title: Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study.
abstract: OBJECTIVE
  To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU).
  
  
  METHODS
  This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate.
  
  
  RESULTS
  The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed.
  
  
  CONCLUSIONS
  Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.
authors.affiliation: Klinik für Kinder-und Jugendmedizin Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany. ftrefz@ramedis.de
authors.forename: Friedrich K
authors.initials: FK
authors.lastname: Trefz
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: Mercedes Martinez-Pardo
authors.initials: MM
authors.lastname: Casanova
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gruskin
authors.forename: Alex
authors.initials: A
authors.lastname: Dorenbaum
authors.forename: Emil D
authors.initials: ED
authors.lastname: Kakkis
authors.forename: Eric A
authors.initials: EA
authors.lastname: Crombez
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: Paul
authors.initials: P
authors.lastname: Harmatz
authors.forename: Mark H
authors.initials: MH
authors.lastname: Lipson
authors.forename: Andrzej
authors.initials: A
authors.lastname: Milanowski
authors.forename: Linda Marie
authors.initials: LM
authors.lastname: Randolph
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
authors.forename: Jon A
authors.initials: JA
authors.lastname: Wolff
authors.forename: Judith
authors.initials: J
authors.lastname: Bebchuk
authors.forename: Heidi
authors.initials: H
authors.lastname: Christ-Schmidt
authors.forename: Julia B
authors.initials: JB
authors.lastname: Hennermann
mesh_terms: D000465:Algorithms; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood*; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy*
chemical_list: D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin