PhenylketonuriaPhase 3PKU-015NCT00838435
Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
A Phase 3 study testing sapropterin dihydrochloride in people with Phenylketonuria, run by BioMarin Pharmaceutical at 19 sites in 2 countries.
Trial summary
This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old. Read more about this study
- Who is it for?
- Ages Up to 6 years
- Conditions the study is for
- Phenylketonuria
- What is being tested?
- sapropterin dihydrochloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 95 participants
- Where
- 19 sitesin 2 countries
- Study dates
- Feb 2009to 14 Sep 2018
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 Up to 6 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Established diagnosis of PKU with hyperphenylalaninemia (HPA) documented in the medical record by at least 2 blood Phe concentrations greater than or equal to 360 micromole/L (6 mg/dL) taken at least 3 days apart
- Documented blood Phe control (defined by the standard used at each treatment center) prior to study enrollment, if applicable (eg, the subject is old enough for these data to be collected); blood Phe concentrations for subjects < 6 months old at Screening must be considered controlled and stable by the Investigator
- Willing to adhere to a prescribed Phe restricted diet in order to maintain blood Phe concentrations within the recommended ranges established at the subject's study site
- Age 0 to 6 years old, inclusive, at Screening
- Parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
- Parent(s) or guardian(s) willing and able to comply with all study procedures
- Female subjects of childbearing potential (as determined by the investigator) and sexually mature male subjects willing to use a medically accepted method of contraception throughout the study. Female subjects of childbearing potential willing to undergo periodic pregnancy tests during the course of the study
Who cannot join
- Established diagnosis of primary tetrahydrobiopterin (BH4) deficiency
- Known hypersensitivity to Kuvan or its excipients
- History of organ transplantation
- Perceived to be unreliable or unavailable for study participation or to have parents or legal guardians who are perceived to be unreliable or unavailable
- Use of methotrexate or other medications that inhibit folate metabolism
- Serious neuropsychiatric illness (eg, major depression) not currently under medical control
Show all 10Show fewer
- Use of Kuvan or any investigational agent within 30 days prior to Screening, or known requirement for any investigational agent prior to completion of all scheduled study assessments
- Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin dependent diabetes)
- Any condition that, in the view of the Principal Investigator (PI), renders the subject at high risk for failure to comply with treatment or to complete the study
- Use of phosphodiesterase type 5 (PDE5) inhibitor.
Trial locations and contacts
19 sites in 2 countries.
19 sites in 2 countries
United States12 sites
Study site
Boston, Massachusetts
Study site
Chicago, Illinois
Study site
Cleveland, Ohio
Study site
Columbus, Ohio
Study site
Hershey, Pennsylvania
Study site
Kansas City, Missouri
Study site
La Jolla, California
Study site
Milwaukee, Wisconsin
Study site
Nashville, Tennessee
Study site
Orange, California
Study site
Salt Lake City, Utah
Study site
Tampa, Florida
Canada7 sites
Study site
Edmonton, Alberta
Study site
Hamilton, Ontario
Study site
Montreal, Quebec
Study site
Sainte-Foy, Quebec
Study site
Toronto, Ontario
Study site
Vancouver, British Columbia
Study site
Winnipeg, Manitoba
About this study
Official title: A Phase 3b Open-Label Study to Evaluate the Effect of Kuvan® on Neurocognitive Function, Maintenance of Blood Phenylalanine Concentrations, Safety, and Population Pharmacokinetics in Young Children With Phenylketonuria
This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old.
Read the detailed description
Rigorous control of diet is typically advocated in children 4 years and under with PKU because brain sensitivity to high Phe concentrations is expected to be greatest during these years of rapid neurocognitive development.
Prolonged high blood Phe concentrations are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe concentrations through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe concentrations in patients with PKU has been shown to decrease the long term risk of neurologic injury.
It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.
The strongest determinant of intelligence quotient (IQ) and cognitive function is compliance with blood Phe control. Several clinical studies with Kuvan have already demonstrated efficacy in reducing blood Phe in subjects older than 4 years. This study will examine whether addition of Kuvan to the standard of care at an early age in children with well controlled diets can lower blood Phe levels (ie, reach and maintain a goal of ≤ 240 micromole/L) and preserve neurocognitive functioning. In addition, this study will provide data on Kuvan exposure, rate of uptake, half life, and clearance in young children.
- Conditions
- Phenylketonuria
- Being tested
- sapropterin dihydrochloride
- Keywords
- Phenylketonuria, PKU, Kuvan, Phenoptin, Biopten, Neurocognitive Function, Phenylalanine
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
sapropterin dihydrochlorideDrug
Also called Kuvan, Phenoptin, BH4, 6R BH4
A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.
| Study group | Role | What they receive |
|---|---|---|
| sapropterin dihydrochloride | Experimental | A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food. Receives: Drug: sapropterin dihydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
Full-Scale Intelligence Quotient (FSIQ) Score
Full Scale Intelligence Quotient (FSIQ) is a score derived through administration of selected subtests from age appropriate Wechsler Intelligence assessments. Weschler Preschool and Primary Scale of Intelligence (WPPSI)-III is used for children >30 months and ≤6 years; and Weschler Intelligence Scale for Children (WISC)-IV is used for children >6 years old. The outcome variable will be the FSIQ score from WPPSI-III and/or WISC-IV tests.
FSIQ results can range from 40 being the lowest and 160 being the highest. Higher scores are associated with higher intelligence quotient.
Measured: Assessments through 84 months.
Secondary outcomes (9)
Number of Subjects With Adverse Events (AEs)
Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, and that does not necessarily have a causal relationship with this treatment.
Drug Related Adverse all noxious and unintended responses to a medical product related to any dose. This means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled out.
A serious adverse event (SAE) is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Measured: Up to 7 years
Change From Baseline in Growth Measurements - Height Z-Scores
Z-scores of Height determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older.
A height z-score is a standardized height measure after considering important factors like age and gender, in which higher z-scores are associated with taller children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of standard deviation (SD) unit above the 50%; and a negative value is a factor of SD unit below 50%.
Measured: Baseline and up to 84 months
Change From Baseline in Growth Measurements - Weight Z-Scores
Z-scores of Weight determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months or older.
A weight z-score is a standardized weight measure after considering important factors like age and gender, in which higher z-scores are associated with heavier children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.
Measured: Baseline and up to 84 months
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Z-scores of Head Circumference determined using World Health Organization(WHO) growth charts for children <24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older.
A head circumference z-score is a standardized head circumference measure after considering important factors like age and gender, in which higher z-scores are associated with children with larger heads. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.
Measured: Baseline and up to 84 months
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
The Bayley-III is a tool for assessing all facets of development in infants within an age range of 12 to 30 months, with normative data available for infants as young as 16 days. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a range of 40 to 160. Higher scores are a better outcome.
Measured: At Month 6, 12, 18 and 24
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Baseline concentration of BH4(C0) with associated inter-individual variability.
Measured: At predose and postdose - 0.22, 3.2 and 7 hours
Absorption Rate Constant (Ka) of Kuvan
Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Measured: At predose and postdose - 0.22, 3.2 and 7 hours
Apparent Volume of Distribution (V/F) of Kuvan
Population pharmacokinetic parameter apparent volume of distribution (V/F)
Measured: At predose and postdose - 0.22, 3.2 and 7 hours
Apparent Clearance (CL/F) of Kuvan
Population pharmacokinetic parameter apparent clearance (CL/F)
Measured: At predose and postdose - 0.22, 3.2 and 7 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2009 (estimated)
- Study startFeb 2009
- Primary completion14 Sep 2018
- Study completion14 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for PhenylketonuriaStudies of the same condition, open and under way.
- More trials run by BioMarin PharmaceuticalThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 95 participants (actual)
Sponsor and investigators
- Lead sponsor
- BioMarin Pharmaceutical
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Joshua Lilienstein, M.D., Study director, BioMarin Pharmaceutical
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00838435
- Sponsor's protocol ID
- PKU-015
- Acronym
- PKU-015
- Status last verified
- Dec 2020
- First submitted
- 5 Feb 2009
- Last updated
- 22 Dec 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 3b Open-Label Study to Evaluate the Effect of Kuvan® on Neurocognitive Function, Maintenance of Blood Phenylalanine Concentrations, Safety, and Population Pharmacokinetics in Young Children With Phenylketonuria
- ClinicalTrials.gov ID
- NCT00838435
- Acronym / sponsor ID
- PKU-015 / PKU-015
- Conditions
- Phenylketonuria
- Keywords
- Phenylketonuria, PKU, Kuvan, Phenoptin, Biopten, Neurocognitive Function, Phenylalanine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 95 participants (actual)
- Lead sponsor
- BioMarin PharmaceuticalIndustry (pharma, biotech, devices)
- Study start
- Feb 2009
- Primary completion
- 14 Sep 2018 (actual)
- Study completion
- 14 Sep 2018 (actual)
- First posted
- 6 Feb 2009 (estimated)
- Results
- Posted 22 Dec 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old.
Detailed description
Rigorous control of diet is typically advocated in children 4 years and under with PKU because brain sensitivity to high Phe concentrations is expected to be greatest during these years of rapid neurocognitive development.
Prolonged high blood Phe concentrations are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe concentrations through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe concentrations in patients with PKU has been shown to decrease the long term risk of neurologic injury.
It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.
The strongest determinant of intelligence quotient (IQ) and cognitive function is compliance with blood Phe control. Several clinical studies with Kuvan have already demonstrated efficacy in reducing blood Phe in subjects older than 4 years. This study will examine whether addition of Kuvan to the standard of care at an early age in children with well controlled diets can lower blood Phe levels (ie, reach and maintain a goal of ≤ 240 micromole/L) and preserve neurocognitive functioning. In addition, this study will provide data on Kuvan exposure, rate of uptake, half life, and clearance in young children.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| sapropterin dihydrochloride | Experimental | Drug: sapropterin dihydrochlorideA dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food. |
Who may qualify
- Ages
- Up to 6 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (7 listed)
- Established diagnosis of PKU with hyperphenylalaninemia (HPA) documented in the medical record by at least 2 blood Phe concentrations greater than or equal to 360 micromole/L (6 mg/dL) taken at least 3 days apart
- Documented blood Phe control (defined by the standard used at each treatment center) prior to study enrollment, if applicable (eg, the subject is old enough for these data to be collected); blood Phe concentrations for subjects < 6 months old at Screening must be considered controlled and stable by the Investigator
- Willing to adhere to a prescribed Phe restricted diet in order to maintain blood Phe concentrations within the recommended ranges established at the subject's study site
- Age 0 to 6 years old, inclusive, at Screening
- Parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures
Key exclusion criteria (10 listed)
- Established diagnosis of primary tetrahydrobiopterin (BH4) deficiency
- Known hypersensitivity to Kuvan or its excipients
- History of organ transplantation
- Perceived to be unreliable or unavailable for study participation or to have parents or legal guardians who are perceived to be unreliable or unavailable
- Use of methotrexate or other medications that inhibit folate metabolism
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| sapropterin dihydrochlorideAlso: Kuvan, Phenoptin, BH4, 6R BH4A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food. | Drug | sapropterin dihydrochloride |
Primary outcome
Full-Scale Intelligence Quotient (FSIQ) Score
Time frame: Assessments through 84 months.
Full Scale Intelligence Quotient (FSIQ) is a score derived through administration of selected subtests from age appropriate Wechsler Intelligence assessments. Weschler Preschool and Primary Scale of Intelligence (WPPSI)-III is used for children >30 months and ≤6 years; and Weschler Intelligence Scale for Children (WISC)-IV is used for children >6 years old. The outcome variable will be the FSIQ score from WPPSI-III and/or WISC-IV tests. FSIQ results can range from 40 being the lowest and 160 being the highest. Higher scores are associated with higher intelligence quotient.
9 secondary outcomes
Number of Subjects With Adverse Events (AEs)
Time frame: Up to 7 years
Change From Baseline in Growth Measurements - Height Z-Scores
Time frame: Baseline and up to 84 months
Change From Baseline in Growth Measurements - Weight Z-Scores
Time frame: Baseline and up to 84 months
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Time frame: Baseline and up to 84 months
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Time frame: At Month 6, 12, 18 and 24
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Absorption Rate Constant (Ka) of Kuvan
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Apparent Volume of Distribution (V/F) of Kuvan
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Apparent Clearance (CL/F) of Kuvan
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Dec 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Joshua Lilienstein, M.D. study director
BioMarin Pharmaceutical
19 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing sapropterin dihydrochloride in people with Phenylketonuria, run by BioMarin Pharmaceutical at 19 sites in 2 countries.
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 7 inclusion and 10 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 22 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States, 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.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Full-Scale Intelligence Quotient (FSIQ) Score (time frame: Assessments through 84 months.). 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 22 Dec 2020.