Phenylketonurias
Conditions
Brief summary
The primary objective of this trial is to evaluate the ability of Phenoptin to increase phenylalanine (phe) tolerance in children with phenylketonuria who are following a phe-restricted diet.
Interventions
Phenoptin, provided in tablets containing 100 mg of sapropterin dihydrochloride each, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4-8 oz (120-240 mL) of water or apple juice for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.
DRUGPlacebo
Placebo, provided as tablets similar to Phenoptin tablets, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4 8 oz (120-240 mL) of water or apple juice. for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
4 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by at least one blood Phe measurement \>/=360 umol/L (6 mg/dL) * Under dietary control with a Phe-restricted diet as evidenced by:· Estimated daily Phe tolerance \</=1000 mg/day * At least 6 months of blood Phe control (mean level of \</=480 μmol/L) prior to enrolling in the study * Aged 4 to 12 years inclusive at screening * A blood Phe level \</=480 μmol/L at screening * Female subjects of childbearing potential (as determined by the principal investigator) must have a negative blood or urine pregnancy test at entry (prior to the first dose). Note: All female subjects of childbearing potential and sexually mature male subjects must be advised to use a medically accepted method of contraception throughout the study. Female subjects of childbearing potential must be willing to undergo periodic pregnancy tests during the course of the study * Willing and able to comply with all study procedures * Willing to provide written assent (if applicable) and written informed consent by a parent or legal guardian after the nature of the study has been explained and prior to any research-related procedures
Exclusion criteria
* Any condition that, in the view of the PI, renders the subject at high risk from treatment compliance and/or completing the study * Prior history of organ transplantation * Perceived to be unreliable or unavailable for study participation or have parents or legal guardians who are perceived to be unreliable or unavailable * Use of any investigational agent within 30 days prior to screening, or requirement for any investigational agent or vaccine prior to completion of all scheduled study assessments * ALT \> 2 times the upper limit of normal (i.e., Grade 1 or higher based on World Health Organization Toxicity Criteria) at screening * Concurrent disease or condition that would interfere with study participation or safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin-dependent diabetes)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Amount of Dietary Supplemented Phenylalanine (Phe)Tolerated in Children With Phenylketonuria | at Week 10 |
Secondary
| Measure | Time frame |
|---|---|
| Change in Phenylalanine Levels From Baseline to Week 3 | Baseline to Week 3 |
Countries
United States
Participant flow
Pre-assignment details
In Part 1, subjects received Phenoptin for 8 days as part of their evaluation for Phenoptin responsiveness. Subjects who met response criteria were randomized 3:1 to Phenoptin or placebo for additional 10 weeks in Part 2, following a minimum 1-week wash-out period.
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Dihydrochloride Phenoptin, provided in tablets containing 100 mg of sapropterin dihydrochloride each, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4-8 oz (120-240 mL) of water or apple juice for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study. | 33 |
| Placebo Placebo, provided as tablets similar to Phenoptin tablets, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4 8 oz (120-240 mL) of water or apple juice. for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study. | 12 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1: Responsiveness | Lost to Follow-up | 1 | 0 |
| Part 2: Blinded, Placebo Control Period | Lack of Efficacy | 1 | 0 |
| Part 2: Blinded, Placebo Control Period | Patient Uncooperative | 0 | 1 |
| Part 2: Blinded, Placebo Control Period | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Sapropterin Dihydrochloride |
|---|---|---|---|
| Age, Continuous | 7.1 years STANDARD_DEVIATION 2 | 7.5 years STANDARD_DEVIATION 2.6 | 7.7 years STANDARD_DEVIATION 2.8 |
| Race Caucasian | 11 Participants | 44 Participants | 33 Participants |
| Race Hispanic | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 19 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 26 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / — | 8 / — |
| serious Total, serious adverse events | 0 / 33 | 0 / 12 |
Outcome results
Primary
Amount of Dietary Supplemented Phenylalanine (Phe)Tolerated in Children With Phenylketonuria
Time frame: at Week 10
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapropterin Dihydrochloride | Amount of Dietary Supplemented Phenylalanine (Phe)Tolerated in Children With Phenylketonuria | 20.9 mg/kg/day | Standard Deviation 15.4 |
| Placebo | Amount of Dietary Supplemented Phenylalanine (Phe)Tolerated in Children With Phenylketonuria | 2.9 mg/kg/day | Standard Deviation 4 |
Comparison: Compared Week 10 to Baseline.p-value: <0.001t-test, 1 sided
Comparison: Compared Week 10 to Baseline.p-value: 0.027t-test, 1 sided
Secondary
Change in Phenylalanine Levels From Baseline to Week 3
Time frame: Baseline to Week 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapropterin Dihydrochloride | Change in Phenylalanine Levels From Baseline to Week 3 | -147.4 umol/L | Standard Error 29 |
| Placebo | Change in Phenylalanine Levels From Baseline to Week 3 | -90.3 umol/L | Standard Error 48.3 |
p-value: 0.009Longitudinal Model