Phenylketonuria
Conditions
Keywords
Phenylketonuria, Sapropterin, Placebo, Cognitive Abilities, Kuvan®
Brief summary
This is a Phase 2a multicenter, double-blind, placebo-controlled, randomized, 2-arm pilot trial designed to assess the effect of sapropterin on cognitive abilities in young adults with Phenylketonuria (PKU) over a 26-week treatment period.
Interventions
DRUGSapropterin
Sapropterin tablets will be administered orally once daily at a dose of 20 milligram per kilogram (mg/kg) during both the 2-Week response test period and 24-Week study period.
DRUGPlacebo
Sapropterin tablets will be administered orally once daily at a dose of 20 milligram per kilogram (mg/kg) during both the 2-Week response test period and Placebo tablets matching to sapropterin will be administered orally once daily during the 24-Week study period.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 29 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent given before any trial-related activities are carried out * Women or men with documented PKU diagnosed by at least two phenylalanine levels equal or greater than 600 micromole per liter (mcmol/L) * For women of childbearing potential: a negative urine pregnancy test is required at screening and willingness to use a highly effective method of contraception is required during the study and follow-up periods * Aged greater than or equal to (\>=) 18 to 29 years, inclusive * Mean blood phenylalanine levels 600 to 1000 mcmol/L during 12 months preceding inclusion in the study. The mean should be calculated from at least 3 blood phenylalanine values over the last 12 months. Screening blood phenylalanine level can be one of these values. There should be at least one value dated between Month -12 and -6 before Screening and at least one value dated between Month -6 and Screening * An intelligence quotient (IQ) score greater than or equal to 85, assessed a maximum of 2 years before screening with an age-appropriate Wechsler scale. If no IQ test result is available, IQ testing must be performed as part of Screening using an age-appropriate Wechsler scale before the subject can be included * Subjects willing to comply with all study procedures, including willingness to continue current dietary recommendations during the whole trial duration
Exclusion criteria
* Subjects with tetrahydrobiopterin (BH4) deficiency * Previous exposure to sapropterin or BH4 for greater than 30 days (or exposure to sapropterin or BH4 for less than or equal to 30 days but within the previous 6 months prior to Screening visit) * Subjects who, according to the Investigator, will not be able to comply with study procedures and computerized neuropsychological testing * Any significant illness which, according to the Investigator, might preclude participation in the study (including neurological disease, cardio-vascular disease, history of seizure, predisposition to convulsions, renal or hepatic insufficiency, and active malignancy) * Any significant illness, medication or substance abuse which, according to the Investigator, might affect cognitive function and cognitive testing (for example, significant visual or motor impairment, history of major head trauma, history of stroke, alcoholism, drug dependency, psychological disorder requiring chronic use of psychotropic medications such as anxiolytics, antidepressants, antipsychotic medication, mood stabilizers, and hypnotics) * Concomitant forbidden medication as described in the Kuvan® Summary of Product Characteristics, namely, inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim), medications that are known to affect nitric oxide synthesis (for example, glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, molsidomin, phosphodiesterase type 5 inhibitors, and minoxidil), and levodopa, as it may cause increased excitability and irritability * Known hypersensitivity to sapropterin or any ingredients in the product's formulation, or to other approved or non-approved formulations of BH4 * Subjects who have undergone cognitive neuropsychological testing similar to that to be performed as part of this trial with the following time limits: tasks with limited practice effect performed in the last 6 months, and tasks with important practice effect (such as tasks involving development of strategies) performed in the year preceding inclusion in the trial. Whether a task falls into one or the other category is left to Investigator judgment * Female subjects who are pregnant or in the lactation period * Subjects currently participating to another clinical trial or who participated in a previous clinical trial within 30 days prior to screening * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | Screening up to 24 weeks + 4-week follow-up | An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was 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. |
Countries
Italy, Switzerland
Participant flow
Recruitment details
First/Last subject (informed consent): 24 Feb 2014/12 Aug 2014. Study premature termination date: 07 Nov 2014; Subjects were randomized at 2 study centers.
Pre-assignment details
A total of 10 subjects were screened and 7 subjects were included in the 2-Week response test period. Out of 7 subjects, only 2 subjects were responders and they were enrolled and randomized to receive study drug into the 24-Week study period.
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Subject was administered with 20 mg/kg sapropterin tablets orally once daily during the 2-week response test period. The subject upon completing the 2-Week response test period was randomized to receive sapropterin during the 24-week study period. The subject underwent the study assessments and procedures according to the study protocol until the study was terminated by the Sponsor. | 1 |
| Placebo Subject was administered with 20 mg/kg sapropterin tablets orally once daily during the 2-week response test period. The subject upon completing the 2-Week response test period was randomized to receive placebo tablets matching to sapropterin orally once daily during the 24-week study period. The subject underwent the study assessments and procedures according to the study protocol until the study was terminated by the Sponsor. | 1 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor terminated the study | 1 | 1 |
Baseline characteristics
| Characteristic | Sapropterin | Placebo | Total |
|---|---|---|---|
| Age, Customized >=18 to 29 Years | 1 Subjects | 1 Subjects | 2 Subjects |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was 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: Screening up to 24 weeks + 4-week follow-up
Population: The safety analysis population included all the randomized subjects who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sapropterin | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs | 1 Subjects |
| Sapropterin | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | SAEs | 0 Subjects |
| Sapropterin | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Subjects |
| Sapropterin | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs leading to death | 0 Subjects |
| Placebo | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Subjects |
| Placebo | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs | 0 Subjects |
| Placebo | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | SAEs | 0 Subjects |
| Placebo | Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation | AEs leading to death | 0 Subjects |