Amino Acid Metabolism, Inborn Errors, Brain Diseases, Brain Diseases, Metabolic, Brain Diseases, Metabolic, Inborn, Genetic Diseases, Inborn, Metabolic Disease, Metabolism, Inborn Errors, Phenylketonurias
Conditions
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.
Interventions
PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU.
Sponsors
Prekulab Ltd ApS
Rigshospitalet, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Crossover study: at 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Change in specific binding ratio of dopamine transporter (DaT) with \[18F\]FE-PE2I |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adult attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS v1.1) | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Patient-Reported Outcome Measure of attention in adults, 0-23, lowest is best |
| Symptom Checklist-90-Revised (SCL-90-R) | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Patient-Reported Outcome Measure of psychopathological symptoms, percentile, lowest is best |
| Neuropsychological testing of flexibility and verbal fluency | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Change in flexibility and verbal fluency using the Delis-Kaplan Executive Function System (D-KEFS) customized for study |
| Behaviour Rating Inventory of Executive Function - Adult version (BRIEF-A) | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Patient-Reported Outcome Measure of executive functioning (ages 18 to 90), percentile, lowest is best |
| PKU-QOL Questionnaire Adult version | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Patient-Reported Outcome Measure of the impact of PKU and the PKU diet on quality of life |
| Computerized neuropsychological testing (responses over study iPad) | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Cambridge Neuropsychological Test Automated Assessment Battery (CANTAB) customized for study |
| Urine peripheral biomarkers of neurotransmitters | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | 6-sulfatoxymelatonin and dopamine |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Baseline to week 80 | Subjects with at least one TEAE or serious TEAE |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fasting plasma amino acids, dried blood spots (finger-prick method) | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Biomarkers such as the plasma Phe, Phe/Tyr ratio, Tyr/LNAA, Trp/LNAA ratio |
| Adherence to dietary treatment | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | 3-day diet record |
| Brain perfusion measures | Crossover study: at baseline, 8, 10 and 18 weeks from baseline, Extension study: at 12 months from baseline | Dynamic PET Imaging differences between groups and with intervention |
| Brain Magnetic Resonance Imaging (MRI) | Inclusion | Percent of patients with anatomic anomalies on MRI of the brain |
| Wechsler Adult Intelligence Scale (WAIS) - IV | Inclusion | Baseline measure of cognitive ability, 40-160, highest is best |
Countries
Denmark
Contacts
Primary ContactAllan Lund, Professor, MD, DMSc
Backup ContactOlivia Fjellbirkeland, MD
Outcome results
None listed