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| Name | Class |
|---|---|
| Prekulab Ltd ApS | UNKNOWN |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LNAA supplementation, Then Low-Phe diet | Experimental | 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. |
|
| Low-Phe diet, Then LNAA supplementation | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PreKUnil® LNAA Medical Food for PKU | Other | PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU. |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Incidence and severity of treatment-emergent adverse events (TEAEs) |
| 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 |
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:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Allan Lund, Professor, MD, DMSc | Contact | +4535451303 | allan.lund@regionh.dk | |
| Olivia Fjellbirkeland, MD | Contact | olivia.welle.fjellbirkeland@regionh.dk |
| Name | Affiliation | Role |
|---|---|---|
| Allan Lund, Professor, MD, DMSc | Rigshospitalet, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Inherited Metabolic Diseases | Recruiting | Copenhagen | 2300 | Denmark |
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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.
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Subjects with at least one TEAE or serious TEAE |
| Baseline to week 80 |
| 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 |
| 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 |
| Copenhagen University Hospital, Rigshospitalet | Not yet recruiting | Copenhagen | Denmark |
|
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D001928 | Brain Diseases, Metabolic |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D030342 | Genetic Diseases, Inborn |
| D008661 | Metabolism, Inborn Errors |
| D000592 | Amino Acid Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D010661 | Phenylketonurias |
| ID | Term |
|---|---|
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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