Phenylketonuria
Conditions
Keywords
Phenylketonuria, PKU, Kuvan, Phenoptin, Biopten, Neurocognitive Function, Phenylalanine
Brief 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.
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.
Interventions
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.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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 * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Full-Scale Intelligence Quotient (FSIQ) Score | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Growth Measurements - Height Z-Scores | Baseline and up to 84 months | 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%. |
| Change From Baseline in Growth Measurements - Weight Z-Scores | Baseline and up to 84 months | 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%. |
| Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Baseline and up to 84 months | 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%. |
| Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | At Month 6, 12, 18 and 24 | 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. |
| Number of Subjects With Adverse Events (AEs) | Up to 7 years | 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. |
| Absorption Rate Constant (Ka) of Kuvan | At predose and postdose - 0.22, 3.2 and 7 hours | Population pharmacokinetic parameter, Absorption Rate Constant (Ka) |
| Apparent Volume of Distribution (V/F) of Kuvan | At predose and postdose - 0.22, 3.2 and 7 hours | Population pharmacokinetic parameter apparent volume of distribution (V/F) |
| Apparent Clearance (CL/F) of Kuvan | At predose and postdose - 0.22, 3.2 and 7 hours | Population pharmacokinetic parameter apparent clearance (CL/F) |
| Baseline Concentration of Tetrahydrobiopterin (BH4)(C0) | At predose and postdose - 0.22, 3.2 and 7 hours | Baseline concentration of BH4(C0) with associated inter-individual variability. |
Countries
Canada, United States
Participant flow
Recruitment details
This was a multicenter study conducted at 20 sites in the U.S. and Canada.
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Dihydrochloride A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. | 95 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part 2 (7 Years) | Adverse Event | 2 |
| Part 2 (7 Years) | Lost to Follow-up | 2 |
| Part 2 (7 Years) | Physician Decision | 1 |
| Part 2 (7 Years) | Sponsor Decision | 6 |
| Part 2 (7 Years) | Withdrawal by Subject | 5 |
| PK Sub-Study 2 (4 Weeks) | no postdose blood sample | 1 |
| Safety/Efficacy Sub-Study 1 (6 Months) | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Sapropterin Dihydrochloride |
|---|---|
| Age, Continuous | 3.2 years STANDARD_DEVIATION 1.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 94.8 cm STANDARD_DEVIATION 17.7 |
| Race/Ethnicity, Customized Asian | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Other | 9 Participants |
| Race/Ethnicity, Customized White | 79 Participants |
| Sex: Female, Male Female | 57 Participants |
| Sex: Female, Male Male | 38 Participants |
| Weight | 15.6 kg STANDARD_DEVIATION 6.08 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 95 |
| other Total, other adverse events | 90 / 95 |
| serious Total, serious adverse events | 12 / 95 |
Outcome results
Primary
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.
Time frame: Assessments through 84 months.
Population: Efficacy population is based on all subjects from the enrolled population who have at least 2 WPPSI/ WISC assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 84 | 104.22 score on a scale | Standard Deviation 12.236 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Baseline | 101.06 score on a scale | Standard Deviation 14.039 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 12 | 103.64 score on a scale | Standard Deviation 13.202 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 24 | 104.69 score on a scale | Standard Deviation 11.697 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 36 | 103.78 score on a scale | Standard Deviation 12.759 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 48 | 104.25 score on a scale | Standard Deviation 13.242 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 60 | 100.76 score on a scale | Standard Deviation 14.28 |
| Kuvan 20 mg/kg Once Daily | Full-Scale Intelligence Quotient (FSIQ) Score | FSIQ Month 72 | 104.57 score on a scale | Standard Deviation 11.012 |
Comparison: A random coefficient model was used to calculate the slope (per year) of FSIQ over the entire study period. Factors in the model included visit and testing sequence, with change in FSIQ score as the dependent variable. Random terms include both intercept and visit. The treatment was considered successful if the lower 95% confidence limit of the mean change excluded a decline of greater than 5 points over a 2-year window.95% CI: [-1.6004, 0.4468]
Secondary
Absorption Rate Constant (Ka) of Kuvan
Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Population: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Absorption Rate Constant (Ka) of Kuvan | 0.235 l/hour | Standard Error 23.8 |
Secondary
Apparent Clearance (CL/F) of Kuvan
Population pharmacokinetic parameter apparent clearance (CL/F)
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Population: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Apparent Clearance (CL/F) of Kuvan | 815 L/hour | Standard Error 50.9 |
Secondary
Apparent Volume of Distribution (V/F) of Kuvan
Population pharmacokinetic parameter apparent volume of distribution (V/F)
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Population: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Apparent Volume of Distribution (V/F) of Kuvan | 1209 L | Standard Error 56.4 |
Secondary
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Baseline concentration of BH4(C0) with associated inter-individual variability.
Time frame: At predose and postdose - 0.22, 3.2 and 7 hours
Population: Eighty patients were evaluable from PKU-015 PK Sub-Study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Baseline Concentration of Tetrahydrobiopterin (BH4)(C0) | 16.6 µg/L | Standard Error 4.1 |
Secondary
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.
Time frame: At Month 6, 12, 18 and 24
Population: Efficacy Population, analysis only comprised of subjects less than 30 months of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Cognitive: Baseline | 102.31 score on a scale | Standard Deviation 9.081 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Cognitive: Change from Baseline Month 6 | 5.68 score on a scale | Standard Deviation 10.943 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Cognitive: Change from Baseline Month 12 | 2.11 score on a scale | Standard Deviation 13.157 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Cognitive: Change from Baseline Month 18 | 2.27 score on a scale | Standard Deviation 20.17 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Cognitive: Change from Baseline Month 24 | 0.83 score on a scale | Standard Deviation 23.962 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Language: Baseline | 100.73 score on a scale | Standard Deviation 12.914 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Language: Change from Baseline Month 6 | 2.59 score on a scale | Standard Deviation 10.966 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Language: Change from BaselineMonth 12 | 1.37 score on a scale | Standard Deviation 14.469 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Language: Change from Baseline Month 18 | 4.82 score on a scale | Standard Deviation 22.903 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Language: Change from Baseline Month 24 | -3.00 score on a scale | Standard Deviation 18.407 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Motor: Baseline | 104.96 score on a scale | Standard Deviation 11.837 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Motor: Change from Baseline Month 6 | 1.32 score on a scale | Standard Deviation 10.952 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Motor: Change from Baseline Month 12 | 2.11 score on a scale | Standard Deviation 12.297 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Motor: Change from Baseline Month 18 | 0.18 score on a scale | Standard Deviation 19.894 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results | Motor: Change from Baseline Month 24 | 7.50 score on a scale | Standard Deviation 18.512 |
Secondary
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%.
Time frame: Baseline and up to 84 months
Population: Efficacy Population, subjects less than 36 months of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Baseline | 0.2 Z-score change from baseline | Standard Deviation 0.95 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Week 4 | 0.1 Z-score change from baseline | Standard Deviation 0.69 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 3 | 0.0 Z-score change from baseline | Standard Deviation 0.4 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 6 | 0.1 Z-score change from baseline | Standard Deviation 0.7 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 12 | 0.1 Z-score change from baseline | Standard Deviation 0.56 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 18 | -0.1 Z-score change from baseline | Standard Deviation 1 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 24 | 0.2 Z-score change from baseline | Standard Deviation 0.74 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Head Circumference Z-Scores | Change from Baseline Month 30 | 0.8 Z-score change from baseline | Standard Deviation 0.81 |
Secondary
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%.
Time frame: Baseline and up to 84 months
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Baseline | 0.4 Z-score change from baseline | Standard Deviation 0.97 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Week 4 | 0.0 Z-score change from baseline | Standard Deviation 0.44 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 3 | 0.1 Z-score change from baseline | Standard Deviation 0.57 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 6 | 0.1 Z-score change from baseline | Standard Deviation 0.72 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 12 | -0.1 Z-score change from baseline | Standard Deviation 0.73 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 18 | 0.0 Z-score change from baseline | Standard Deviation 0.78 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 24 | 0.0 Z-score change from baseline | Standard Deviation 0.71 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 30 | -0.1 Z-score change from baseline | Standard Deviation 0.72 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 36 | -0.1 Z-score change from baseline | Standard Deviation 0.71 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 42 | -0.1 Z-score change from baseline | Standard Deviation 0.73 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 48 | -0.2 Z-score change from baseline | Standard Deviation 0.77 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 54 | -0.2 Z-score change from baseline | Standard Deviation 0.78 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 60 | -0.2 Z-score change from baseline | Standard Deviation 0.75 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 66 | -0.2 Z-score change from baseline | Standard Deviation 0.77 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 72 | -0.3 Z-score change from baseline | Standard Deviation 0.78 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 78 | -0.2 Z-score change from baseline | Standard Deviation 0.78 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Height Z-Scores | Change from Baseline Month 84 | -0.2 Z-score change from baseline | Standard Deviation 0.83 |
Secondary
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%.
Time frame: Baseline and up to 84 months
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 3 | 0.0 Z-score change from baseline | Standard Deviation 0.26 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 6 | 0.0 Z-score change from baseline | Standard Deviation 0.36 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Baseline | 0.4 Z-score change from baseline | Standard Deviation 0.84 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Week 4 | 0.0 Z-score change from baseline | Standard Deviation 0.24 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 12 | 0.1 Z-score change from baseline | Standard Deviation 0.45 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 18 | 0.1 Z-score change from baseline | Standard Deviation 0.59 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 24 | 0.1 Z-score change from baseline | Standard Deviation 0.62 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 30 | 0.1 Z-score change from baseline | Standard Deviation 0.68 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 36 | 0.1 Z-score change from baseline | Standard Deviation 0.71 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 42 | 0.0 Z-score change from baseline | Standard Deviation 0.75 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 48 | 0.0 Z-score change from baseline | Standard Deviation 0.79 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 54 | 0.0 Z-score change from baseline | Standard Deviation 0.84 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 60 | 0.0 Z-score change from baseline | Standard Deviation 0.91 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 66 | 0.0 Z-score change from baseline | Standard Deviation 0.85 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 72 | 0.0 Z-score change from baseline | Standard Deviation 0.77 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 78 | 0.0 Z-score change from baseline | Standard Deviation 0.81 |
| Kuvan 20 mg/kg Once Daily | Change From Baseline in Growth Measurements - Weight Z-Scores | Change from Baseline Month 84 | 0.0 Z-score change from baseline | Standard Deviation 0.85 |
Secondary
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.
Time frame: Up to 7 years
Population: Enrolled Population consists of all subjects who enter Part 2. This population involves subjects who respond to Kuvan and had a Bayley-III or IQ test score ≥80 within 6 weeks of determination of Kuvan responsiveness in Part 1. Kuvan 20 mg/kg once daily.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Any Adverse Events (AEs) | 65 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Drug-Related Adverse Events | 35 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Any Serious Adverse Events | 11 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Drug-Related Serious Adverse Events | 2 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Any AEs causing study discontinuation | 2 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Drug-related AEs causing study discontinuation | 2 Participants |
| Kuvan 20 mg/kg Once Daily | Number of Subjects With Adverse Events (AEs) | Death | 0 Participants |