PhenylketonuriaNCT01869972
Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
An observational study of Phenylketonuria and Hyperphenylalaninemia, run by Hamilton Health Sciences Corporation at 2 sites in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 4 years and older
- Conditions the study is for
- Phenylketonuria, Hyperphenylalaninemia
- How many people
- 32 participants
- Where
- 2 sitesCanada
- Study dates
- May 2013to Dec 2015
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Metabolic and/or PKU clinic
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
2 sites in 1 country.
Canada2 sites
McMaster Children's Hospital
Hamilton, Ontario, L8S 4J9
Children's Hospital of Eastern Ontario
Ottawa, Ontario, K1H 8L1
About this study
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.
Read the detailed description
Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme phenylalanine hydroxylase, (PAH, Enzyme Classification 1.14.16.1). 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.
OBJECTIVES:
Determine short-term biologic variation in people with hyperphenylalaninemia, with and without KuvanTM therapy.
- Conditions
- Phenylketonuria, Hyperphenylalaninemia
- Keywords
- PKU, phenylketonuria, hyperphenylalaninemia, Kuvan, sapropterin
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Standard deviation of blood phenylalanine level (sdPHE)
16 to 17 blood phenylalanine levels will be measured over 24 hours. The standard deviation of those measurements will be the sdPHE.
Measured: 24 hour period
Secondary outcomes (2)
Peak phenylalanine level
The highest blood phenylalanine level in the 24 hour period
Measured: 24 hour
peak phenylalanine / tyrosine ratio
The highest blood phenylalanine / tyrosine ratio, with phenylalanine and tyrosine measured on the same sample
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2013 (estimated)
- Study startMay 2013
- Primary completionDec 2015
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PhenylketonuriaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hamilton Health Sciences Corporation
- Sponsor type
- University, hospital or other
- Collaborators
- McMaster Children's Hospital, Children's Hospital of Eastern Ontario, BioMarin Pharmaceutical
- Responsible party
- Sponsor
- Investigators
- Murray Potter, MD, Principal investigator, Hamilton Health Sciences Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01869972
- Sponsor's protocol ID
- PKUvar-01
- Status last verified
- Dec 2015
- First submitted
- 3 Jun 2013
- Last updated
- 11 Dec 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
- ClinicalTrials.gov ID
- NCT01869972
- Acronym / sponsor ID
- PKUvar-01
- Conditions
- Phenylketonuria, Hyperphenylalaninemia
- Keywords
- PKU, phenylketonuria, hyperphenylalaninemia, Kuvan, sapropterin
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- Hamilton Health Sciences CorporationUniversity, hospital or other
- Collaborators
- McMaster Children's Hospital, Children's Hospital of Eastern Ontario, BioMarin Pharmaceutical
- Study start
- May 2013
- Primary completion
- Dec 2015 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 5 Jun 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme phenylalanine hydroxylase, (PAH, Enzyme Classification 1.14.16.1). 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.
OBJECTIVES:
Determine short-term biologic variation in people with hyperphenylalaninemia, with and without KuvanTM therapy.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 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). |
Who may qualify
- Ages
- 4 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Metabolic and/or PKU clinic
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (4 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
2 secondary outcomes
Peak phenylalanine level
Time frame: 24 hour
peak phenylalanine / tyrosine ratio
Time frame: 24 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Murray Potter, MD principal investigator
Hamilton Health Sciences Corporation
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Phenylketonuria and Hyperphenylalaninemia, run by Hamilton Health Sciences Corporation at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Dec 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Standard deviation of blood phenylalanine level (sdPHE) (time frame: 24 hour period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2015.