Phenylketonuria
Conditions
Keywords
EMR 700733_510, Genetic disorder, Phenylketonuria, phenylalanine, Kuvan, sapropterin dihydrochloride
Brief summary
This is an open-label, non-comparative, Phase 3 study to evaluate the degree, frequency of response and safety of Kuvan® (sapropterin dihydrochloride) in subjects aged 4 to 18 years who have phenylketonuria and with elevated blood phenylalanine level of greater than or equal to 450 micromole per liter.
Interventions
DRUGKuvan®
Kuvan® (sapropterin dihydrochloride) will be administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment will be continued at the same dose for further 6 weeks.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide written informed consent (for children under 18 years old the parent\[s\]/guardians give informed consent, subjects 14-17 years old give additionally their own written informed consent) * Age of 4 - 18 years, inclusive * Confirmed clinical and biochemical hyperphenylalaninemia due to phenylketonuria documented by past medical history with at least 2 blood phenylalanine level greater than or equal to 400 micromole per liter obtained in 2 separate occasions * Blood phenylalanine level at screening greater than or equal to 450 micromole per liter (mean of two measurements) * 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 while participating in the study * Subject and/or the parent/guardian willing and able to comply with study procedures * Subject and/or the parent/guardian willing to continue current diet unchanged during the 8 days response test and to adapt the diet according to phenylalanine therapeutic target range during the 6 week treatment period
Exclusion criteria
* Subject already assessed for responsiveness to sapropterin dihydrochloride or other tetrahydrobiopterin (BH4) * Used any investigational agent other than Kuvan® (sapropterin dihydrochloride) within 30 days of screening, or required any investigational agent or vaccine prior to completion of all scheduled study assessments * Pregnant or breastfeeding, or considering pregnancy * Concurrent disease or conditions that would interfere with study participation or safety (for example, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient) * Concurrent use of required concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate), levodopa, phosphodiesterase type-5 (PDE-5) inhibitors (such as, sildenafil, vardenafil or tadalafil), medications that are known to affect nitric oxide synthesis metabolism or action * Any conditions, that, in the view of the Principal Investigator renders the subject at high risk for failure to comply with treatment or to complete the study * Clinical diagnosis of primary BH4 deficiency * Known hypersensitivity to Kuvan® (sapropterin dihydrochloride) or its excipients or to other approved or non-approved formulation of tetrabiopterin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment | Day 8 | Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population | Baseline, Day 8 | Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)\*100/ blood phenylalanine level at baseline. |
| Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders | Baseline, Day 8 | Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)\*100/ blood phenylalanine level at baseline. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population | Baseline up to Week 11 | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (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
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Kuvan® Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks. | 90 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Kuvan® |
|---|---|
| Age, Continuous | 9.59 years STANDARD_DEVIATION 4.09 |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 90 |
| serious Total, serious adverse events | 1 / 90 |
Outcome results
Primary
Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment
Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.
Time frame: Day 8
Population: Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Kuvan® | Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment | 33.3 percentage of participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (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: Baseline up to Week 11
Population: Overall safety population included all participants who received at least 1 dose of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Kuvan® | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population | AEs | 24 participants |
| Kuvan® | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population | SAEs | 1 participants |
Secondary
Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population
Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)\*100/ blood phenylalanine level at baseline.
Time frame: Baseline, Day 8
Population: Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan® | Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population | -14.14 percent change | Standard Deviation 28.35 |
Secondary
Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders
Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)\*100/ blood phenylalanine level at baseline.
Time frame: Baseline, Day 8
Population: Sub-population of responders included participants with reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kuvan® | Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders | -44.25 percent change | Standard Deviation 15.13 |