Clinical trial NCT03788343: Phenylalanine and Its Impact on Cognition
Official title: PICO: Phenylalanine and Its Impact on Cognition - Impact of Phenylalanine on Cognitive, Cerebral and Neurometabolic Parameters in Adult Patients With Phenylketonuria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Phenylketonuria
Keywords: Phenylketonuria
PKU
Phenylalanine
Diet
Neuropsychology
Working Memory
Neuroimaging
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: University of Zurich
First posted: 2018-12-27
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility 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

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

Primary outcomes:
measure: Working memory (accuracy)
timeFrame: After intervention phase 1 (after 4 weeks from baseline)
measure: Working memory (accuracy)
timeFrame: After intervention phase 2 (after 12 weeks from baseline)
Secondary outcomes:
measure: Working memory (reaction time)
timeFrame: 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)
measure: Inhibition
timeFrame: 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)
measure: Cognitive flexibility
timeFrame: 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)
measure: Functional Magnetic Resonance Imaging (fMRI) (working memory)
timeFrame: 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)
measure: Resting-state fMRI
timeFrame: 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)
measure: Magnetic Resonance Spectroscopy (MRS)
timeFrame: 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)
Other outcomes:
measure: Diffusion Tensor Imaging (DTI)
timeFrame: 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)
measure: Arterial Spin Labeling (ASL)
timeFrame: 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)
measure: Structural MRI (cortical thickness) & working memory
timeFrame: Baseline
measure: Structural MRI (cortical surface area) & working memory
timeFrame: Baseline
measure: Structural MRI (cortical volume) & working memory
timeFrame: Baseline
measure: Structural MRI (cortical curvature) & working memory
timeFrame: Baseline
measure: MRS & working memory
timeFrame: Baseline
measure: Blood concentration of Phe & working memory
timeFrame: Baseline
measure: Working memory (accuracy): Patients vs. Controls
timeFrame: Baseline
measure: Working memory (reaction time): Patients vs. Controls
timeFrame: Baseline
measure: Inhibition: Patients vs. Controls
timeFrame: Baseline
measure: Cognitive flexibility: Patients vs. Controls
timeFrame: Baseline
measure: DTI: Patients vs. Controls
timeFrame: Baseline
measure: fMRI of working memory: Patients vs. Controls
timeFrame: Baseline
measure: ASL: Patients vs. Controls
timeFrame: Baseline
measure: Resting-state fMRI: Patients vs. Controls
timeFrame: Baseline
measure: Structural MRI (cortical thickness): Patients vs. Controls
timeFrame: Baseline
measure: Structural MRI (cortical surface area): Patients vs. Controls
timeFrame: Baseline
measure: Structural MRI (cortical volume): Patients vs. Controls
timeFrame: Baseline
measure: Structural MRI (cortical curvature): Patients vs. Controls
timeFrame: Baseline
measure: Mood (POMS)
timeFrame: 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)
measure: Mood (BDI-II)
timeFrame: 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)
measure: PKU Quality of Life
timeFrame: 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)
Locations:
city: Bern
country: Switzerland
facility: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital
Study officials:
affiliation: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital
name: Regula Everts, Prof. Dr. phil.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trepp R, Muri R, Abgottspon S, Bosanska L, Hochuli M, Slotboom J, Rummel C, Kreis R, Everts R. Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial. Trials. 2020 Feb 13;21(1):178. doi: 10.1186/s13063-019-4022-z.