Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response

Study Overview
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Brief Summary
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The investigators will investigate the effect of blood phenylalanine on Kuvan responsiveness in the same patients with PKU when their blood phenylalanine concentrations are altered by diet. Lowering blood phenylalanine concentrations in Kuvan non-responsive patients with PKU will increase the frequency of Kuvan responsiveness.

Official Title
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Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: Kuvan
* Other: Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all patients with a diagnosis of phenylketonuria patients who are over the age of 4 years, patients with a fasting blood phenylalanine ≥600µmol/l Exclusion Criteria: female patients who are pregnant or attempting to become pregnant children under four years of age Concurrent disease of condition that would interfere with study participation or safety such as history of neurological compromise or major medical, psychiatric or learning disorder unrelated to PKU Any condition that, in the view of the Investigators, places subject at high risk of poor treatment compliance or of not completing the study Use of L-Dopa, methotrexate, or other drugs that may inhibit folate metabolism

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute 24 Hour Component<br>Participants will receive one dose of Kuvan 20 mg/kg on Day 1 and assessed for Acute 24 hour Kuvan response. | Drug: Kuvan<br>* 20mg/kg by mouth once daily<br>* Other names: sapropterin dihydrochloride, Tetrahydrobiopterin (BH4);|
| Experimental: Phase 1 Group<br>After completion of acute 24 hour component, participants can enroll in Phase 1 and will receive Kuvan 20 mg/kg by mouth once daily for 28 consecutive days | Drug: Kuvan<br>* 20mg/kg by mouth once daily<br>* Other names: sapropterin dihydrochloride, Tetrahydrobiopterin (BH4);|
| Experimental: Phase 2 Group<br>Participants in Phase 1 that was not responsive will continue on to the Phase 2 of the study. Positive response is defined as a decrease of blood phenylalanine of 30% or greater from baseline taken from morning blood serum. The Phase 2 component of the study will be a 2 week period of dietary restriction. | Other: Diet<br>* Phenylalanine-restricted diet (4-10 mg/kg/day phenylalanine) using the prescribed phenylalanine-free medical formula and low protein foods tested with the patients for taste and acceptance to lower blood phenylalanine levels below 600 umol/l.<br>|
| Experimental: Phase 3 Group<br>Participants in Phase 2 that achieves a fasting blood phenylalanine of less than 600 umol/l after 2 week dietary restriction will be retreated with Kuvan 20 mg/kg by mouth once daily for a period of 28 consecutive days. | Drug: Kuvan<br>* 20mg/kg by mouth once daily<br>* Other names: sapropterin dihydrochloride, Tetrahydrobiopterin (BH4);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Blood Phenylalanine | Percent change in phenylalanine in (uM) on Kuvan Response evaluated via fasting morning blood serum. A decrease of 30% or greater indicates positive response on Kuvan. | Baseline to Day 1 of the Acute Phase, Baseline to Day 28 of Phase 1, Baseline to Day 28 of Phase 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, Kuvan, BH4, tetrahydrobiopterin