The Effects of CGMP in Children and Adults With PKU

Vitaflo International, Ltd12 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Phenylketonurias

Interventions

CGMP protein substituteDIETARY_SUPPLEMENT

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 substituteDIETARY_SUPPLEMENT

Patient may choose from a list of products, specified in the protocol, that are nutritionally comparable to PKU Sphere.

Eligibility

Sex: ALLMin age: 4 Years

Medical Language ↔ Plain English

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.

Locations (3)

Rigshospitalet

Copenhagen, Denmark

Bristol Royal Hospital for Children

Bristol, Avon, United Kingdom

Birmingham Children's Hospital

Birmingham, West Midlands, United Kingdom

Outcomes

Primary Outcomes

Change in overnight fasting plasma Phe

Overnight fasting plasma phenylalanine level (μmol/l)

Time frame: Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)

Change in overnight fasting plasma Tyr

Overnight fasting plasma tyrosine level (μmol/l)

Time frame: Measured at days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)

Change in overnight fasting blood Phe

Overnight fasting blood phenylalanine level (μmol/l) using blood spots

Time frame: Measured twice per week up to 32 weeks

Change in overnight fasting blood Tyr

Overnight fasting blood tyrosine level (μmol/l) using blood spots

Time frame: Measured twice per week up to 32 weeks

Secondary Outcomes

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).

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

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

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in gut health: Stool calprotectin

From stool sample

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Change in gut health: Short chain fatty acids

From stool sample

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in gut health: Immunoglobulin A

From stool sample

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

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

Time frame: Completed for 7 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in gut health: 3 day weighed diet diary

3 day weighed diet diary

Time frame: Completed for 3 days prior to days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in anthropometric measurements: weight

Weight (kg)

Time frame: Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in anthropometric measurements: height

Height (cm)

Time frame: Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Albumin

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Pre-albumin

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Transferrin

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Retinol-binding protein

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Glucose

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Haemoglobin A1C

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in IGF-1

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in C-peptide

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Short chain fatty acids

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change insulin production

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in alanine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in arginine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in asparagine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in citrulline

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in cystine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in glutamate

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in glutamine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in glycine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in histidine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in isoleucine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in leucine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in lysine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in methionine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in proline

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in ornithine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in phenylalanine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in serine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in taurine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in threonine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in tryptophan

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in tyrosine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in valine

Total plasma amino acids following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in renal biomarkers: Serum cystatin C

Blood sample following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in renal biomarkers: Serum creatinine

Blood sample following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in renal biomarkers: Blood urea nitrogen

Blood sample following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Adiponectin

Following overnight fasting. An anti-inflammatory marker and related with both adipose tissue and insulin sensitivity

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in C-reactive protein (high sensitivity measurement)

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Serum myeloid-related protein

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Soluble Interleukin 2 Receptor

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in Inflammatory cytokine panel

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in oxidative stress: White cells glutathione (GSH)

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in oxidative stress: Plasma thiobarbituric acid-reactive species (TBAR)

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

Change in oxidative stress:Total antioxidant reactivity (TAR)

Following overnight fasting

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5).

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)

Time frame: Days 84 (visit 3) and 196 (visit 5)

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)

Time frame: Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5)