Evaluating the Efficacy and Safety of Large Neutral Amino Acids in the Treatment of Classical Phenylketonuria

Metabolic Disease Clinical Trial

Official title:

Effect of Large Neutral Amino Acids in Classical Phenylketonuria

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06337864
• Other study ID #: H-24017055
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 2024
• Est. completion date: December 2027

Study information

• Verified date: March 2024
• Source: Rigshospitalet, Denmark
• Contact: Allan Lund, Professor, MD, DMSc
• Phone: +45 3545 1303
• Email: allan.lund[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This research investigates the effectiveness and safety of large neutral amino acid (LNAA) supplementation in patients with classical phenylketonuria (PKU). Advanced brain imaging techniques alongside comprehensive neuropsychological and functional assessments will be employed. Short-term and long-term follow-up of participants will be conducted.

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.

Two separate crossover studies will be conducted to assess the safety and efficacy of LNAA supplementation in PKU patients.

Study 1: LNAA vs. No Treatment: This crossover trial investigates the effects of LNAA supplementation compared to no treatment. Participants will undergo both treatment phases in a randomized order:

• Phase 1: Semi-free diet with LNAA [duration: 8 weeks]

• Phase 2: Semi-free diet with no supplementation [duration: 1 week]

Study 2: LNAA vs. Phe-restricted Diet: This crossover trial compares LNAA supplementation to the current standard treatment, the Phe-restricted diet. Participants will undergo both treatment phases in a randomized order:

• Phase 1: Semi-free diet with LNAA [duration: 8 weeks]

• Phase 2: Standard Phe-restricted diet [duration: 8 weeks]

An optional open-label extension study will be offered to participants from both crossover studies. This study will assess the long-term safety and effectiveness of LNAA therapy over a period of 16 months.

A healthy control group will be recruited to obtain baseline outcome measures. Subsequently, they will be administered LNAA supplementation for a period of 1 week and then reassessed.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 30
• Est. completion date: December 2027
• Est. primary completion date: December 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 16 Years to 50 Years

Eligibility

Patients = 16 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 (ideally < 10 days of age)

• Intelligence quotient (> 84) based upon the baseline neuropsychological evaluation

• Conventional dietary treatment up to minimum 15 years of age

• Written 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 sapropterin (BH4) supplementation or Pegvaliase-pqpz (PALYNZIQ)

• Failing to submit at least one blood Phe home sample during the year before study initiation

• Standard MRI contraindications

Related Conditions & MeSH terms

• Amino Acid Metabolism, Inborn Errors
• Brain Diseases
• Brain Diseases, Metabolic, Inborn
• Genetic Diseases, Inborn
• Metabolic Disease
• Metabolic Diseases
• Metabolism, Inborn Errors
• Phenylketonurias

Intervention

Other:
• PreKUnil® LNAA Medical Food for PKU
PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU.

Locations

Country	Name	City	State
Denmark	Copenhagen University Hospital, Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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 trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Other	Brain perfusion measures	Dynamic PET Imaging differences between groups and with intervention	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Other	Adherence to dietary treatment	3-day diet record	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Other	Brain Magnetic Resonance Imaging (MRI)	Percent of patients with anatomic anomalies on MRI of the brain	Inclusion
Other	Wechsler Adult Intelligence Scale (WAIS) - IV	Baseline measure of cognitive ability, 40-160, highest is best	Inclusion
Primary	Dynamic positron emission tomography (PET) imaging with the fluorine-18-labeled tracer [18F]-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl phenyl)nortropane ([18F]FE-PE2I)	Change in specific binding ratio of dopamine transporter (DaT) with [18F]FE-PE2I	Crossover trial 1: at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline Crossover trial 2: at 8 and 16 weeks from baseline Extension study: at 4 months and 12 to 16 months from baseline
Primary	Computerized neuropsychological testing (responses over study iPad)	Cambridge Neuropsychological Test Automated Assessment Battery (CANTAB) customized for study	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	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 trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Behaviour Rating Inventory of Executive Function - Second edition (BRIEF-2)	Patient-Reported Outcome Measure of executive functioning (ages 11 to 18), percentile, lowest is best	Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	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 trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Adolescent ADHD Self-Report Scale	Patient-Reported Outcome Measure of attention in adolescents, 0-75, lowest is best	Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	PKU-QOL Questionnaire Adolescent or Adult version	Patient-Reported Outcome Measure of the impact of PKU and the PKU diet on quality of life	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Symptom Checklist-90-Revised (SCL-90-R)	Patient-Reported Outcome Measure of psychopathological symptoms, percentile, lowest is best	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Behavior Assessment System for Children, Third Edition (BASC-3)	Adolescent Self-Report form for measure of psychological general well-being, percentile, lowest is best	Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	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 trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Urine peripheral biomarkers of neurotransmitters	6-sulfatoxymelatonin and dopamine	Crossover trial 1: Baseline, at 1 and 9 weeks from baseline, or at 8 and 9 weeks from baseline; Crossover trial 2: Baseline, at 8 and 16 weeks from baseline; Extension study: at 4 months and 12 to 16 months from baseline
Secondary	Incidence and severity of treatment-emergent adverse events (TEAEs)	Subjects with at least one TEAE or serious TEAE	Baseline to week 80