Phenylketonuria
Conditions
Keywords
PKU, Phenylketonuria, BH4, Kuvan, Tetrahydrobiopterin, Sapropterin Dihydrochloride, Nutrition, PHE, Phenylalanine, PAH, Phenylalanine hydroxylase, Neurotransmitters, Serotonin, Catecholamines, Diet, Body Fat, Bone Density
Brief summary
HYPOTHESIS: The investigators hypothesize that KuvanTM therapy could influence nutritional and body composition parameters and neurotransmitter concentrations in pediatric and adult PKU subjects. SUMMARY: Though the investigators know that KuvanTM lowers blood Phe levels and improves tolerance for natural protein in at least half of the PKU (Phenylketonuria) patient population, investigators do not know the full effects this medicine will have on the patient's diet, or what impact the medicine or diet changes will have on the body composition or nutrient status of PKU patients. Since KuvanTM may also help the body produce neurotransmitters, investigators also want to find out if taking KuvanTM changes neurotransmitter levels in PKU patients, and if PKU patients who are benefitting from KuvanTM feel less stigmatized and have a better outlook on life as a result of the treatment. Therefore, the research study has several objectives. These are to investigate the impact KuvanTM therapy has on (1) body composition parameters of PKU patients: such as lean body mass, percent body fat, bone density, weight gain, and growth (2) dietary changes, and the effect of those changes, on intake of calories and essential nutrients (3) changes in blood biomarkers of certain nutrients (4) blood and urine neurotransmitter levels, since these changes could indicate improved neurological functioning, (5) and quality of life of PKU patients, who may feel less burdened due to the dietary freedom KuvanTM provides.
Detailed description
BACKGROUND : Tetrahydrobiopterin (BH4) is a treatment option newly available to phenylketonuria (PKU) patients within the United States as the pharmaceutical KuvanTM. This small molecule functions as a cofactor in multiple enzyme systems, including the metabolism of phenylalanine into tyrosine by the enzyme phenylalanine hydroxylase (PAH). HYPOTHESIS: The investigators hypothesize that KuvanTM therapy could influence nutritional and body composition parameters and neurotransmitter concentrations in pediatric and adult PKU subjects. OBJECTIVES: 1. To record nutritional biomarkers, body composition, bone density, and measures of nutrient intake in a phenylketonuria subject group at baseline and for one year after start of KuvanTM therapy. 2. To investigate changes in monoamine neurotransmitter synthesis in a phenylketonuria subject group at baseline and for one year after start of KuvanTM therapy. 3. Evaluate changes in quality of life (QOL) for PKU subjects beginning KuvanTM therapy METHODOLOGY: Investigators intend to enroll 60 PKU patients, ages 4 to adulthood, who are planning to begin BH4 treatment as prescribed by their medical provider. Patients will be given 4 weeks to demonstrate a response to KuvanTM as determined by a drop in plasma PHE by ≥15%. All patients, regardless of response to KuvanTM, will be allowed to continue in the study. All subjects will be followed for a full 12 months while monitoring nutrient intake, nutritional biomarkers, serotonin and catecholamine levels, and QOL. Two-tailed statistical analysis with α=0.05 will be used to compare results between responders and nonresponders, as well as compare follow-up values with baseline measures.
Interventions
DRUGKuvanTM Therapy
BH4 treatment was prescribed by each participant's medical provider, not an intervention that was assigned as part of the current study.
Sponsors
BioMarin Pharmaceutical
Atlanta Clinical and Translational Science Institute
Emory University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Diagnosed with PKU * ability to provide informed consent (or have legal guardian who can provide informed consent) * at least 4 years of age * planning on trying BH4 treatment
Exclusion criteria
* Pregnant * unable to provide informed consent * less than 4 years of age * currently taking BH4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Phenylalanine Intake at 12 Months | Baseline and 12 months | Total dietary phenylalanine assessed through 3-day food records - calculated as average phenylalanine intake (grams/day) in the 3 days recorded |
| Change From Baseline in BMI at 12 Months | Baseline and 12 months | Change in Body mass index (BMI) from baseline of Kuvan study to 12 months post-baseline |
| Change From Baseline in Bone Mineral Density (BMD) at 12 Months | Baseline and 12 months | Change in bone mineral density (BMD) from baseline of Kuvan study to 12 months post-baseline |
| Change From Baseline in Percent (%) Lean Mass at 12 Months | Baseline and 12 months | % lean mass was measured via dual energy x-ray absorptiometry (DXA) |
| Change From Baseline in Percent (%) Fat Mass at 12 Months | Baseline and 12 months | Percent fat mass measured via dual energy x-ray absorptiometry (DXA) |
| Change From Baseline in Plasma Phenylalanine at 12 Months | Baseline and 12 months | Full amino acid panel, including phenylalanine, analyzed in fasting plasma samples. |
| Change From Baseline in Total Dietary Protein Intake at 12 Months | Baseline and 12 months | Total dietary protein intake assessed through 3-day food records - calculated as average protein intake (grams/day) in the 3 days recorded |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serotonin at 12 Months | Baseline and 12 months | Objective: 1 year prospective cohort of PKU patients introduced to sapropterin (Kuvan)to evaluate peripheral neurotransmitter changes across time. |
Countries
United States
Participant flow
Recruitment details
Recruitment lasted 1 year from October 2008 - October 2009. Recruitment occurred at the Emory University Genetics Clinic, Department of Human Genetics in Decatur, GA.
Pre-assignment details
There were no exclusions of subjects once enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy Subjects with Phenylketonuria starting sapropterin therapy for the purpose of lowering blood phenylalanine levels. | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 10 |
Baseline characteristics
| Characteristic | Subjects With Phenylketonuria Starting Sapropterin Therapy |
|---|---|
| Age, Categorical <=18 years | 38 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 17 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 58 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 58 |
| serious Total, serious adverse events | 0 / 58 |
Outcome results
Primary
Change From Baseline in BMI at 12 Months
Change in Body mass index (BMI) from baseline of Kuvan study to 12 months post-baseline
Time frame: Baseline and 12 months
Population: Data missing for 2 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in BMI at 12 Months | -0.65574 kg/m^2 | Standard Deviation 8.060658 |
Comparison: Objective was to evaluate BMI across one year in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.692782t-test, 2 sided
Primary
Change From Baseline in Bone Mineral Density (BMD) at 12 Months
Change in bone mineral density (BMD) from baseline of Kuvan study to 12 months post-baseline
Time frame: Baseline and 12 months
Population: Data missing for 3 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Bone Mineral Density (BMD) at 12 Months | 0.005401 grams/centimeter^2 | Standard Deviation 0.0243 |
Comparison: Objective was to evaluate total body bone mineral density (BMD) one year via DXA in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: <0.001t-test, 2 sided
Primary
Change From Baseline in Percent (%) Fat Mass at 12 Months
Percent fat mass measured via dual energy x-ray absorptiometry (DXA)
Time frame: Baseline and 12 months
Population: Data missing for 3 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Percent (%) Fat Mass at 12 Months | 1.208889 Percent Fat Mass | Standard Deviation 3.519867 |
Comparison: Objective was to evaluate % fat mass across one year via DXA in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.026009t-test, 2 sided
Primary
Change From Baseline in Percent (%) Lean Mass at 12 Months
% lean mass was measured via dual energy x-ray absorptiometry (DXA)
Time frame: Baseline and 12 months
Population: Data missing for 3 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Percent (%) Lean Mass at 12 Months | 2.419224 Percent Lean Mass | Standard Deviation 3.4666 |
Comparison: Objective was to evaluate % lean mass across one year via DXA in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.017941t-test, 2 sided
Primary
Change From Baseline in Phenylalanine Intake at 12 Months
Total dietary phenylalanine assessed through 3-day food records - calculated as average phenylalanine intake (grams/day) in the 3 days recorded
Time frame: Baseline and 12 months
Population: Dietary intake not submitted by 11 participants at 12 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Phenylalanine Intake at 12 Months | 0.131676 grams per day | Standard Deviation 0.797247 |
Comparison: Objective was to evaluate dietary phenylalanine intake across one year in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.3811t-test, 2 sided
Primary
Change From Baseline in Plasma Phenylalanine at 12 Months
Full amino acid panel, including phenylalanine, analyzed in fasting plasma samples.
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Plasma Phenylalanine at 12 Months | -67.5187 Micromoles per liter | Standard Deviation 362.9412 |
Comparison: Objective was to evaluate plasma phenylalanine across one year in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.303864t-test, 2 sided
Primary
Change From Baseline in Total Dietary Protein Intake at 12 Months
Total dietary protein intake assessed through 3-day food records - calculated as average protein intake (grams/day) in the 3 days recorded
Time frame: Baseline and 12 months
Population: Dietary intake not submitted by 11 participants at 12 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects With Phenylketonuria Starting Sapropterin Therapy | Change From Baseline in Total Dietary Protein Intake at 12 Months | -10.9549 grams per day | Standard Deviation 20.10814 |
Comparison: Objective was to evaluate protein intake (grams per day) across one year in PKU patients introduced to sapropterin after baseline. Study was prospective cohort in design.p-value: 0.00088t-test, 2 sided
Other Pre-specified
Change From Baseline in Serotonin at 12 Months
Objective: 1 year prospective cohort of PKU patients introduced to sapropterin (Kuvan)to evaluate peripheral neurotransmitter changes across time.
Time frame: Baseline and 12 months