Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period

Phase 4

Completed

Conditions: Phenylketonuria

Interventions: Drug: Kuvan®

Registration Number: NCT01082328

Lead Sponsor: Merck KGaA, Darmstadt, Germany

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Kuvan®	Kuvan®	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.