Study of Phenoptin to Increase Phenylalanine Tolerance in Phenylketonuric Children on a Phenylalanine-restricted Diet

• 1. To evaluate the ability of Phenoptin to reduce blood Phe levels in children with phenylketonuria who are following a Phe-restricted diet
• 2. To compare the ability of Phenoptin versus placebo to increase Phe tolerance in children with phenylketonuria who are following a Phe-restricted diet
• 3. To evaluate the safety of Phenoptin as compared with placebo in this subject population
• 4. To explore the potential reduction in the cost of medical foods and Phe-free formulas

The primary objective of this trial is to evaluate the ability of Phenoptin to increase phenylalanine (phe) tolerance in children with phenylketonuria who are following a phe-restricted diet.

• Drug: Sapropterin Dihydrochloride
  Phenoptin, provided in tablets containing 100 mg of sapropterin dihydrochloride each, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4-8 oz (120-240 mL) of water or apple juice for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.
• Drug: Placebo
  Placebo, provided as tablets similar to Phenoptin tablets, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4 8 oz (120-240 mL) of water or apple juice. for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.

• Experimental: Sapropterin Dihydrochloride
  Phenoptin, provided in tablets containing 100 mg of sapropterin dihydrochloride each, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4-8 oz (120-240 mL) of water or apple juice for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.
  Intervention: Drug: Sapropterin Dihydrochloride
• Placebo Comparator: Placebo
  Placebo, provided as tablets similar to Phenoptin tablets, was administered orally once daily in the morning as the number of tablets equivalent to a 20mg/kg/day dose dissolved in 4 8 oz (120-240 mL) of water or apple juice. for 6 weeks. A follow-up call or visit was made 4 weeks later during this double-blind, placebo-controlled study.
  Intervention: Drug: Placebo

Inclusion Criteria:

• Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by at least one blood Phe measurement >/=360 umol/L (6 mg/dL)
• Under dietary control with a Phe-restricted diet as evidenced by:· Estimated daily Phe tolerance </=1000 mg/day
• At least 6 months of blood Phe control (mean level of </=480 μmol/L) prior to enrolling in the study
• Aged 4 to 12 years inclusive at screening
• A blood Phe level </=480 μmol/L at screening
• Female subjects of childbearing potential (as determined by the principal investigator) must have a negative blood or urine pregnancy test at entry (prior to the first dose). Note: All female subjects of childbearing potential and sexually mature male subjects must be advised to use a medically accepted method of contraception throughout the study. Female subjects of childbearing potential must be willing to undergo periodic pregnancy tests during the course of the study
• Willing and able to comply with all study procedures
• Willing to provide written assent (if applicable) and written informed consent by a parent or legal guardian after the nature of the study has been explained and prior to any research-related procedures

Exclusion Criteria:

• Any condition that, in the view of the PI, renders the subject at high risk from treatment compliance and/or completing the study
• Prior history of organ transplantation
• Perceived to be unreliable or unavailable for study participation or have parents or legal guardians who are perceived to be unreliable or unavailable
• Use of any investigational agent within 30 days prior to screening, or requirement for any investigational agent or vaccine prior to completion of all scheduled study assessments
• ALT > 2 times the upper limit of normal (i.e., Grade 1 or higher based on World Health Organization Toxicity Criteria) at screening
• Concurrent disease or condition that would interfere with study participation or safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin-dependent diabetes)