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Hamilton Health Sciences Corporation

Brief Summary:

Phenylketonuria (PKU) is a rare disease where the level of phenylalanine (one of the amino acids) in the body is greatly increased. High levels can cause brain damage, especially in babies and children. This brain damage can be prevented if a special low phenylalanine diet is started soon after birth. A new drug, sapropterin, can also lower phenylalanine levels in some patients. PKU therapy is monitored by measuring the blood phenylalanine every week, with the goal to keep the level within a target range. Recently, studies have suggested that the variation in the blood phenylalanine may be just as important as the absolute blood phenylalanine level for brain outcome.

The investigators will look at the variation in blood phenylalanine level over 24 hours to see how much the level changes. The investigators will measure this in patients with typical PKU who are compliant with the diet and in patients who are not compliant with the diet. The investigators will also measure this in patients with "mild" PKU who do not usually have as high levels of phenylalanine. Finally, the investigators will see if patients on sapropterin have lower variation.

Condition or disease
Phenylketonuria Hyperphenylalaninemia

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Detailed Description:

Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme phenylalanine hydroxylase, (PAH, Enzyme Classification A deficiency of this enzyme leads to elevated blood and tissue levels of the amino acid phenylalanine upon exposure to normal amounts of dietary protein. The elevated phenylalanine in the brain is harmful to cognitive development, usually resulting in permanent severe mental retardation. Soon after the development of a special dietary treatment for PKU and of a simple screening test to detect elevated phenylalanine, newborn screening for PKU became widespread and early detection and treatment largely prevented the severe neurological effects of PKU.

With population-based detection of hyperphenylalaninemia, it soon became apparent that there was significant biological variation of phenylalanine levels between patients (i.e. inter-individual biological variation) with phenylketonuria (PKU) and this now forms part of the classification system for hyperphenylalaninemia (i.e. benign hyperphenylalaninemia, mild, moderate or classical phenylketonuria). While variations of the classification system exist, most commonly "classical" PKU refers to individuals with plasma phenylalanine levels greater than 1200 µmol/L on an unrestricted diet. "Moderate" PKU refers to levels between 900 and 1200 µmol/L, while "mild" PKU refers to levels between 600 and 900 µmol/L. "Non-PKU" or "benign" hyperphenylalaninemia refers to phenylalanine levels less than 600 µmol/L on an unrestricted diet, that while greater than normal phenylalanine levels (< 100 µmol/L), historically have not been prescribed dietary restriction of phenylalanine. This inter-individual variation is generally due to variable residual enzyme activity and genotype in PKU patients.

Intra-individual variation (the changes of phenylalanine levels in one individual) has been observed by all clinicians who treat PKU. While some of this variation is simply the expression of the underlying genotype when a patient's dietary phenylalanine level exceeds prescribed amounts (i.e. "cheating" on their diet), other variation represents shifts from anabolic to catabolic states in a diurnal pattern or during intercurrent illness. While overall exposure to high phenylalanine has long been known to adversely affect IQ scores, recently increased variability in phenylalanine levels has been reported to be linked to lower IQ, highlighting the importance of improving our understanding of intra-individual variation.

New treatments for PKU, therefore, need to be assessed in terms of their effect on biological variation of phenylalanine. Sapropterin dihydrochloride (KuvanTM) is a small molecule drug that can lower phenylalanine levels in patients with phenylalanine hydroxylase deficiency by a direct interaction with the enzyme . The pharmacokinetics of KuvanTM have been evaluated in adults and are undergoing evaluation in pediatric patients, however, the biological effect of KuvanTM in terms of lowering of blood phenylalanine levels would be expected to have a longer profile than the blood levels of the drug itself because the half-life of the activated enzyme would be longer. This suggests that KuvanTM may have a modulating effect on variation of blood phenylalanine levels in PKU patients.

In this observational study, the investigators will directly measure the short-term biological variation of blood phenylalanine in hyperphenylalaninemic patients by frequent measurements of phenylalanine levels over a 24 hour period. The investigators will enroll subjects already followed at one of the two study sites who are treated by diet alone or who are treated with KuvanTM therapy (+/- diet). During the 24 hour period subjects will be asked to maintain their typical diet/therapy.

Hypothesis: Biological variation will be less in KuvanTM treated patients than in classical phenylketonuria treated by diet alone.


Determine short-term biologic variation in people with hyperphenylalaninemia, with and without KuvanTM therapy.

Study Type : Observational
Actual Enrollment : 32 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
Study Start Date : May 2013
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015

Wide PHE group
Subjects prescribed diet alone to treat their PKU who have >1/3 of monitoring phenylalanine levels (with at least 3 levels measured) outside the target treatment range in the 6 months preceding enrolment. Target therapeutic range is 120 - 360 umol/L for age <12 years and 120 - 600 umol/L for age ≥ 12 years.
Target PHE group
Subjects prescribed diet alone to treat their PKU who have ≤ 1/3 of monitoring phenylalanine levels (with at least 3 levels measured) outside the target treatment range in the 6 months preceding enrolment. Target therapeutic range is 120 - 360 umol/L for age <12 years and 120 - 600 umol/L for age ≥ 12 years.
Kuvan(TM) group
Subjects on Kuvan(TM) (any dose for at least 3 months with no dosage change for most recent 1 month) ± diet therapy
Control group
Subjects with non-PKU hyperphenylalaninemia (maximum phenylalanine level 120 - 599 umol/L on no therapy).

Primary Outcome Measures :
  1. Standard deviation of blood phenylalanine level (sdPHE) [ Time Frame: 24 hour period ]
    16 to 17 blood phenylalanine levels will be measured over 24 hours. The standard deviation of those measurements will be the sdPHE.

Secondary Outcome Measures :
  1. Peak phenylalanine level [ Time Frame: 24 hour ]
    The highest blood phenylalanine level in the 24 hour period

  2. peak phenylalanine / tyrosine ratio [ Time Frame: 24 hours ]
    The highest blood phenylalanine / tyrosine ratio, with phenylalanine and tyrosine measured on the same sample

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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Metabolic and/or PKU clinic

Inclusion Criteria:

• Subjects ≥4 years of age with hyperphenylalaninemia. Must have at least 1 documented blood phenylalanine level >600 µmol/L for study groups (Wide PHE, Target PHE, Kuvan groups) or >120 µmol/L for control group.

Exclusion Criteria:

  • Significant cognitive impairment (IQ <70 or clinical judgment).
  • Pregnancy
  • Other specific PKU therapies, including enzyme replacement therapy or any amino acid supplement designed to block uptake or transport of phenylalanine (i.e. large neutral amino acid mixtures)
  • Any intercurrent illness within the previous 5 days (any of fever, vomiting, diarrhea, decreased intake, upper respiratory tract infection).

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 identifier (NCT number): NCT01869972

Canada, Ontario
McMaster Children's Hospital
Hamilton, Ontario, Canada, L8S 4J9
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada, K1H 8L1
Sponsors and Collaborators
Hamilton Health Sciences Corporation
McMaster Children's Hospital
Children's Hospital of Eastern Ontario
BioMarin Pharmaceutical
Principal Investigator: Murray Potter, MD Hamilton Health Sciences Corporation

Responsible Party: Hamilton Health Sciences Corporation Identifier: NCT01869972     History of Changes
Other Study ID Numbers: PKUvar-01
First Posted: June 5, 2013    Key Record Dates
Last Update Posted: December 11, 2015
Last Verified: December 2015

Keywords provided by Hamilton Health Sciences Corporation:

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