Phenylketonuria, Oxidative Stress, and BH4

The Ability of Kuvan® (Sapropterin Dihydrochloride) to Prevent Meal-induced Lipid Peroxidation and Endothelial Dysfunction in Patients With Phenylketonuria: a Pilot Study

The purpose of this study is to see how tetrahydrobiopterin therapy (BH4; also known as sapropterin dihydrochloride or Kuvan) affects measures of oxidative stress and endothelial function in patients with Phenylketonuria (PKU).

Study Overview

• Status: Terminated
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: Kuvan; Other: Meal Challenge

Detailed Description

Oxidative stress will be induced by having participants eat a meal in polyunsaturated fats. The investigators will see how participants respond to the meal challenge over the course of 6 hours.

• PKU participants who are currently on BH4 therapy will be evaluated while taking BH4 with the meal at a single study visit.
• PKU participants who did not responded to BH4 therapy will be evaluated twice. At the first study visit the investigators will see how you react to the meal challenge when you are not given BH4. You will be given BH4 for two weeks, then return for a second meal challenge study visit while taking BH4.
• Healthy controls will be evaluated after consuming the meal only (no BH4) at a single study visit.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 45 years (ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have read, understood, and signed this consent form (and assent form, if <18 years old)
• Are between the ages of 10-45 years
• Weigh at least 75 pounds (34 kg)
• Meet group-specific criteria

Exclusion Criteria:

• Smoke
• Have any history of cardiovascular disease
• Have hepatic impairment, or demonstrate abnormal baseline liver function lab test results
• Have donated blood within 3 months prior to the study or are anemic as shown by the baseline lab results
• Are unwilling to discontinue dietary supplements (excluding medical food) two weeks prior to their first study visit
• Are currently take medications that will interfere with the interpretation of selected endpoints (such as lipid-lowering medication)
• Are currently pregnant or breastfeeding
• Excluding PKU, have a chronic illness, disorder, or condition (including but not limited to diabetes, hypertension, cancer)
• Have taken any investigational drug (including Kuvan for Kuvan-unresponsive participants & controls) within 3 months prior to the study
• In the opinion of the Investigator, should not be included in the study for any reason, including inability to follow study procedures

Study Plan

How is the study designed?

Design Details

• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BH4 Non-Responders; Participants in this group have PKU and were deemed unresponsive to the drug. They will attend their first study visit, and proceed through the meal challenge without BH4. They will then take BH4 for 2 weeks. The second meal challenge will be performed with the participant's final dose of BH4.	Drug: Kuvan; Participants in the BH4 Non-Responder group will be given a 20 mg/kg body weight/day dose of Kuvan to take on a daily basis for two weeks. The last dose will be administered at the participant's study visit 2.; Other Names: Sapropterin dihydrochloride; tetrahydrobiopterin; BH4; Other: Meal Challenge; At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction
EXPERIMENTAL: Healthy Controls; Participants in this group match an enrolled PKU participant in terms of age, gender, and body mass index class. They will participate in a single study visit and will not be given BH4.	Other: Meal Challenge; At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction
EXPERIMENTAL: BH4 Responders; Participants in this group will use their already prescribed BH4 with the meal challenge and be assessed at a single study visit. They will take their prescribed BH4 with the meal.	Other: Meal Challenge; At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid Peroxidation	Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.	Lipid peroxidation will be measured every other hour for six hours at baseline (study visit 1) for all study groups
C-Reactive Protein (CRP)	Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.	CRP will be measured every other hour for six hours at baseline (study visit 1) for all study groups and again during a second visit 2 weeks after baseline in BH4 Non-Responders only (study visit 2)

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Rani H Singh, PhD, Emory University

Publications and helpful links

Helpful Links

• Study Website

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: June 23, 2011
• First Submitted That Met QC Criteria: July 14, 2011
• First Posted (ESTIMATE): July 15, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): August 28, 2014
• Last Update Submitted That Met QC Criteria: August 27, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Oxidative stress; tetrahydrobiopterin; Phenylketonuria; PKU; Kuvan; BH4; sapropterin dihydrochloride
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: IRB00046153