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

Primary Purpose

Phenylketonurias

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
PreKUnil® LNAA Medical Food for PKU
Sponsored by
University of Southern California
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Phenylketonurias focused on measuring N-of-1 randomized controlled trials

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Southern CaliforniaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active LNAA

Inactive LNAA

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
December 13, 2021
Last Updated
October 6, 2022
Sponsor
University of Southern California
Collaborators
National PKU Alliance
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1. Study Identification

Unique Protocol Identification Number
NCT05174559
Brief Title
Additional Dietary Large Neutral Amino Acids (LNAA) for Improved Symptoms in Adult Classical Phenylktonuria (PKU)
Official Title
Can Care of Adult PKU Be Improved With Additional Dietary Large Neutral Amino Acids: An N-of-1 Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2022 (Actual)
Primary Completion Date
July 31, 2023 (Anticipated)
Study Completion Date
October 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Southern California
Collaborators
National PKU Alliance

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Phenylketonurias
Keywords
N-of-1 randomized controlled trials

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
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
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
6 (Anticipated)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kathryn Moseley, RD, MS
Phone
714-642-8790
Email
kmoseley@usc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Annie Prince, RD. PhD
Phone
9713733482
Email
ap_867@usc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shoji Yano, MD, PhD
Organizational Affiliation
Keck School of Medicine at USC
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Southern California
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kathryn Moseley
Email
kmoseley@usc.edu
First Name & Middle Initial & Last Name & Degree
Shoji Yano, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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

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