Clinical trial NCT06337864: Effect of Large Neutral Amino Acids in Adults With Classical Phenylketonuria
Official title: Safety and Efficacy of Treatment With Large Neutral Amino Acids in Patients With Classical Phenylketonuria
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Amino Acid Metabolism, Inborn Errors
Metabolic Disease
Phenylketonurias
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Prekulab Ltd ApS
First posted: 2024-03-29
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, open-label, crossover trial. Participants will be randomly assigned to receive either LNAA treatment or the classic dietary treatment for 8 weeks, followed by a washout period of 2 weeks before receiving the other intervention for 8 weeks. Additionally, a healthy control group will be recruited for baseline measures.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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

Primary outcomes:
measure: 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)
timeFrame: Crossover study: at 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Secondary outcomes:
measure: Urine peripheral biomarkers of neurotransmitters
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Incidence and severity of treatment-emergent adverse events (TEAEs)
timeFrame: Baseline to week 80
measure: Adult attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS v1.1)
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Symptom Checklist-90-Revised (SCL-90-R)
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Neuropsychological testing of flexibility and verbal fluency
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Behaviour Rating Inventory of Executive Function - Adult version (BRIEF-A)
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: PKU-QOL Questionnaire Adult version
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Computerized neuropsychological testing (responses over study iPad)
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Other outcomes:
measure: Brain Magnetic Resonance Imaging (MRI)
timeFrame: Inclusion
measure: Wechsler Adult Intelligence Scale (WAIS) - IV
timeFrame: Inclusion
measure: Fasting plasma amino acids, dried blood spots (finger-prick method)
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Adherence to dietary treatment
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
measure: Brain perfusion measures
timeFrame: Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline
Locations:
city: Copenhagen
country: Denmark
facility: Center for Inherited Metabolic Diseases
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Allan Lund, Professor, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References: