Phenylalanine and Its Impact on Cognition

Study Overview
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Brief Summary
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The PICO-Study is a randomized, placebo-controlled, crossover, non-inferiority trial conducted to add evidence to the current European treatment guidelines for adult patients with phenylketonuria.

Detailed Description
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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.

Official Title
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PICO: Phenylalanine and Its Impact on Cognition - Impact of Phenylalanine on Cognitive, Cerebral and Neurometabolic Parameters in Adult Patients With Phenylketonuria

Conditions
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Phenylketonuria

Intervention / Treatment
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* Dietary Supplement: Phenylalanine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phenylalanine<br>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<br>* The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group.<br>|
| Placebo Comparator: Placebo<br>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<br>* Placebo capsules are indistinguishable in their appearance from Phe capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory (accuracy) | Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with phenylketonuria (PKU). | After intervention phase 1 (after 4 weeks from baseline) | 
| Working memory (accuracy) | Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU. | After intervention phase 2 (after 12 weeks from baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory (reaction time) | Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU. | 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) | 
| Inhibition | Influence of 4 weeks of oral Phe administration vs. Placebo on inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) in adult patients with PKU. | 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) | 
| Cognitive flexibility | Influence of 4 weeks of oral Phe administration vs. Placebo on cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS in adult patients with PKU. | 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) | 
| Functional Magnetic Resonance Imaging (fMRI) (working memory) | Influence of 4 weeks of oral Phe administration vs. Placebo on intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner in adult patients with PKU. | 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) | 
| Resting-state fMRI | Influence of 4 weeks of oral Phe administration vs. Placebo on strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI in adult patients with PKU. | 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) | 
| Magnetic Resonance Spectroscopy (MRS) | Influence of 4 weeks of oral Phe administration vs. Placebo on brain Phe concentrations as measured by MRS in adult patients with PKU. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, Phenylketonuria, Phenylalanine, Diet, Neuropsychology, Working Memory, Neuroimaging