Trefz 2009.

Methods	Randomized, double‐blind placebo‐controlled trial. Multicentre, North America and Europe.
Participants	90 children with PKU between 4 to 12 years of age, under phe‐restricted diet with a phe tolerance ≤ 1000 mg/d, and blood phe ≤ 480 μmol/L; exclusion criteria: history of organ transplantation, usage of investigational agent within 30 days before screening, serum alanine aminotransferase levels more than twice upper limit of normal, concurrent disease, using drugs that inhibit folate synthesis, primary BH4 deficiency. 46 children eligible for inclusion (see 'Notes' below).
Interventions	Sapropterin 20 mg/kg/d versus placebo; treatment was for a period of 10 weeks.
Outcomes	Change in blood phe concentration. Change in phe tolerance.
Notes	Trial conducted in two parts. Eligible participants (N = 90) entered part 1, received oral sapropterin 20 mg/kg/d for eight days. Those who had a ≥30% reduction in blood phe and had a blood phe ≤ 300 μmol/L were included in part 2 (N = 46) which was for 10 weeks. The phe supplement was added at the beginning of week 3. Only part 2 of the trial is eligible to be included in the analysis.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described that randomisation was performed by a computer program and interactive voice response system using block sizes of four.
Allocation concealment (selection bias)	Low risk	Described that a central interactive voice response system was used; stated that block sizes were not divulged to investigators or trial sponsor until the trial was completed.
Blinding (performance bias and detection bias) All outcomes	Low risk	Stated as double‐blind. Sapropterin and placebo tablets had similar taste and appearance.
Incomplete outcome data (attrition bias) All outcomes	Low risk	One participant randomized to the sapropterin group did not return to for week 0 visit. The data was not included in the analysis.
Selective reporting (reporting bias)	High risk	Comparison of the trial protocol available at the ClinicalTrials.gov web site and also the 'Methods' section with the results reported in the final paper showed all the detailed outcomes in the protocol were reported in the published reports. But the data could not be included in meta‐analysis as the details in control group were not given.
Other bias	Unclear risk	Sponsored by BioMarin Pharmaceutical Inc.

BH4: tetrahydrobiopterin
 Phe: phenylalanine
 PKU: phenylketonuria