Kuvan® in Phenylketonuria Patients Less Than 4 Years Old
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Intervention: Kuvan®; Phenylalanine (Phe)-restricted diet
Intervention description: Kuvan® (sapropterin dihydrochloride) tablets will be administered orally at the dose of 10 mg/kg/day and will be escalated to 20 mg/kg/day if after 4 weeks a subject's Phe tolerance is not increased by at least 20% versus baseline.; Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Maximum age: 4 Years
Healthy volunteers: No
Keywords: Phenylketonuria (PKU); Kuvan® (Sapropterin); Phe-restricted diet; Paediatric <4 years old; responders to BH4; Phe tolerance

Summary:

      This is a Phase 3b, multicenter, open-label, randomized, controlled study to evaluate
      efficacy, safety and population pharmacokinetics of sapropterin dihydrochloride (Kuvan®) in
      less than 4 year-old infants and children with phenylketonuria (PKU).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female PKU infants and young children less than (<) 4 years of age at the
             scheduled Day 1 visit of the 26-week study period (taking into consideration the
             maximum of 21 days in the screening period)

          -  Confirmed clinical and biochemical PKU, including at least two previous blood Phe
             levels greater than or equal to (>=) 400 micromol per liter (mcmol/L) obtained on 2
             separate occasions

          -  Previously responded, as assessed by the Investigator, to a tetrahydrobiopterin (BH4)
             test, if all 3 of the following criteria are satisfied:

               1. The BH4 dose was 20 milligram per kilogram per day (mg/kg/day)

               2. The duration of the test was at least for 24 hours

               3. A 30% decrease in blood Phe levels.

          -  Defined level of dietary Phe tolerance consistent with the diagnosis of PKU

          -  Good adherence to dietary treatment, including prescribed dietary Phe restriction and
             prescribed amounts of Phe-free protein supplements and low-Phe foods

          -  Maintenance of blood Phe levels within the therapeutic target range of 120-360 mcmol/L
             (defined as >=120 to <360 mcmol/L) over a 4-month period prior to Screening, as
             assessed by the Investigator

          -  Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain
             strict adherence to the diet, and willing and able to provide written, signed informed
             consent after the nature of the study has been explained and prior to any study
             procedures

        Exclusion Criteria:

          -  Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within
             the previous 30 days, unless for the purposes of a BH4 responsiveness test

          -  Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of
             tetrahydrobiopterin for greater than (>)30 days

          -  Known hypersensitivity to Kuvan® or its excipients

          -  Known hypersensitivity to other approved or non-approved formulations of
             tetrahydrobiopterin

          -  Previous diagnosis of BH4 deficiency

          -  Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors

          -  Current use of medications that are known to affect nitric oxide synthesis, metabolism
             or action

          -  Current use of levodopa

          -  Current use of experimental/other investigational or unregistered drugs that may
             affect the study outcomes

          -  Inability to comply with study procedures

          -  Inability to tolerate oral intake

          -  History of organ transplantation

          -  Concurrent disease or condition that would interfere with study participation or
             increase the risk for adverse events, including seizure disorders, corticosteroid
             administration, active malignancy, diabetes mellitus, severe congenital heart disease,
             renal or hepatic failure

          -  Other significant disease that in the Investigator's opinion would exclude the subject
             from the trial

          -  Any condition 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