Phenylketonuria
Conditions
Keywords
Phenylketonuria, PKU, Phenylalanine, Diet, Neuropsychology, Working Memory, Neuroimaging
Brief summary
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
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.
Interventions
DIETARY_SUPPLEMENTPhenylalanine
The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group.
DRUGPlacebo
Placebo capsules are indistinguishable in their appearance from Phe capsules
Sponsors
University of Zurich
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Working memory (accuracy) | After intervention phase 1 (after 4 weeks from baseline) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on brain Phe concentrations as measured by MRS in adult patients with PKU. |
| 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) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood concentration of Phe & working memory | Baseline | Relationship between blood concentrations of Phe and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
| Working memory (accuracy): Patients vs. Controls | Baseline | Differences in working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls. |
| Working memory (reaction time): Patients vs. Controls | Baseline | Differences in working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls. |
| Inhibition: Patients vs. Controls | Baseline | Differences in inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) between adult patients with PKU and healthy controls. |
| Cognitive flexibility: Patients vs. Controls | Baseline | Differences in cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS between adult patients with PKU and healthy controls. |
| DTI: Patients vs. Controls | Baseline | Differences in white matter integrity (DTI) between adult patients with PKU and healthy controls. |
| fMRI of working memory: Patients vs. Controls | Baseline | Differences in intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner between adult patients with PKU and healthy controls. |
| ASL: Patients vs. Controls | Baseline | Differences in cerebral blood flow assessed using ASL between adult patients with PKU and healthy controls. |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on white matter integrity assessed using DTI in adult patients with PKU. |
| Structural MRI (cortical thickness): Patients vs. Controls | Baseline | Differences in cortical thickness between adult patients with PKU and healthy controls. |
| Structural MRI (cortical surface area): Patients vs. Controls | Baseline | Differences in cortical surface area between adult patients with PKU and healthy controls. |
| Structural MRI (cortical volume): Patients vs. Controls | Baseline | Differences in cortical volume between adult patients with PKU and healthy controls. |
| Structural MRI (cortical curvature): Patients vs. Controls | Baseline | Differences in cortical curvature between adult patients with PKU and healthy controls. |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using the short form of the Profile of Mood States (POMS) in adult patients with PKU. |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using Beck's Depression Inventory (BDI-II) in adult patients with PKU. The total score indicates severity, ranging from 0 (no depression) to 63 (severe depression). |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on the total score in the questionnaire PKU quality of life (PKUQOL) in adult patients with PKU. |
| Resting-state fMRI: Patients vs. Controls | Baseline | Differences in strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI between adult patients with PKU and healthy controls. |
| 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) | Influence of 4 weeks of oral Phe administration vs. Placebo on cerebral blood flow assessed using ASL in adult patients with PKU. |
| Structural MRI (cortical thickness) & working memory | Baseline | Relationship between cortical thickness and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
| Structural MRI (cortical surface area) & working memory | Baseline | Relationship between cortical surface area and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
| Structural MRI (cortical volume) & working memory | Baseline | Relationship between cortical volume and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
| Structural MRI (cortical curvature) & working memory | Baseline | Relationship between cortical curvature and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
| MRS & working memory | Baseline | Relationship between brain concentrations of Phe (MRS) and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU. |
Countries
Switzerland
Outcome results
None listed