Phenylalanine and Its Impact on Cognition
关键词
抽象
描述
Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by deficiency of the phenylalanine hydroxylase enzyme leading to an impaired conversion of the amino acid phenylalanine (Phe) to tyrosine. Increased Phe concentrations in blood and brain during childhood can lead to severe intellectual disability, epilepsy and behavioral problems. However, since the introduction of newborn screening and early treatment with a dietary restriction of Phe (low protein diet) and Phe-free protein substitutes (amino acid mixtures) initiated soon after birth, patient with PKU no longer develop profound and irreversible intellectual disability. While there is a wide agreement on the treatment strategy and target Phe concentrations in childhood, no consensus on the safe Phe concentrations in adulthood has been reached so far. Traditionally, the low protein diet had been enforced only during childhood and adolescence, leaving adult patients with PKU "off-diet". Over the last decade, observational and cross-sectional studies associated high Phe in early-treated adult patients with cognitive problems, psychiatric symptoms and behavioral abnormalities. These association studies and one small interventional study led to substantially differing recommendations of national and international guidelines with regard to Phe target levels in adult patients with PKU. One of these guidelines is the highly controversial grade D recommendation of the most recent European guidelines to keep Phe concentrations below 600 μmol/L throughout adulthood. Consequently, the recommendations are not only unequally accepted by the treating metabolic specialists, more than 50 % of adults with PKU exhibit substantial difficulty in maintaining the compliance necessary to reach the recommended target Phe concentrations. Therefore, prospective intervention studies in adult patients with PKU are strongly needed to evaluate the effects of dietary restrictions on cognition, cerebral markers and quality of life. The PICO-Study aims at adding evidence to current guidelines and improving treatment recommendations. To this end, adult patients with PKU will participate in a randomized, placebo-controlled, double-blind, crossover, non-inferiority trial. With the intervention, the project evaluates the impact of temporarily elevated blood Phe levels on cognition and functional properties of the brain of adult patients. Results of the PICO-Study will help to increase knowledge about impaired cognitive functioning and neural abnormalities in adult patients with PKU and will improve guidelines on dietary treatment in these patients. Such guidelines can greatly influence clinical routine as well as patients' adherence to their diet and ultimately their quality of life.
日期
| 最后验证: | 08/31/2019 |
| 首次提交: | 12/16/2018 |
| 提交的预估入学人数: | 12/20/2018 |
| 首次发布: | 12/26/2018 |
| 上次提交的更新: | 09/03/2019 |
| 最近更新发布: | 09/05/2019 |
| 实际学习开始日期: | 08/18/2019 |
| 预计主要完成日期: | 01/31/2021 |
| 预计完成日期: | 01/31/2021 |
状况或疾病
干预/治疗
Dietary Supplement: Phenylalanine
Drug: Placebo
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Experimental: Phenylalanine Capsules containing 250 mg Phenylalanine (Phe). The daily dose will be chosen according to gender and weight at the time of T1 and will be divided in 3 separate doses. The assigned dose of the IMP will be kept throughout the whole study and weight fluctuations will not be considered.
Female
<60 kg: 1500 mg per day (divided in 3 doses): 250 mg 2-2-2-0
≥60 kg: 2000 mg per day (divided in 3 doses): 250 mg 2-2-4-0
Male
<60 kg: 2500 mg per day (divided in 3 doses): 250 mg 4-2-4-0
≥60 kg: 3000 mg per day (divided in 3 doses): 250 mg 4-4-4-0
Phe capsules can be ingested before, during or after a meal or together with other amino acid supplements. The last capsule of the given intervention period will be timed to be ingested with the last meal before the study visit.
Patients will take Phe for 4 weeks. | Dietary Supplement: Phenylalanine The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group. |
| Placebo Comparator: Placebo Capsules containing 250mg Placebo. Placebo capsules will be administered in identical manner to Phe capsules.
Patients will take the Placebo for 4 weeks. | Drug: Placebo Placebo capsules are indistinguishable in their appearance from Phe capsules |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | PATIENTS Inclusion Criteria: - PKU diagnosed after a positive newborn screening - Treatment with Phe-restricted diet starting within the first 30 days of life - Age ≥18 years - Capable of following the study design - Written informed consent Exclusion Criteria: - Patients with PKU not following a Phe-restricted diet within 6 months before the study - Phe concentration above 1600 µmol/L within 6 months before the study - Concomitant disease states suspected to significantly affect primary or secondary outcomes, e. g. untreated vitamin B12 deficiency - Known or suspected non-compliance, drug or alcohol abuse - Change in medications likely to significantly interfere with cognitive function testing - Known or suspected hypersensitivity or allergy to one of the ingredients of the placebo - Women who are pregnant or intent to get pregnant during the course of the study or who are breast feeding - Female participants of childbearing potential, not using and not willing to continue using one (or more) highly efficient (Pearl index less than 1) method of contraception for the entire study duration. - Inability to follow the procedures of the study, e. g. due to language problems (lack of fluency in German or French), psychological disorders, dementia, etc. of the participant. - Participation in another interventional study within the 30 days preceding and during the present study. - Previous enrolment into the current study - Conditions interfering with MRI such as magnetic (metallic) particles in the skull or brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or permanent retainers HEALTHY CONTROLS Inclusion Criteria: - Age ≥18 years - Comparable to patients with regard to age, gender and educational level - Capable of following the study design - Written informed consent Exclusion Criteria: - Known or suspected drug or alcohol abuse - Change in medications likely to significantly interfere with cognitive function testing - Women who are pregnant or intent to get pregnant during the course of the study or who are breast feeding - Inability to follow the procedures of the study, e. g. due to language problems (lack of fluency in German or French), psychological disorders, dementia, etc. of the participant. - Participation in another interventional study within the 30 days preceding and during the present study. - Previous enrolment into the current study - Conditions interfering with MRI such as magnetic (metallic) particles in the skull or brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or permanent retainers |
结果
主要结果指标
1. Working memory (accuracy) [After intervention phase 1 (after 4 weeks from baseline)]
2. Working memory (accuracy) [After intervention phase 2 (after 12 weeks from baseline)]
次要成果指标
1. Working memory (reaction time) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
2. Inhibition [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
3. Cognitive flexibility [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
4. Functional Magnetic Resonance Imaging (fMRI) (working memory) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
5. Resting-state fMRI [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
6. Magnetic Resonance Spectroscopy (MRS) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
其他成果措施
1. Diffusion Tensor Imaging (DTI) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
2. Arterial Spin Labeling (ASL) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
3. Structural MRI (cortical thickness) & working memory [Baseline]
4. Structural MRI (cortical surface area) & working memory [Baseline]
5. Structural MRI (cortical volume) & working memory [Baseline]
6. Structural MRI (cortical curvature) & working memory [Baseline]
7. MRS & working memory [Baseline]
8. Blood concentration of Phe & working memory [Baseline]
9. Working memory (accuracy): Patients vs. Controls [Baseline]
10. Working memory (reaction time): Patients vs. Controls [Baseline]
11. Inhibition: Patients vs. Controls [Baseline]
12. Cognitive flexibility: Patients vs. Controls [Baseline]
13. DTI: Patients vs. Controls [Baseline]
14. fMRI of working memory: Patients vs. Controls [Baseline]
15. ASL: Patients vs. Controls [Baseline]
16. Resting-state fMRI: Patients vs. Controls [Baseline]
17. Structural MRI (cortical thickness): Patients vs. Controls [Baseline]
18. Structural MRI (cortical surface area): Patients vs. Controls [Baseline]
19. Structural MRI (cortical volume): Patients vs. Controls [Baseline]
20. Structural MRI (cortical curvature): Patients vs. Controls [Baseline]
21. Mood (POMS) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
22. Mood (BDI-II) [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
23. PKU Quality of Life [4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)]
