Phenylketonuria
Conditions
Keywords
Phenylketonuria (PKU), Hyperphenylalaninemia (HPA), Kuvan®, Sapropterin dihydrochloride, Kuvan responder, Tetrahydrobiopterin (BH4)
Brief summary
The primary objective of the study is to evaluate the proportion of responders (that is, greater than or equal to \[\>=\] 30 percent reduction from Baseline in blood phenylalanine \[Phe\] level) to treatment with Kuvan® (sapropterin dihydrochloride) 20 milligram per kilogram per day (mg/kg/day) for 28 days.
Interventions
DRUGKuvan®
Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) will be given once daily for 28 +/- 1 days.
Sponsors
Merck Serono Norway
Smerud Medical Research International AS
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects aged 4 years or older at the time the informed consent is obtained * Subjects diagnosed with PKU (subgroups defined as: classic PKU \[blood Phe greater than {\>}1200 micromole per liter {mcmol/L}\], mild PKU \[blood Phe 600 to1200 mcmol/L\] or mild hyperphenylalaninemia (HPA) \[blood Phe 300 to 600 mcmol/L\] * Subjects who have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin \[BH4\]) * Subjects adherent to their normal diet and willing to adhere to the given diet for the 4 weeks study period * Subjects who provide a signed (by parent if below 18 years) written informed consent * Subjects with documented genotyping for both phenylalanine hydroxylase (PAH) mutations (PKU genotype) * Phenylketonuria (PKU) diagnosis should be documented with at least two historical blood Phe levels above 400 mcmol/L * Female subjects of childbearing potential (and, if appropriate, male subjects with female partners of childbearing potential) must be willing to avoid pregnancy by using an adequate method of contraception (defined as two barrier methods or one barrier method with spermicide, or intrauterine device or use of the oral female contraceptive) for 4 weeks prior to, during and 12 weeks after the last dose of trial medication * Women of childbearing potential (for the purpose of this trial, women of childbearing potential are defined as All female subjects after puberty unless they are post-menopausal for at least 2 years, are surgically sterile or are sexually inactive) must have a negative urine pregnancy test at the Baseline visit
Exclusion criteria
* Subjects who have documented BH4 deficiency * Subjects who have any contraindications to receive Kuvan® as outlined in the summary of product characteristics (SmPC) not willing or able to comply with the study procedures * Subjects who are pregnant, planning for pregnancy or breastfeeding * Subjects who have been exposed to any investigational medicinal drugs or treatments within 30 days or 5 half-lives, whichever is longer, prior to the Screening visit * Subjects using concomitant treatment with folate synthesis inhibiting drugs * Subjects with concurrent use of Levodopa * Subjects with concurrent use of inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim) * Subjects with concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (for example, glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil * Subjects who have a concurrent disease potentially interfering safety (for example, seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus) * Subjects who have inadequate liver function, defined by alanine aminotransferase (ALT) \>= 2 times upper limit of normal (ULN) * Subjects who have clinically significant renal dysfunction, defined by serum creatinine \> 250 mcmol/L * Have any medical condition that, in the judgment of the investigator, would jeopardize the subject's safety following exposure to study drug or would significantly interfere with the subject's ability to comply with the provisions of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level | Baseline up to Day 28 +/- 1 | Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal | Baseline up to Day 42 +/- 3 | An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered. |
| Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® | Baseline up to Day 28 +/- 1 | Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. Non-responders defined as percentage of participants with a Phe level reduction of less than 10 percent within 28 +/- 1 days. |
| Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Baseline up to Day 28 +/- 1 | The Phenylketonuria (PKU) is categorized as per phenotype into classical PKU: (blood Phe levels greater than \[\>\] 1200 micromole per liter \[mcmol/l\]), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild Hyperphenylalaninaemia (HPA) (blood Phe levels 300 to 600 mcmol/l). |
| Percentage of Early-, Late- and Partial-Responders According to Phenotype | Baseline up to Day 28 +/- 1 | The PKU is categorized as per phenotype into classical PKU: (blood Phe levels \> 1200 mcmol/l), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild HPA (blood Phe levels 300 to 600 mcmol/l). Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. |
| Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio | Baseline, Day 28 | Phenylalanine-to-tyrosine ratio is the best indicator of dopamine availability in PKU. The change in blood phenylalanine-to-tyrosine ratio at Day 28 was calculated as blood phenylalanine-to-tyrosine ratio at Day 28 minus blood phenylalanine-to-tyrosine ratio at Baseline. |
Countries
Norway
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Kuvan® Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) once daily for 28 +/- 1 days. | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Kuvan® |
|---|---|
| Age, Continuous | 21.0 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 58 / 59 |
| serious Total, serious adverse events | 0 / 59 |
Outcome results
Primary
Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level
Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days.
Time frame: Baseline up to Day 28 +/- 1
Population: Full analysis set (FAS) population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Kuvan® | Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level | 75 Percentage of participants |
Secondary
Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio
Phenylalanine-to-tyrosine ratio is the best indicator of dopamine availability in PKU. The change in blood phenylalanine-to-tyrosine ratio at Day 28 was calculated as blood phenylalanine-to-tyrosine ratio at Day 28 minus blood phenylalanine-to-tyrosine ratio at Baseline.
Time frame: Baseline, Day 28
Population: FAS population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kuvan® | Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio | Baseline (n=59) | 10.978 Ratio | Standard Deviation 5.978 |
| Kuvan® | Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio | Change at Day 28 (n=58) | -2.136 Ratio | Standard Deviation 3.948 |
Secondary
Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal
An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered.
Time frame: Baseline up to Day 42 +/- 3
Population: Safety population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Kuvan® | Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal | AEs | 58 Participants |
| Kuvan® | Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal | Treatment Emergent AEs | 57 Participants |
| Kuvan® | Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal | Treatment Related AEs | 36 Participants |
| Kuvan® | Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal | AEs leading to withdrawal | 1 Participants |
Secondary
Percentage of Early-, Late- and Partial-Responders According to Phenotype
The PKU is categorized as per phenotype into classical PKU: (blood Phe levels \> 1200 mcmol/l), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild HPA (blood Phe levels 300 to 600 mcmol/l). Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment.
Time frame: Baseline up to Day 28 +/- 1
Population: FAS population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Classical PKU: Late Responders (n=23) | 17 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild HPA: Late Responders (n=7) | 0 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild HPA: Partial Responders (n=7) | 14 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild HPA: Early Responders (n=7) | 86 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild PKU: Early Responders (n=26) | 85 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild PKU: Late Responders (n=26) | 4 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Mild PKU: Partial Responders (n=26) | 12 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Classical PKU: Early Responders (n=23) | 39 Percentage of participants |
| Kuvan® | Percentage of Early-, Late- and Partial-Responders According to Phenotype | Classical PKU: Partial Responders (n=23) | 43 Percentage of participants |
Secondary
Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®
Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. Non-responders defined as percentage of participants with a Phe level reduction of less than 10 percent within 28 +/- 1 days.
Time frame: Baseline up to Day 28 +/- 1
Population: FAS population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Kuvan® | Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® | Early Responders | 64.4 Percentage of participants |
| Kuvan® | Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® | Late Responders | 10.2 Percentage of participants |
| Kuvan® | Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® | Partial Responders | 25.4 Percentage of participants |
| Kuvan® | Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® | Non-responders | 0 Percentage of participants |
Secondary
Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes
The Phenylketonuria (PKU) is categorized as per phenotype into classical PKU: (blood Phe levels greater than \[\>\] 1200 micromole per liter \[mcmol/l\]), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild Hyperphenylalaninaemia (HPA) (blood Phe levels 300 to 600 mcmol/l).
Time frame: Baseline up to Day 28 +/- 1
Population: FAS population included all the participants with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure. 'n' signifies number of participants who were evaluable for specified categories at different time points.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild HPA: >= 30 percent (n=7) | 57 Percentage of participants | — |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild HPA: 20 to 30 percent (n=7) | 29 Percentage of participants | 24.9 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild HPA: 10 to 20 percent (n=7) | 0 Percentage of participants | 25.4 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild HPA: < 10 percent (n=7) | 14 Percentage of participants | 33.4 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild PKU: >= 30 percent (n=26) | 69 Percentage of participants | 96.2 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild PKU: 20 to 30 percent (n=26) | 8 Percentage of participants | 64.9 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild PKU: 10 to 20 percent (n=26) | 4 Percentage of participants | 60.8 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Mild PKU: < 10 percent (n=26) | 19 Percentage of participants | 69.3 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Classical PKU: >= 30 percent (n=22) | 45 Percentage of participants | 83.8 |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Classical PKU: 20 to 30 percent (n=22) | 0 Percentage of participants | — |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Classical PKU: 10 to 20 percent (n=22) | 23 Percentage of participants | — |
| Kuvan® | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes | Classical PKU: < 10 percent (n=22) | 32 Percentage of participants | — |