Effect of Large Neutral Amino Acids in Adults With Classical Phenylketonuria

Safety and Efficacy of Treatment With Large Neutral Amino Acids in Patients With Classical Phenylketonuria

The overall aim of this study is to evaluate LNAA treatment as a potential alternative to conventional dietary treatment for PKU. This study investigates the effects of LNAA treatment compared to the classic dietary treatment on cerebral dopamine synthesis in patients with classic PKU. We will assess LNAAs effectiveness on neurotransmitter synthesis, cognitive function, mental health, and safety, compared to the standard diet.

Study Overview

• Status: Recruiting
• Conditions: Brain Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Phenylketonurias; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Metabolic Disease
• Intervention / Treatment: Other: PreKUnil® LNAA Medical Food for PKU

Detailed Description

Standard treatment for Phenylketonuria (PKU) involves a lifelong, phenylalanine-restricted diet. Strict adherence to the diet is crucial, but often challenging. Large neutral amino acid (LNAA) supplementation is a potential alternative therapeutic approach for PKU management. The proposed mechanism involves competitive inhibition of phenylalanine (Phe) transport across the blood-brain barrier by high-dose LNAA, leading to reduced brain Phe levels. However, further investigation is needed to validate its efficacy and safety for PKU management.

A randomized, open-label, crossover trial will be conducted to assess the safety and efficacy of LNAA supplementation in PKU patients. After completion of the crossover study, participants will have the option to participate in an open-label extension study aimed at evaluating the long-term safety and efficacy of LNAA.

A healthy control group will be recruited to obtain baseline outcome measures. This project is expected to provide much-needed insights into the potential of LNAA in PKU management. The study also aims to gain a deeper understanding of the underlying pathophysiology of the disease. Finally, this work could lead to more personalized management strategies for PKU patients.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Allan Lund, Professor, MD, DMSc; Phone Number: +4535451303; Email: allan.lund@regionh.dk
• Study Contact Backup: Name: Olivia Fjellbirkeland, MD; Email: olivia.welle.fjellbirkeland@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Not yet recruiting
    • Copenhagen University Hospital, Rigshospitalet
    • Contact: Olivia Welle Fjellbirkeland, MD; Email: olivia.welle.fjellbirkeland@regionh.dk
  • Copenhagen, Denmark, 2300
    • Recruiting
    • Center for Inherited Metabolic Diseases
    • Contact: Olivia Fjellbirkeland; Phone Number: 40552002; Email: Fjell.olivia@outlook.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Patients ≥ 18 years of age with Classical PKU molecularly confirmed via the finding of two pathogenic variants in the phenylalanine hydroxylase (PAH) gene and/or historical evidence of Phe concentrations ≥1200 μmol/L in the medical history

Inclusion Criteria:

• Treatment initiation within the first month of life
• Intelligence quotient over 84, based upon the baseline neuropsychological evaluation
• Conventional dietary treatment up to minimum 15 years of age
• Signed informed consent
• Willing and able to comply with the protocol and study procedures

Exclusion Criteria:

• Unable or unwilling to adhere to the requirements of the study
• A female who is pregnant or breastfeeding or planning to get pregnant during the study period
• Concomitant medication that may interfere with the PET analysis, as judged by the investigator
• A serious neuropsychiatric disease that could interfere with the subject's ability to participate in the study at the discretion of the investigator
• Concomitant treatment with BH4 supplementation (sapropterin) or Pegvaliase-pqpz (PALYNZIQ)
• Failing to submit at least one blood Phe home sample during the year before study initiation
• Standard MRI contraindications
• Body weight over 110 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LNAA supplementation, Then Low-Phe diet; Phase 1: LNAA Treatment Period (8 weeks) Each participant will be prescribed a specific dosage of LNAA tablets to be taken three times daily. Phase 2: Washout (2 weeks) Participants will follow a liberalized diet and refrain from taking any LNAA or amino acid supplement. Phase 3: Low-Phe diet (8 weeks) Each participant will follow a low-phenylalanine diet. LNAA therapy will not be administered during this phase.	Other: PreKUnil® LNAA Medical Food for PKU; PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU.
Experimental: Low-Phe diet, Then LNAA supplementation; Phase 1: Low-Phe diet (8 weeks) Each participant will follow a low-phenylalanine diet. LNAA therapy will not be administered during this phase. Phase 2: Washout (2 weeks) Participants will follow a liberalized diet and refrain from taking any LNAA or amino acid supplement. Phase 3: LNAA Treatment Period (8 weeks) Each participant will be prescribed a specific dosage of LNAA tablets to be taken three times daily.	Other: PreKUnil® LNAA Medical Food for PKU; PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dynamic positron emission tomography (PET) imaging with the fluorine-18-labeled tracer [18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl phenyl)nortropane ([18F]FE-PE2I)	Change in specific binding ratio of dopamine transporter (DaT) with [18F]FE-PE2I	Crossover study: at 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of treatment-emergent adverse events (TEAEs)	Subjects with at least one TEAE or serious TEAE	Baseline to week 80
Urine peripheral biomarkers of neurotransmitters	6-sulfatoxymelatonin and dopamine	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Adult attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS v1.1)	Patient-Reported Outcome Measure of attention in adults, 0-23, lowest is best	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Symptom Checklist-90-Revised (SCL-90-R)	Patient-Reported Outcome Measure of psychopathological symptoms, percentile, lowest is best	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Neuropsychological testing of flexibility and verbal fluency	Change in flexibility and verbal fluency using the Delis-Kaplan Executive Function System (D-KEFS) customized for study	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Behaviour Rating Inventory of Executive Function - Adult version (BRIEF-A)	Patient-Reported Outcome Measure of executive functioning (ages 18 to 90), percentile, lowest is best	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
PKU-QOL Questionnaire Adult version	Patient-Reported Outcome Measure of the impact of PKU and the PKU diet on quality of life	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Computerized neuropsychological testing (responses over study iPad)	Cambridge Neuropsychological Test Automated Assessment Battery (CANTAB) customized for study	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Magnetic Resonance Imaging (MRI)	Percent of patients with anatomic anomalies on MRI of the brain	Inclusion
Wechsler Adult Intelligence Scale (WAIS) - IV	Baseline measure of cognitive ability, 40-160, highest is best	Inclusion
Fasting plasma amino acids, dried blood spots (finger-prick method)	Biomarkers such as the plasma Phe, Phe/Tyr ratio, Tyr/LNAA, Trp/LNAA ratio	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Adherence to dietary treatment	3-day diet record	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Brain perfusion measures	Dynamic PET Imaging differences between groups and with intervention	Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Prekulab Ltd ApS
• Investigators: Principal Investigator: Allan Lund, Professor, MD, DMSc, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: March 15, 2024
• First Submitted That Met QC Criteria: March 22, 2024
• First Posted (Actual): March 29, 2024

Study Record Updates

• Last Update Posted (Actual): April 6, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Phenylketonurias; Brain Diseases; Metabolic Diseases; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Brain Diseases, Metabolic, Inborn
• Other Study ID Numbers: H-24041030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No