Phenylalanine and Its Impact on Cognition

NCT03788343 | Completed Phase 4 DMC

• 2 other identifiers: 2018-016093837
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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.

Conditions

Phenylketonuria

Keywords

Phenylketonuria; PKU; Phenylalanine; Diet; Neuropsychology; Working Memory; Neuroimaging

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• 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)

• 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)

• 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)

• 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)

• 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)

Other Outcomes (23)

• 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)

• 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)

• Structural MRI (cortical thickness) & working memory

  Baseline

Study Arms (2)

Phenylalanine

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Phenylalanine DIETARY_SUPPLEMENT

The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group.

Phenylalanine

Placebo DRUG

Placebo capsules are indistinguishable in their appearance from Phe capsules

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Age ≥18 years
• Comparable to patients with regard to age, gender and educational level

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• University of Zurich: collaborator

Study Sites (1)

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital

Bern, 3010, Switzerland

Location

Related Publications (2)

• Trepp R, Muri R, Maissen-Abgottspon S, Haynes AG, Hochuli M, Everts R. Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial. Am J Clin Nutr. 2024 Apr;119(4):908-916. doi: 10.1016/j.ajcnut.2023.11.007. Epub 2024 Feb 9.

  PMID: 38569786 DERIVED

• 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.

  PMID: 32054509 DERIVED

MeSH Terms

Conditions

Phenylketonurias

Interventions

Phenylalanine

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Regula Everts, Prof. Dr. phil.

  Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 27, 2018
• Study Start: August 19, 2019
• Primary Completion: June 17, 2022
• Study Completion: June 17, 2022
• Last Updated: March 7, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)