Additional Dietary Large Neutral Amino Acids (LNAA) for Improved Symptoms in Adult Classical Phenylktonuria (PKU)

Study Overview
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Brief Summary
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This research investigates the effects of combining a phenylalanine restricted diet (usual care) with LNAA supplementation (adjuvant LNAA) in well-controlled adults with classical PKU. The hypothesis is that symptoms are improved in well-controlled patients who receive adjuvant LNAA therapy compared with diet monotherapy. Six symptomatic classical PKU adults will be enrolled to test the hypothesis in a small series of N-of-1 randomized controlled trials over 18-weeks. All assessments will be collected in patient's homes. A 3-month follow-up period will assess the longer-term effects of adjuvant LNAA in patients who show clinical benefit at the end of the intervention period.

Detailed Description
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Clinical care of PKU confronts an increasing proportion of early-treated well-controlled adults, with a treatment goal that quality of life be as normal as possible. Even adults who have successfully managed their blood phenylalanine levels from birth can have symptoms which impact daily function. New therapies that target symptoms are needed, especially for symptomatic well-controlled classical adults with few treatment options. In Denmark and the LAC+USC U.S. clinic, adults are offered large neutral amino acid (LNAA) supplements when diet monotherapy becomes less effective for symptom management, or the patient wants a less restrictive diet. Many patients report improved symptoms. LNAA supplementation doesn't significantly reduce blood phenylalanine, suggesting a different mechanism for patient perceived benefits. Both LNAA supplementation and a phenylalanine restricted diet aim to improve brain neurotransmitter biochemistry to optimize outcomes through dietary intervention. The overall objective of this research is to evaluate additional dietary LNAAs on symptom management in adults with classical PKU at an individual level. N-of-1 randomized controlled trials will provide the highest level of evidence. The scientific premise is that manipulation of dietary LNAAs affects blood LNAA concentrations. LNAAs compete with phenylalanine for a shared transporter from blood to brain, dependent on blood concentrations and transporter affinities. Higher blood phenylalanine levels in adult PKU, with high transport affinity, produces excessive phenylalanine brain entry at the expense of other LNAAs. Insufficient LNAAs impairs synthesis of chemicals in the brain (neurotransmitters), a suggested mechanism of action for adult PKU symptoms. Additional dietary LNAAs may help to overcome this limitation of adult usual care. The study uses established PKU treatment products (medical foods) and biomarkers, (1) to determine effect of the adjuvant LNAA diet in symptom management; and (2) to evaluate correlations between changes in biomarkers and changes in symptoms during the intervention. Should findings show additive clinical value of LNAAs to the PKU diet, the strategy may become a useful adjunct. For participants, results will bring them closer to evidence-based individualized care. This work could advance the field closer toward personalized management.

Official Title
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Can Care of Adult PKU Be Improved With Additional Dietary Large Neutral Amino Acids: An N-of-1 Study

Conditions
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Phenylketonurias

Intervention / Treatment
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* Other: PreKUnil® LNAA Medical Food for PKU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 18 years diagnosis of classical PKU (blood phenylalanine ≥1200 µmol pre-treatment or off-treatment ≥ 2 PKU-related symptoms with clinically meaningful negative impact on daily life is in regular clinical monitoring and is treated with a PKU diet with a natural protein restriction and medical foods average blood phenylalanine levels between 360 and 900 µmol in past one year able and willing to provide consent demonstrates capacity to complete all requirements of the protocol if on medications approved by the Principal Investigator agrees not to alter dose for duration of study has stable daily access to phone, internet, and physical address Exclusion Criteria: women who are breastfeeding, pregnant or planning to become pregnant in the next year use of adjuvant PKU treatments (LNAAs, Kuvan®, Palinziq®) within past 3 months use of psychotropic medications, melatonin, or any serotonin-reuptake inhibitors within past 3 months demonstrates insufficient motivation or time required to complete full trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized controlled trials in individual patients (interventional N-of-1 RCTs) offer an alternative research design to parallel group randomized controlled trials. The N-of-1 study attempts to determine the more effective treatment for one patient using multiple crossovers, with repetition providing statistical power.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active LNAA<br>Active LNAA tablets are given to each participant in 3 multiple crossovers for a total exposure to the Active Comparator 3 times. The allocation is randomized within each cycle of two treatments (active/inactive). There are 3 total cycles for each participant. The intervention is PreKUnil® tablets. | Other: PreKUnil® LNAA Medical Food for PKU<br>* PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU. PreKUnil® inactive LNAA is a customized placebo for this research.<br>|
| Placebo Comparator: Inactive LNAA<br>Inactive LNAA tablets (placebos) are given to each participant in 3 multiple crossovers for a total exposure to the Inactive Comparator 3 times. The allocation is randomized within each cycle of two treatments (inactive/active). There are 3 total cycles for each participant. The placebo intervention is PreKUnil® placebo tablets. | Other: PreKUnil® LNAA Medical Food for PKU<br>* PreKUnil® LNAA Medical Food for PKU is a commercially available active LNAA treatment product for PKU. PreKUnil® inactive LNAA is a customized placebo for this research.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Personalized Symptom Index | Assesses the subjective effect of the interventions on the personally relevant two most bothersome symptoms for the individual patient as identified in a Symptom Elicitation Interview | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute plasma phenylalanine concentration, dried blood spots (finger-prick method) | Primary FDA-qualified biomarker for PKU | 3 weeks | 
| Fasting plasma LNAAs, dried blood spots (finger-prick method) | Secondary biomarkers such as the plasma Phe/Tyr ratio, Tyr/LNAA, Trp/LNAA ratio | 3 weeks | 
| Urine peripheral biomarkers of neurotransmitters, dried urine spots | 6-sufatoxymelatonin and dopamine | 3 weeks | 
| Computerized neuropsychological testing (responses over study iPad from home) | Cambridge Neuropsychological Test Automated Assessment Battery (CANTAB) customized for study | 3 weeks | 
| PKU-QOL Questionnaire Adult version (responses over study iPad from home) | 65-item (20 min) Patient-Reported Outcome Measure of the impact of PKU and the PKU diet on quality of life | 3 weeks | 
| Psychological General Well-Being Index (responses over study iPad from home) | 22-item (15 min) Patient-Reported Outcome Measure of well-being | 3 weeks | 
| Adult ADHD Self-Report Scale (ASRS v1.1) | 9-item inattention subscale (10 min) Patient-Reported Outcome Measure of attention | 3 weeks | 
| 3-Day Diet Record | Complete recording of 24-hr intake for 3 days (45 min) | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-of-1 randomized controlled trials