Carrier of PhenylketonuriaNCT07220265
Impact of Phenylalanine Elevations on Brain and Cognition in Adult PKU Carriers
A study testing Phenylalanine (Phe) in people with Carrier of Phenylketonuria and Healthy, run by University of Missouri-Columbia at 1 site in United States.
Trial summary
The goal of this clinical trial is to advance our understanding of the cognitive and neurophysiologic sequelae associated with suboptimal phenylalanine (Phe) metabolism in heterozygous carriers of phenylketonuria (PKU). Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Carrier of Phenylketonuria, Healthy
- What is being tested?
- Phenylalanine (Phe)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 36 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Dec 2025to 1 Mar 2027
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age 18-60 years
- For the PKU carrier group: Individuals who are the parent of an individual with PKU or who are otherwise have confirmed PKU carrier status (e.g., a sibling of someone with PKU who has had genetic testing done)
- For the non-carrier group: Individuals who do not have PKU or a family history of PKU
Who cannot join
- Obesity as defined by a body mass index (BMI) over 30*
- Taking oral contraceptives on the day of testing session*
- Positive cotinine urine test showing nicotine use
- History of major neurologic condition (e.g., multiple sclerosis, severe closed head injury, Parkinson's disease)) unrelated to PKU and known to adversely impact brain health and function
- Contraindications for safe MRI participation such as (a) pregnancy or plans to become pregnant during period of study enrollment; or (b) metallic objects inside the body (e.g., surgical staples left in the body following surgery, middle ear prosthesis, metal foreign objects lodged inside the eye, heart pacemakers).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Missouri-Columbia
Columbia, Missouri, 65201
Shawn Christ, 573-884-8140, christse@missouri.edu
About this study
Official title: The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)
The goal of this clinical trial is to advance our understanding of the cognitive and neurophysiologic sequelae associated with suboptimal phenylalanine (Phe) metabolism in heterozygous carriers of phenylketonuria (PKU). The main questions it aims to answer are:
- Do PKU carriers experience prolonged elevations in brain Phe levels following oral ingestion of dietary Phe?
- Do PKU carriers experience disruptions in cognitive functioning following oral ingestion of dietary Phe?
- Do PKU carriers experience atypical brain activity following oral ingestion of dietary Phe? Researchers will compare PKU carriers and non-carriers following oral ingestion of dietary Phe and a placebo.
Read more
Participants will:
- Consume Phe or a placebo at two separate visits to our facility
- At each visit, they will complete a series of MRIs and cognitive tests throughout the day
Read the detailed description
Limitations inherent in past studies of phenylketonuria (PKU) carriers (e.g., poor genetic characterization of sample resulting in inclusion of homozygous non-PKU relatives, reliance on rudimentary or overly broad behavioral assessment tools) make it difficult to conclude the extent to which neurophysiologic and cognitive processes are affected in these individuals. To address this gap in the literature, we propose to conduct a double-blind crossover study in a sample of genetically-confirmed sample of 18 heterozygous PKU carriers and 18 non-carriers. A principled investigation of the effects of elevated phenylalanine (Phe) on neurocognition will involve participants performing an fMRI n-back WM task, resting state scan, and a battery of select cognitive tests at 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo. Blood and brain levels of Phe and Tyr will also be assessed at each timepoint.
- Conditions
- Carrier of Phenylketonuria, Healthy
- Being tested
- Phenylalanine (Phe), Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Phenylalanine (Phe)Dietary supplement
Oral ingestion of phenylalanine (Phe)
PlaceboDietary supplement
Oral ingestion of Placebo (Vitamin C)
| Study group | Role | What they receive |
|---|---|---|
| PKU Carriers | Other | Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU) Receives: Dietary Supplement: Phenylalanine (Phe); Dietary Supplement: Placebo |
| Non-Carriers | Other | Individuals who do not carry a pathogenic variant of the PAH gene Receives: Dietary Supplement: Phenylalanine (Phe); Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Phenylalanine Levels
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Brain Phenylalanine Levels
Brain Phenylalanine Levels estimated using magnetic resonance spectroscopy (MRS)
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Brain Phenylalanine-to-Tyrosine Ratio
Ratio of Phenylalanine-to-Tyrosine concentrations in the brain as estimated using magnetic resonance spectroscopy (MRS)
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Neural Activity during Go/No-Go Task
Pattern of brain activation as captured using functional MRI while performing a go/no-go inhibitory task
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Operational Span Task
Performance-based measure of working memory ability. In this task, participants first solve a math problem and then see a letter, and then solve another math problem, and see another letter. This math-letter sequence is repeated from three to seven times for each trial with an unpredictable length each time. After each math-letter sequence, participants are asked to recall, in order, the preceding letters. Scores are calculated by summing the number of letters correctly recalled in the correct order.
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Multi-Source Interference Task
Performance-based measure of focused attention. ). In this task, participants are shown a display containing three horizontally-aligned numbers (i.e., 1, 2, or 3) and asked to respond as quickly as possible to the location (position #1, 2, or 3) of the number stimulus that is different from the others. The location may be congruent (e.g., "323") or incongruent (e.g., "112") with identity of the target number. Mean response time and error rate will served as the outcome variables.
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Grooved Pegboard Test
Performance-based measure of processing speed \& fine motor control
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Resting-State Functional Connectivity
Synchronization of neural activity within brain networks as measured by functional MRI while participants are at rest
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Secondary outcomes (9)
Brain concentrations of glutamate, glutathione, creatine, and other metabolites
Concentrations of various brain metabolites as estimated using magnetic resonance spectroscopy (MRS)
Measured: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
PROMIS Anxiety - Short Form 8a
A patient-reported outcome (PRO) measure assessing symptoms of anxiety. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.
Measured: Baseline only
PROMIS Depression - Short Form 8a
A patient-reported outcome (PRO) measure assessing symptoms of depression. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.
Measured: Baseline only
PROMIS Sleep - Short Form 8a
A patient-reported outcome (PRO) measure assessing symptoms of sleep disturbance. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.
Measured: Baseline only
PROMIS Fatigue - Short Form 8a
A patient-reported outcome (PRO) measure assessing symptoms of fatigue. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.
Measured: Baseline only
PROMIS Cognitive Function - Short Form 8a
A patient-reported outcome (PRO) measure assessing symptoms of cognitive dysfunction. Scores range from 8 to 40, with higher scores indicating more/worse symptoms.
Measured: Baseline only
• Executive Function, Attention, and Speed Symptom Inventory (EASSI)
Patient-reported outcome (PRO) measure of everyday symptoms of cognitive dysfunction. Scores range from 72 to 360, with higher scores indicating more/worse symptoms.
Measured: Baseline only
Adult ADHD Self-Report Scale (ASRS)
Patient-reported outcome (PRO) measure of ADHD symptoms. Scores range from 0 to 124, with higher scores indicating more/worse symptoms.
Measured: Baseline only
Matrix Reasoning subtest from the WASI-2
Performance-based measure of fluid intelligence
Measured: Baseline only
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2025
- Study start19 Dec 2025
- Primary completion1 Mar 2027 (estimated)
- Study completion1 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Carrier of PhenylketonuriaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 36 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Missouri-Columbia
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Shawn Christ, University of Missouri-Columbia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07220265
- Sponsor's protocol ID
- 2092228
- Other IDs
- R21HD115129-01A1
- Status last verified
- Oct 2026
- First submitted
- 20 Oct 2025
- Last updated
- 22 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Demographic, blood amino acid levels, cognitive test performance, and MRI data (structural, spectroscopy, functional) will be acquired from 18 healthy adult carriers for PKU and 18 matched healthy controls. All data will be de-identified prior to deposit in the NIMH Data Archive (NDA).