Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Intervention: Kuvan®
Intervention description: Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) will be given once daily for 28 +/- 1 days.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 59.0
Sex: All
Minimum age: 4 Years
Healthy volunteers: No
Keywords: Phenylketonuria (PKU); Hyperphenylalaninemia (HPA); Kuvan®; Sapropterin dihydrochloride; Kuvan responder; Tetrahydrobiopterin (BH4)

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.
    

Eligibility criteria:

        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