Multimodal Neuroimaging and Neurocognitive Assessment of Biomarkers and Response to Sapropterin Dihydrochloride Treatment in Phenylketonuria
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Neuroimaging biomarkers
研究概览
简要总结
The investigators will use different types of brain imaging (MRI) in patients with Phenylketonuria (PKU) who are currently not on a strict diet to test the hypothesis that there is improvement in brain circuitry and biochemistry after return to diet and/or sapropterin dihydrochloride (Kuvan).
详细描述
We plan to enroll 36 subjects with PKU. They will all be counseled to follow the PKU diet. They will be randomized to receive Kuvan. We will plan to enroll 12 in the diet alone group and 24 in the Kuvan group with the hope of 12 being responders (as defined by a 30% drop in blood phe levels). Those who do not have a blood response with decreased Phe will still be evaluated for a neurological response as measured by neurocognitive testing and neuroimaging as outlined in this protocol. All 24 in the Kuvan group will receive a 1 month trial of Kuvan and then the responders will have their insurance cover the drug and for the non responders Biomarin will supply Kuvan.
Aim 1: To test the hypothesis that stable patients with PKU who are not currently on diet have specific brain biomarkers quantifiable by DTI, fMRI and MRS and that the levels of these biomarkers correlate with the clinical severity and outcome. Our pilot study and the research of others have suggested the following as potential biomarkers for neural injury in PKU:
- Metabolic abnormalities: elevated Phe concentrations as measured by MRS.
- White matter microstructure: measured by apparent diffusion coefficient, (ADC), using DTI.
- Working memory and attention/executive function: measured by fMRI, Near infrared spectroscopy (NIRS) and neuropsychological testing.
We will study these potential biomarkers in a group of well characterized adults with PKU who are not currently on diet or a strict diet as evidenced by elevated Phe, but who were identified by the newborn screen and may have been on diet during childhood, with varying severity of clinical involvement.
Aim 2: To measure changes in biomarkers validated in Aim 1 after return to diet +/- Kuvan (sapropterin dihydrochloride; Kuvan)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with PKU identified on Newborn screening and with phe concentration >12mg/dl on the newborn screen
- •Baseline phe level at study enrollment > 20 mg/dl (this is the level required for inclusion in the study, regardless of the level used to make diagnosis)
- •Age range: 18-45 years
- •Able to comply with neuroimaging without requiring sedation (typically requires IQ over 65). The IQ will be checked with the WASI (Weschler Adult scales of intelligence) before determining eligibility
- •Able to undergo neuroimaging safely (i.e. without presence of ferromagnetic devices)
- •Subject has ability to follow instructions in English
- •Female of childbearing age who is sexually active agrees to urine pregnancy test
- •Availability to come to Washington, DC to participate in this study
排除标准
- •Age range <18 or >45 years
- •Inability to comply with neuroimaging without the use of sedation (low IQ or claustrophobic)
- •Presence of ferromagnetic device(s) that preclude safe imaging including cardiac pacemaker, neural pacemaker, surgical clips in the brain or blood vessels, surgically implanted metal plates, screws or pins, cochlear implants or metal objects in their body
- •Pregnant female or breastfeeding at screening or planning to become pregnant at any time during the study.
- •Baseline phe < 20 mg/dl
- •Currently on Kuvan
- •History of substance abuse
研究组 & 干预措施
Diet
12 participants will be randomized to diet. Phe levels will be followed by blood levels. A dietician will analyze diet for phe content and advise
干预措施: diet (Dietary Supplement)
sapropterin dihydrochloride
Intervention: 24 participants will be randomized to receive the drug 10 mg/kg per day. Responders and non responders will remain on drug for four months
干预措施: sapropterin dihydrochloride (Drug)
结局指标
主要结局
Neuroimaging biomarkers
时间窗: at 4 months
An estimate of the change in white matter damage and biochemistry in participants with PKU after either diet/Kuvan
次要结局
- Brain biochemistry(at 4 months)
研究者
Andrea Gropman
Associate Professor
Children's National Research Institute