Methods

Randomised, double‐blind placebo‐controlled study.

Multicentre, North America and Europe.

Participants

89 children and adults with PKU, over 8 years of age, with blood phe ≥450μmol/L; individuals who had a reduction of 30% or more in blood phe concentration after 8 days of treatment with sapropterin at a dose of 10 mg/kg in a previous screening test (PKU 001) were eligible for the study.

Participants had been involved in a phase 1 screening study.

Interventions

Sapropterin 10 mg/kg/day versus placebo; treatment was for a period of 6 weeks.

Outcomes

Change in blood phe concentration.

Notes

Data published only as a six week study; further details requested from the author.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Treatment allocations were made centrally from randomisation lists generated by a computer program. Each randomisation list started with a block of two, followed by blocks of four.

Allocation concealment (selection bias)

Low risk

Described that a central interactive voice response system was used; investigators, patients and sponsors were kept unaware of treatment allocation until database was locked; block size was not divulged to sponsors or investigators until study was completed.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Stated as double blind; sapropterin and placebo tablets were identical in taste and appearance.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Two withdrawals (one from each group) described.

One withdrawal from the study in the sapropterin group before closing due to an inability to comply with the study course. The data was not included in the analysis as the patient did not receive even one dose of study drug.

There was another withdrawal from the control group due to non‐compliance with specified dosing, but the data was 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. However, in the Levy study they measured data at several time points (weeks 0, 1, 2, 4,and 6) but only reported them at 6 weeks.

Other bias

Unclear risk

Sponsored by BioMarin Pharmaceutical Inc.

Methods

Randomised, double‐blind placebo‐controlled study.

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

Study 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 the part 2 of the study is eligible to be included in 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 study sponsor until the study 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 randomised 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.