Whole Body Metabolism in Children Before and After Treatment of CNS Tumor

CNS Tumor, Childhood Clinical Trial

Official title:

Whole Body Metabolism in Children Before and After Treatment of CNS Tumor

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06380387
• Other study ID #: H-21046543
• Status: Recruiting
• Phase: N/A
• Start date: March 23, 2023
• Est. completion date: December 2026

Study information

• Verified date: April 2024
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

At the center of pediatric oncology in Copenhagen the investigators experience that the children with brain tumor, more or less have a healthy body with normal skeletal muscle mass and are physical active to the same level as their friends at the same age. The treatment period for brain tumor is approximately two years. After the treatment period, the children are more sedative with less interest in coming out doing physical activities and thus the investigators suspect that they have altered hormonal response, low skeletal muscle mass and perhaps are in risk of developing metabolic syndrome.

By comparing children with newly diagnosed CNS tumor with children finished treated for CNS tumor, we wish to describe the metabolic path during the approximately two years treatment period these children go through. These results will also be compared with results from healthy controls.

The investigators aim to include 10 children (aged 6-18 years) with newly diagnosed CNS tumor, 10 children (aged 6-18 years) finished treated for CNS tumor and 10 healthy controls (aged 6-18 years). By using stable isotope technique the investigators will investigate systemic fat, glucose and protein metabolism together with liver protein degradation and glucose production. Furthermore, by using DXA scan the investigators will describe the quality and distribution of skeletal muscle. Lastly, the investigators will determine the skeletal muscle signal pathway and metabolism in skeletal muscle via the Bergström biopsy technique in vastus lateralis.

Description:

By comparing children with newly diagnosed CNS tumor with children finished treated for CNS tumor, the investigators wish to describe the metabolic path during the approximately two years treatment period these children go through. These results will also be compared with results from healthy controls.

Trial design and time frame:

A prospective, non-randomized, cross-sectional study.

There will be three different patient groups included:

• Patient group A: Children with newly diagnosed CNS tumor

• Patient group B: Children finished treated for CNS tumor

• Healthy controls: Children admitted to the hospital at the Epilepsy monitor unit (EMU)

The trial will be conducted over a total of two days and takes place at the Department of Pediatrics and Adolescent Medicine, Rigshospitalet and the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet.

• Study day 1: Is estimated to last approximately 2 hours.

• Study day 2: Is estimated to last approximately 8 hours.

Study Day 1: The children will be DXA-scanned and complete life quality questionnaires and pain scores. In some cases, study day 1 will be done after study day 2, depending on the cancer treatment plan for each patient.

Study Day 2: For the patients newly diagnosed with CNS tumor: The investigators strive to conduct study day 2 within the first week of hospital admission due to newly diagnosed CNS tumor. However, the investigators do accept study day 2 being conducted within the first month after time of diagnose.The subjects will arrive around 08.00, at Copenhagen Neuromuscular Centre (CNMC), Rigshospitalet.

On arrival, EMLA (local anesthetics cream) will be applied on the skin of the children in order to minimize any discomfort that may occur during iv-insertion. Two peripheral venous catheters are inserted, one in the medial cubital vein for infusion of stable isotopes, and one in a dorsal vein of the hand for blood sampling. If the child has a central venous catheter (CVK), we will only insert one peripheral venous catheter, in the medial cubital vein for infusion of the stable isotopes.

After 1 hour and 45 minutes of basal tracer infusion, basal blood samples are drawn (time -15 and 0) for the determination of basal steady state tracer enrichments and hormone concentrations. At time= 0, a liquid mixed meal is provided. Blood samples are drawn frequently for 6 hours relative to start of the test meal (at 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300 and 360 minutes)[24], [25]. If the child becomes upset or we for other reasons want to stop earlier than 6 hours, we will use the already obtained results.

The tracers: In this study, the investigators will intravenously infuse small amounts of metabolites labelled with stable isotopes in primed continuous intravenous infusions of: D8-Phenylalanine, D2-Tyrosine, 13C18-Oleate acid, D2-Glucose, D5-Glycerol. This method is well-established at both CIMT and CNMC and has been used investigating several of patients categories before: Neonates (ongoing study), gastric sleeve, elderly and neuromuscular patients.

The tracers are prepared from the hospital pharmacy. All tracers are purchased from Cambridge Isotope Laboratories, Andover, MA, USA suitable for human use. Stable isotopes are non-radioactive and naturally occurring in food (e.g. in corn).

Food intervention: At time= 0 (120 minutes after infusion), a liquid mixed meal adjusted by weight is given. The meal consists of: Intrinsically labelled D5-Phenylalanine and D3-Leucine labelled casein protein, 13C16palmitate, 13C6-Glucose in a mix of glucose, casein protein and rape seed oil dissolved in water in an energy density of 50% CHO, 35% fat and 15% protein. Intrinsically labeled caseinate was produced via an infusion of [D5]-phenylalanine and [D3]leucine into a lactating cow to obtain enriched milk Foulumn, Arhus University, from which the caseinate fraction was isolated at Arla Foods according to Good Manufacturing Practice (GMP) and safety checked an store under appropriate regulatory conditions until use (Nørre Vium, Denmark) following a previously described procedure.

Analyses of blood samples:The samples will be collected in syringes containing 10μL EDTA/mL to prevent coagulation. The blood is immediately centrifuged at 4oC to separate plasma from red blood cells. The samples will be frozen in coded tubes and stored at -80C until analysis.

Routine blood samples: Will be analysed immediately at the Department of Clinical Biochemistry, Rigshospitalet:

• Blood samples include: Insulin, HbA1C, Cholesterol, HDL, LDL, triglycerides

Glucose and lactate: will be analyzed (ABL 700) immediately as the blood is drawn.

Specific blood samples:

• Free fatty acids: will be analyzed using fluorometry.

• Hormones (catecholamines, insulin, incretins and glucagon): will be analyzed using RIA and Elisa Methods respectively.

• Stable isotope enrichments in blood: will be analyzed using Liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) (Thermo Scientific, Palo Alto, CA, USA and Bremen, Germany).

Calculations: Whole body metabolite quantitative kinetics will be calculated using Steele's equation for non-steady state adapted for analysis of stable isotopes under the post-absorptive conditions.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Years to 18 Years

Eligibility

Inclusion Criteria:

• Patient group A: Children with newly diagnosed CNS tumor, included just before the start of treatment or right after possible surgery.

• Patient group B: Children who have completed treatment for a CNS tumor within the last month.

• Healthy controls: Children admitted to the EMU because of either

• Suspected convulsions

• Nocturnal EEG changes

• 6-18 years

• Signed informed consent to participation in the trial.

Exclusion Criteria:

• Inability to understand the purpose of the trial or cooperate in the conduction of the experiments. For the children this will concern of course the parents or the guardians of the child.

• Competing conditions at risk of compromising the results of the study.

• Participation in other trials that may interfere with the results.

• Intake of medications that may interfere with the results, evaluated by investigator.

• Pregnancy or breastfeeding.

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• CNS Tumor, Childhood

Intervention

Dietary Supplement:
• Meal
Liquid meal

Locations

Country	Name	City	State
Denmark	Department of Pediatrics and Adolescent Medicine and Copenhagen Neuromuscular Center, Rigshospitalet	Copenhagen	Copenhagen Ø

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Protein breakdown	Phenylalanine Rate of appearance micro mol/kgFFM/min	10 hours
Primary	Protein synthesis	Phenylalanine Rate of disappearance micro mol/kgFFM/min	10 hours
Primary	Phenylalanine concentration	micromol/l	10 hours
Primary	Phe oxidation to TYR	micromol/kg FFM/min	10 hours
Primary	Whole-body protein synthesis	micromol Phe/kg FFM/min	10 hours
Primary	Whole-body protein degradation	micromol Phe /kg FFM/min	10 hours
Primary	Netto protein balance	micromol Phe /kg FFM/min	10 hours
Primary	Glucose Rate of appearance	micromol/kg FFM/min	10 hours
Primary	Total glucose Rate of appearance	micromol/kg FFM/min	10 hours
Primary	Total glucose Rate of disappearance	micromol/kg FFM/min	10 hours
Primary	Endogenous glucose	micromol/kg FFM/min	10 hours
Primary	Oral phenylalanine Rate of appearance	micromol/kg FFM/min	10 hours
Primary	Phenylalanine oxidation	% of phenylalanine Rate of appearance	10 hours
Primary	Rate of Appearance of Palmitate in Plasma	µmol/kg/min	10 hours
Primary	Rate of Disappearance of Palmitate	µmol/kg/min	10 hours
Primary	Concentration of ketones	mmol/L	10 hours
Secondary	Glucose	Nutritional, meal, absorption kinetics of proteins, carbohydrates and fat including first bypass losses (interstitial and liver). In case of fat that included synthesis rates of chylomicrons and their breakdown rate by determining the overflow of the nutritional fatty acids into the main circulation.	10 hours
Secondary	Quality of Skeletal Muscle	Dual-energy X-ray absorptiometry (DEXA) scan	10 hours
Secondary	Protein synthesis rate	Blood, mainly liver, proteins synthesis rate and liver function parameter from, A. liver glucose; B. VLDL-TAG production rate; C. phenylalanine hydroxylation rates	10 hours
Secondary	Pain score	Pain score assessment (1-10)	10 hours
Secondary	Life quality score	Life quality score by using PedsQL (0-100)	10 hours
Secondary	Muscle biopsy	Muscle morphology, muscle fiber type and size, atrophy protein markers (MuRF1, MAFbx, FoxO) muscle generating markers (Myo D, Myogenin, IGF1), muscle growth regulating protein (myostatin).	10 hours
Secondary	Incretins	GLP-1 (pmol/L) and GIP, (pmol/L)	10 hours
Secondary	Glucagon	pmol/L	10 hours
Secondary	Liver parameters ALT, AST, GGT	ALT, AST, GGT (U/L)	10 hours
Secondary	Bilirubin	mikromol/L	10 hours
Secondary	International normalized ratio (INR)	Blood sample	10 hours
Secondary	LDH	U/L	10 hours
Secondary	Insulin	pmol/L	10 hours
Secondary	catecholamines	nmol/l nmol/l	10 hours
Secondary	Blood pressure	mmHG	10 hours
Secondary	Waist- and hip circumference	centimeter	10 hours
Secondary	Lipids	HDL , LDL, total cholesterol, TAG (mmol/L)	10 hours
Secondary	Concentration of Plasma Amino Acids	mmol/L	10 hours
Secondary	Concentration of Plasma Glucose	mmol/L	10 hours
Secondary	Concentration of Plasma Palmitate	micromol/L	10 hours
Secondary	Concentration of Plasma Free Fatty Acids	mmol/L	10 hours
Secondary	Level of HbA1c	mmol/mol	10 hours