Effect of Large Neutral Amino Acids in Adults With Classical Phenylketonuria

Rigshospitalet

Status: Enrolling

Conditions: Phenylketonurias; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Disease; Amino Acid Metabolism, Inborn Errors; Brain Diseases

Treatments: Other: PreKUnil® LNAA Medical Food for PKU

Study type: Interventional

Funder types: Other

Identifiers

NCT06337864

H-24041030

Details and patient eligibility

About

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.

Full 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.

Enrollment: 30 estimated patients

Sex: All

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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30 participants in 2 patient groups

LNAA supplementation, Then Low-Phe diet

Experimental group

Description:

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.

Treatment:

Other: PreKUnil® LNAA Medical Food for PKU

Low-Phe diet, Then LNAA supplementation

Experimental group

Description:

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.

Treatment:

Other: PreKUnil® LNAA Medical Food for PKU