The Effects of CGMP in Children and Adults With PKU

Phenylketonurias Clinical Trial

— ELEMENT  

Official title:

The Effects Of Casein Glycomacropeptide On Metabolic Control And General Health Status In Children And Adults With PKU: A Randomised Crossover Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04076176
• Other study ID #: MCT-CGMP-2017-05-23
• Secondary ID: 23952019/NW/0032
• Status: Completed
• Phase: N/A
• Start date: April 26, 2019
• Est. completion date: January 31, 2023

Study information

• Verified date: February 2024
• Source: Vitaflo International, Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: January 31, 2023
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Phenylketonurias

Intervention

Dietary Supplement:
• CGMP protein substitute
PKU sphere is a powdered, low phenylalanine protein substitute, containing a balanced mix of casein glycomacropeptide (CGMP) isolate, essential and non-essential amino acids, carbohydrate, vitamins, minerals, trace elements and the omega-3 long chain polyunsaturated fatty acid (LCP); docosahexaenoic acid.
• L-amino acid protein substitute
Patient may choose from a list of products, specified in the protocol, that are nutritionally comparable to PKU Sphere.

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Kobenhavn
United Kingdom	Birmingham Children's Hospital	Birmingham	West Midlands
United Kingdom	Bristol Royal Hospital for Children	Bristol	Avon

Sponsors (2)

Lead Sponsor	Collaborator
Vitaflo International, Ltd	Arla Foods

Countries where clinical trial is conducted

Denmark,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in overnight fasting plasma Phe	Overnight fasting plasma phenylalanine level (µmol/l)	Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)
Primary	Change in overnight fasting plasma Tyr	Overnight fasting plasma tyrosine level (µmol/l)	Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)
Primary	Change in overnight fasting blood Phe	Overnight fasting blood phenylalanine level (µmol/l) using blood spots	Measured twice per week up to 32 weeks
Primary	Change in overnight fasting blood Tyr	Overnight fasting blood tyrosine level (µmol/l) using blood spots	Measured twice per week up to 32 weeks
Secondary	Change in gut health: PedsQL Gastrointestinal Symptoms Scales, Version 3.0	Five point frequency scale for each question: Never (0), Almost Never (1), Sometimes (2), Often (3), Almost Always (4).	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: Stool pH for reducing sugars	From stool sample. To rule out carbohydrate intolerance as a cause of any irritable bowel syndrome symptoms	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: Stool calprotectin	From stool sample	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: Short chain fatty acids	From stool sample	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: Immunoglobulin A	From stool sample	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: Bristol stool form scale	Bristol stool form scale: Type 1: Separate hard lumps, like nuts (hard to pass); Type 2: Sausage-shaped, but lumpy; Type 3: Like a sausage but with cracks on its surface; Type 4: Like a sausage or snake, smooth and soft; Type 5: Soft blobs with clear cut edges (easy to pass); Type 6: Fluffy pieces with ragged edges, a mushy stool; Type 7: Watery, no solid pieces, entirely liquid	Completed for 7 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in gut health: 3 day weighed diet diary	3 day weighed diet diary	Completed for 3 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in anthropometric measurements: weight	Weight (kg)	Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in anthropometric measurements: height	Height (cm)	Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Albumin	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Pre-albumin	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Transferrin	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Retinol-binding protein	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Glucose	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Haemoglobin A1C	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in IGF-1	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in C-peptide	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Short chain fatty acids	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change insulin production	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in alanine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in arginine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in asparagine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in citrulline	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in cystine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in glutamate	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in glutamine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in glycine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in histidine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in isoleucine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in leucine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in lysine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in methionine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in proline	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in ornithine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in phenylalanine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in serine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in taurine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in threonine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in tryptophan	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in tyrosine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in valine	Total plasma amino acids following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in renal biomarkers: Serum cystatin C	Blood sample following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in renal biomarkers: Serum creatinine	Blood sample following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in renal biomarkers: Blood urea nitrogen	Blood sample following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Adiponectin	Following overnight fasting. An anti-inflammatory marker and related with both adipose tissue and insulin sensitivity	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in C-reactive protein (high sensitivity measurement)	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Serum myeloid-related protein	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Soluble Interleukin 2 Receptor	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in Inflammatory cytokine panel	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in oxidative stress: White cells glutathione (GSH)	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in oxidative stress: Plasma thiobarbituric acid-reactive species (TBAR)	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in oxidative stress:Total antioxidant reactivity (TAR)	Following overnight fasting	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).
Secondary	Change in patient opinion of acceptability of the product	Product acceptability Likert scale: I loved it (5 - best); I liked it (4); I neither liked nor disliked it (3); I didn't like it (2); I really didn't like it (1 - worst)	Days 84 (visit 3) and 196 (visit 5)
Secondary	Change in hunger	Measuring hunger in primary school children Likert scale: I am really hungry! My belly feels very empty and is rumbling! (1 - worst); I am quite hungry and my belly feels a little empty. (2); I feel just right, not too hungry and not too full. (3); I am quite full, but there is still a little room in my belly. (4); I am not hungry at all! My belly feels very full and I cannot eat any more food! (5 - best)	Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)