Impact Of A Phe-Restricted Diet On Gut Health In Children With PKU

NCT07728032 | Recruiting

• 1 other identifier: IRAS project ID: 353831
• Study Type: observational
• Target: 148
• Locations: 1 country
• Sites: 1

Brief Summary

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. The mainstay of treatment is a Phe-restricted diet, which aims to maintain blood Phe concentrations within the recommended range and prevent neurological complications. Some individuals with PKU respond to pharmacological treatments, including sapropterin, a synthetic form of tetrahydrobiopterin (BH4), or sepiapterin. These treatments may increase Phe tolerance and allow a less restrictive diet. Diet is an important determinant of gut microbiota composition and function. However, the effects of the Phe-restricted diet and pharmacologically enabled dietary relaxation on the gut microbiota in PKU remain poorly understood. This observational study includes children and adolescents with PKU aged 3-17 years attending Birmingham Children's Hospital. Participants include those managed exclusively with a Phe-restricted diet, those receiving sapropterin, and those receiving sepiapterin. One healthy household control is recruited for each participant with PKU. Faecal samples are collected for shotgun metagenomic sequencing and metabolite profiling. Dietary intake, gastrointestinal symptoms, stool characteristics, clinical information, and PKU treatment are also assessed. The study investigates whether gut microbiota composition, microbial functional potential, and faecal metabolite profiles differ between participants managed with a Phe-restricted diet, those receiving pharmacological treatment, and healthy household controls. The findings may improve understanding of the relationships between PKU treatment, dietary restriction, gastrointestinal health, and the gut microbiome and may inform future nutritional strategies for individuals with PKU.

Conditions

Phenylketonuria

Outcome Measures

Primary Outcomes (1)

• Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing

  Taxonomic profiles, expressed as the relative abundance of microbial taxa at phylum, genus, and species levels, are derived from shotgun metagenomic sequencing of one faecal sample per participant. Profiles are compared among participants with PKU managed by a phenylalanine-restricted diet alone, sapropterin, or sepiapterin and healthy household controls.

  At enrolment (single faecal sample collection)

Secondary Outcomes (6)

• Faecal gut microbiota alpha diversity assessed by shotgun metagenomic sequencing

  At enrolment, based on a single faecal sample

• Faecal gut microbiota beta diversity assessed by shotgun metagenomic sequencing

  At enrolment, based on a single faecal sample

• Microbial functional potential assessed by shotgun metagenomic sequencing

  At enrolment, based on a single faecal sample

• Gastrointestinal symptom burden assessed using the PedsQL Gastrointestinal Symptoms Module

  At enrolment, based on a single faecal sample

• Stool form assessed using the Bristol Stool Form Scale

  At enrolment, based on a single faecal sample

Study Arms (4)

PKU - Diet Only

Children and adolescents aged 3-17 years with early-treated phenylketonuria who are managed exclusively with a phenylalanine-restricted diet and are not receiving sapropterin or sepiapterin. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.

Other: Phenylalanine-restricted diet alone

PKU - Sapropterin

Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sapropterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment. Sapropterin treatment is not assigned as part of this observational study. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.

Drug: Sapropterin Dihydrochloride

PKU - Sepiapterin

Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sepiapterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment. Sepiapterin treatment is not assigned as part of this observational study. Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.

Drug: Sepiapterin

Healthy Household Controls

Healthy household members without phenylketonuria who are recruited at a ratio of one control for each participant with phenylketonuria. Controls provide a faecal sample and complete the relevant dietary, gastrointestinal symptom, and stool assessments.

Interventions

Phenylalanine-restricted diet alone OTHER

Participants are managed with a phenylalanine-restricted diet and prescribed protein substitutes as part of their usual clinical care. They are not receiving sapropterin or sepiapterin. Dietary treatment is not assigned or modified by this observational study.

PKU - Diet Only

Sapropterin Dihydrochloride DRUG

Participants receive sapropterin as part of their usual clinical care, alongside an individualised phenylalanine-restricted diet. Sapropterin treatment and dosage are prescribed independently of this observational study and are not assigned or modified by the investigators.

Also known as: Kuvan

PKU - Sapropterin

Sepiapterin DRUG

Participants receive sepiapterin as part of their existing clinical management, alongside an individualised phenylalanine-restricted diet. Sepiapterin treatment and dosage are determined independently of this observational study and are not assigned or modified by the investigators.

Also known as: Sephience

PKU - Sepiapterin

Eligibility Criteria

• Age: 3 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Children and adolescents aged 3-17 years with early-treated phenylketonuria receiving clinical care at Birmingham Children's Hospital are recruited into one of three cohorts according to their current treatment: a phenylalanine-restricted diet alone, sapropterin, or sepiapterin. One healthy household control aged 3 years or older, without phenylketonuria or another inherited metabolic disorder, is recruited for each participant with phenylketonuria. All participants are enrolled according to predefined eligibility criteria.

You may qualify if:

• Participants with PKU:
• Aged 3-17 years.
• Confirmed diagnosis of phenylketonuria following newborn screening.
• Receiving ongoing clinical management for PKU.
• For the diet-only cohort: managed with standard phenylalanine-restricted dietary treatment and not receiving sapropterin or sepiapterin.
• For the sapropterin cohort: receiving sapropterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription.
• For the sepiapterin cohort: receiving sepiapterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription.
• Healthy household controls:
• Aged 3 years or older.
• Living in the same household as a participating child or adolescent with PKU.
• No known diagnosis of PKU or another inherited metabolic disorder.

You may not qualify if:

• Congenital malformations.
• Chronic gastrointestinal disease.
• Endocrine, liver, or kidney disease.
• Other chronic medical conditions likely to affect gut microbiota composition.
• Following a therapeutic diet for a medical condition other than PKU within the six months before stool sample collection.

Sponsors & Collaborators

• Birmingham Women's and Children's NHS Foundation Trust: lead
• Universidade Nova de Lisboa: collaborator

Study Sites (1)

Birmingham Children's Hospital

Birmingham, Birmingham, B4 6NH, United Kingdom

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Stool samples are collected and stored at -80°C for microbial DNA extraction and shotgun metagenomic sequencing. The study does not involve the analysis of human genomic DNA. Residual stool samples and extracted microbial DNA are retained in accordance with the approved protocol and participant consent.

MeSH Terms

Conditions

Phenylketonurias

Interventions

sapropterin; sepiapterin

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Anita MacDonald, PhD

  Birmingham Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anita MacDonald, PhD

CONTACT

+44 121 333 9999; anita.macdonald@nhs.net

Catarina Rodrigues, MSc

CONTACT

+44 121 472 1377; catarina.rodrigues1@nhs.net

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2026
• First Posted: July 27, 2026
• Study Start: October 1, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: July 27, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)