The Effectiveness of Kuvan in Amish PKU Patients
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Intervention: saproterin dihydrochloride; Diet treatment
Intervention description: The drug will be given as described in the arm/group descriptions.; Patients will maintain a stable, Phe restricted diet (including formula) that is consistent with their diet at the time of enrollment. This will be monitored by food diaries kept for 3 days of each week.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 7.0
Sex: All
Minimum age: 2 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Saproterin dihydrochloride; Kuvan; Amish

Summary:

      The purpose of this study is to determine if Amish patients with PKU show responsiveness
      after a high dose, prolonged Saproterin trial. The population of interest has a high
      frequency of a specific splice site mutation, the 1066-11G>A mutation. This splice site
      mutation activates a cryptic splice site resulting in an in frame insertion of 9 nucleotides
      preceding exon 11. This leads to protein conformational changes and abrogation of function.
      Previous studies of this genotype have indicated <1% residual activity of the PAH enzyme and
      an insignificant responsiveness to Saproterin. However, in this specific study Phe levels
      were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of
      20mg/kg.

      Based on new clinical information, the investigators hypothesize that if given a prolonged
      trial of Saproterin at a higher dose, Amish patients with PKU, specifically those homozygous
      for the c.1066-11G>A mutation, will have a significant reduction in Phe levels or an increase
      in Phe tolerance and/or improvement in executive functioning and quality of life.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Current diagnosis of PKU with the following:

          -  Age of at least 2 years or older

          -  Baseline Phe level of > 360 umol/L

          -  Willing to maintain a stable diet

          -  Patient or guardian are willing and able to provide written, signed informed consent
             after the nature of the study has been explained and prior to any research-related
             procedures

          -  Are willing to comply with all study procedures

          -  Two identifiable mutations found on PAH gene sequencing

          -  Any patients already taking Saproterin (or have taken in the past), must have a
             treatment end date at least 14 days prior to Day 1 of the study.

        Exclusion Criteria:

          -  Any patient currently taking Saproterin who has taken the medication at any point in
             the 14 days prior to Day 1 of the study

          -  Under 2 years of age

          -  Unwilling to maintain a stable diet

          -  Patients with baseline Phe levels < 360 umol/L

          -  Patients unable to comply with all study procedures

          -  Patients unable to provide written, signed informed consent

          -  One (or no) identifiable mutations found on PAH gene sequencing