The Effects of CGMP in Children and Adults With PKU

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Phenylketonurias

Intervention / Treatment
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* Dietary Supplement: CGMP protein substitute
* Dietary Supplement: L-amino acid protein substitute


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: L-amino Acids<br>The specific amount and timing of L-amino acid consumption will be at the instruction of a dietitian following a review of the individual patient's dietary needs. Consumption period: 12 weeks. | Dietary Supplement: L-amino acid protein substitute<br>* Patient may choose from a list of products, specified in the protocol, that are nutritionally comparable to PKU Sphere.<br>|
| Experimental: PKU Sphere<br>The specific amount and timing of PKU sphere consumption will be at the instruction of a dietitian following a review of the individual patient's dietary needs. Consumption period: 12 weeks. | Dietary Supplement: CGMP protein substitute<br>* 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.<br>* Other names: PKU Sphere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| Change in overnight fasting blood Phe | Overnight fasting blood phenylalanine level (μmol/l) using blood spots | Measured twice per week up to 32 weeks | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 
| 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). | 
| Change in gut health: Stool calprotectin | From stool sample | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| 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). | 
| Change in gut health: Immunoglobulin A | From stool sample | 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 | 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 | 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) | Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in anthropometric measurements: height | Height (cm) | Days -31 (visit 1), 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Albumin | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Pre-albumin | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Transferrin | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Retinol-binding protein | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Glucose | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Haemoglobin A1C | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in IGF-1 | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in C-peptide | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Short chain fatty acids | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change insulin production | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in alanine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in arginine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in asparagine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in citrulline | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in cystine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in glutamate | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in glutamine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in glycine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in histidine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in isoleucine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in leucine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in lysine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in methionine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in proline | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in ornithine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in phenylalanine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in serine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in taurine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in threonine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in tryptophan | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in tyrosine | Total plasma amino acids following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in valine | Total plasma amino acids following overnight fasting | 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 | 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 | 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 | 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 | 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 | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Serum myeloid-related protein | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Soluble Interleukin 2 Receptor | Following overnight fasting | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5). | 
| Change in Inflammatory cytokine panel | Following overnight fasting | 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 | 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 | 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 | 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) | 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) | Days 0 (visit 2), 84 (visit 3), 112 (visit 4) and 196 (visit 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phenylketonuria, PKU, Child, Adult, GMP, Glycomacropeptide