Clinical trial NCT04076176: The Effects of CGMP in Children and Adults With PKU
Official title: The Effects Of Casein Glycomacropeptide On Metabolic Control And General Health Status In Children And Adults With PKU: A Randomised Crossover Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Phenylketonurias
Keywords: Phenylketonuria
PKU
Child
Adult
GMP
Glycomacropeptide
Lead sponsor: Vitaflo International, Ltd
Sponsor class: INDUSTRY
Collaborators: name: Arla Foods
First posted: 2019-09-03
Enrollment: 12
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Randomised controlled trial with a crossover design. For early and continuously treated patients with phenylketonuria (PKU) that are adherent. Two 12-week periods where patients consume either casein glycomacropeptide (CGMP) based protein substitute or a free amino acid (AA) based protein substitute. 4 week wash out period in between. The protein substitutes will be consumed daily together with the patient's regular low protein diet.

Detailed description: The study is a randomised controlled trial with a crossover design conducted at several international study centres.

The study population is early and continuously treated patients with PKU that are adhering to their prescribed diet.

The participants will be given both a CGMP based protein substitute and a free AA based protein substitute as their main protein source on two different 12-week periods in a crossover design. The two periods will be separated by a 4 week wash out period.

The protein substitutes will be consumed daily together with the patient's regular low protein diet during the intervention periods.

Primary Objective The primary objective of the study is to investigate the effects of a CGMP based formula compared to an AA based formula upon mean plasma Phe levels after 12 weeks of daily intake in patients with PKU.

Secondary Objectives The secondary objectives of the study are to investigate if a CGMP based formula compared to an AA based formula in PKU patients provides any long-term health benefits concerning gut health, inflammation, oxidative stress and product acceptability.

Eligibility criteria: Inclusion Criteria:

* PKU patient diagnosed on newborn screening (NBS).
* \> 50% of protein intake from protein substitutes.
* (CHILDREN) Dietary intake of ≤ 1000 mg Phe from natural protein or ≤20 g natural protein inclusive of fruit and vegetables per day.
* (ADULTS) Dietary intake of ≤ 1500 mg Phe from natural protein or ≤ 30 g natural protein inclusive of fruit and vegetables per day.
* (CHILDREN) Three out of the last four consecutive Phe measurements within the target range (≤360 µmol/L in patients aged 4-12 years).
* (ADULTS) Two out of the last four consecutive Phe measurements within the target range (≤600 µmol/L for adults).
* Male or female aged 4-12 years or 18 years and over.
* Early and continuously treated. Adherent to their prescribed PKU diet consisting of a protein-restricted diet and free AA based protein substitute.
* Otherwise in good general health as evidenced by medical history.
* Able to provide written informed consent (patient or parent/guardian).
* Able to comply with the study protocol and take study product according to the opinion of the PI.
* Protein substitute intake provided by L-amino acid supplements only.
* (ADULTS) No studies have been done in pregnant women. To ensure patients safety, female patients of childbearing potential must have a negative pregnancy test prior to completing the screening procedures.
* (ADULTS) All female patients of childbearing potential and sexually mature males should be willing to use a medically accepted method of contraception throughout the study.
* Successful 3-day PKU Sphere taste test.

Exclusion Criteria:

* Concomitant diseases / disorders such as but not limited to renal or gut disease / disorders and diabetes.
* Currently or previously treated with tetrahydrobiopterin (BH4), pegylated recombinant phenylalanine ammonia lyase (PEG PAL), large neutral amino acids.
* Previous intake of CGMP for more than four consecutive weeks.
* Having a current infection.
* Known soya, milk or fish allergies / intolerance.
* Patients who are currently participating in, plan to participate in, or have participated in an interventional investigational drug, food or medical device trial within 30 days prior to screening visit.
* Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National Law in force.

Primary outcomes:
measure: Change in overnight fasting plasma Phe
timeFrame: Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)
measure: Change in overnight fasting plasma Tyr
timeFrame: Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)
measure: Change in overnight fasting blood Phe
timeFrame: Measured twice per week up to 32 weeks
measure: Change in overnight fasting blood Tyr
timeFrame: Measured twice per week up to 32 weeks
Secondary outcomes:
measure: Change in gut health: PedsQL Gastrointestinal Symptoms Scales, Version 3.0
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: Stool pH for reducing sugars
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: Stool calprotectin
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: Short chain fatty acids
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: Immunoglobulin A
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: Bristol stool form scale
timeFrame: Completed for 7 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in gut health: 3 day weighed diet diary
timeFrame: Completed for 3 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in anthropometric measurements: weight
timeFrame: Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in anthropometric measurements: height
timeFrame: Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Albumin
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Pre-albumin
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Transferrin
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Retinol-binding protein
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Glucose
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Haemoglobin A1C
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in IGF-1
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in C-peptide
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Short chain fatty acids
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change insulin production
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in alanine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in arginine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in asparagine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in citrulline
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in cystine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in glutamate
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in glutamine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in glycine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in histidine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in isoleucine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in leucine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in lysine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in methionine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in proline
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in ornithine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in phenylalanine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in serine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in taurine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in threonine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in tryptophan
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in tyrosine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in valine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in renal biomarkers: Serum cystatin C
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in renal biomarkers: Serum creatinine
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in renal biomarkers: Blood urea nitrogen
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Adiponectin
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in C-reactive protein (high sensitivity measurement)
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Serum myeloid-related protein
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Soluble Interleukin 2 Receptor
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in Inflammatory cytokine panel
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in oxidative stress: White cells glutathione (GSH)
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in oxidative stress: Plasma thiobarbituric acid-reactive species (TBAR)
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in oxidative stress:Total antioxidant reactivity (TAR)
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
measure: Change in patient opinion of acceptability of the product
timeFrame: Days 84 (visit 3) and 196 (visit 5)
measure: Change in hunger
timeFrame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)
Other outcomes:
Locations:
city: Kobenhavn
country: Denmark
facility: Rigshospitalet
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
state: Avon
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: West Midlands
Study officials:
affiliation: Birmingham Women's and Children's NHS Foundation Trust
name: Anita MacDonald
role: PRINCIPAL_INVESTIGATOR
References: