Cardiovascular Risk Factors in Coeliac Disease: a Series of Studies

Study Overview
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Brief Summary
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This investigation examines the most important cardiovascular risk factors (e.g., metabolic parameters, body composition) and their changes in coeliac disease. The series of studies allow to assess body composition and cardiovascular risk-related metabolic parameters of newly diagnosed and treated coeliac patients in their complexity and to test if they change during therapy. The interventional part of the investigation aims to answer the question if a dietary intervention mitigates the unfavorable effects of unbalanced diet.

Detailed Description
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The global prevalence of coeliac disease (CD) is increasing, which contributes to the disease's significant public health care burden. Body composition and metabolic parameters of coeliac patients differ from the healthy population. Patients with non-classical CD are not necessarily lean; they usually have normal body weight but can be even overweight or obese. In coeliac patients, bodyweight tends to elevate, whereas the body composition changes unfavourably during a gluten-free diet (GFD). A reason for gaining weight is the improvement of malabsorption but an important contributor is the nutrient composition of the GFD, which generally has a high calorie density with high carbohydrate and fat content while being low in fibre. While terminating or mitigating the inflammatory process - if done without adequate dietary control - a GFD can readily lead to weight gain and unfavourably metabolic consequences (e.g., dyslipidemia, fatty liver disease, insulin resistance). The result can be an increase in cardiovascular risk in CD patients with a normal or high body weight at diagnosis. However, limited information is available on the cardiovascular (CV) risk in coeliac disease, and the data are controversial. This study examines the body composition and cardiovascular risk-related metabolic parameters at the diagnosis and on a gluten-free diet in a Hungarian cohort of CD patients. The randomised controlled trial (RCT) investigates the effect of structured, repeated, group-based dietary education on the examined metabolic parameters and body composition. This study aims to draw attention to a new aspect of the management of CD patients: from a metabolic and cardiovascular point of view. Findings will help to identify which parameters are beneficial to optimize and re-assess during follow-up in CD.

Official Title
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Cardiovascular Risk Factors in Coeliac Disease: a Series of Studies

Conditions
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Coeliac Disease

Intervention / Treatment
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* Other: Dietary intervention
* Other: Standard of care
* Diagnostic Test: Cardiovascular risk-related parameters


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (applies to all subjects): Age should be over 18 years. Blood collection must be indicated with medical conditions. Signed informed consent. Inclusion Criteria (applies to specific cohorts of patients): The diagnosis of CD should be set up according to the current guidelines (based on serology and histology in adults or as per the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guideline in children). The newly diagnosed CD patients should be on a gluten-containing diet. Patients following a GFD for at least 1 year should exhibit good dietary adherence. In the randomized controlled trial, strict dietary adherence will be established based on CD-specific serology (normal level of antibodies), urine gluten immunogenic peptides (negative urine test), and dietary interview (convincing knowledge on the GFD and positive attitude towards strict adherence). Control subjects should be free from CD according to the recent guidelines and should be on a gluten-containing diet. Exclusion Criteria: Chronic conditions: Estimated glomerular filtration rate calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula is <60mL/min/1.73m2 (CKD3 or more severe kidney failure). Liver cirrhosis in Child-Pugh B-C. Heart failure (New York Heart Association (NYHA) III-IV). Active malignant diseases. Any acute diseases or acute deterioration of underlying chronic conditions. Diseases that may be associated with clinically relevant malabsorption. Refractory CD. Pregnancy, lactation. Patients unable to understand the essentials of the informed consent. Lack of consent or withdrawal of consent.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This trial is a series of three multicentric studies. It includes 1) a case-control study, which compares newly diagnosed CD patients (n=37) and CD patients on a GFD (n=99) to matched non-coeliac control subjects (n=136); 2) a prospective cohort study, which investigates how the outcomes change during a 1-year GFD started after diagnosis of CD (n=236); 3) an RCT, which investigates how a dietetic intervention (n=95) influences the outcomes, compared to standard of care (n=95), in CD patients following a strict GFD for at least 1 year. There will be no intervention for the sake of the study in the case-control and the cohort study. Parameters of interest will be assessed only once in the case-control study and twice in the cohort study. In the RCT, randomization will be carried out after the baseline dietary education and interview, in 1:1 allocation ratio. Parameters will be recorded at baseline and the end of the study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dietary intervention<br>Patients randomized to the dietary intervention group. | Other: Dietary intervention<br>* Patients will participate in a structured, group-based dietary counseling. Consultations will be organized online (Zoom meeting) lasting approximately 60 min/occasion. The intervention will include 6 sessions for 1 year (monthly for 5 months and finally at month 9). The aim of the counseling is to maintain a GFD and to develop a healthy lifestyle, in line with the Mediterranean diet.<br>Diagnostic Test: Cardiovascular risk-related parameters<br>* Anthropometric measurements (body height, body composition assessment-InBody 770), questionnaires (symptoms, quality of life, dietary adherence, diet quality, cardiovascular risk), assessment of sarcopenia (handgrip dynamometer), urine collection (dietary adherence - urine gluten immunogenic peptide detection), blood collection (immunological tests, hormone levels complemented with routine laboratory panel), transabdominal US examination to assess the extent of fatty liver disease.<br>|
| Active Comparator: Standard of care<br>Patients randomized to the standard of care group. | Other: Standard of care<br>* Patients will receive standard of care and baseline dietary education.<br>Diagnostic Test: Cardiovascular risk-related parameters<br>* Anthropometric measurements (body height, body composition assessment-InBody 770), questionnaires (symptoms, quality of life, dietary adherence, diet quality, cardiovascular risk), assessment of sarcopenia (handgrip dynamometer), urine collection (dietary adherence - urine gluten immunogenic peptide detection), blood collection (immunological tests, hormone levels complemented with routine laboratory panel), transabdominal US examination to assess the extent of fatty liver disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body height | Height in centimeters measured by a stadiometer. | 4 years | 
| Body weight | Weight in kilograms measured by an InBody 770 body composition analyzer. | 4 years | 
| Body mass index (BMI) | BMI in kg/m2 calculated by an InBody 770 body composition analyzer. | 4 years | 
| Body fat mass | Body fat mass in kilograms measured by an InBody 770 body composition analyzer. | 4 years | 
| Percent body fat | Percent body fat in percentage measured by an InBody 770 body composition analyzer. | 4 years | 
| Skeletal muscle mass | Skeletal muscle mass in kilograms measured by an InBody 770 body composition analyzer. | 4 years | 
| Visceral fat area | Visceral fat area in cm2 measured by an InBody 770 body composition analyzer. | 4 years | 
| Total body water | Total body water in liters measured by an InBody 770 body composition analyzer. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Waist circumference | CV risk assessment will be performed by measuring waist circumference in centimeters. | 4 years | 
| Blood pressure | CV risk assessment will be performed by measuring blood pressure in Hgmm. | 4 years | 
| Fatty liver disease | Transabdominal ultrasonography will be used to assess the extent of fatty liver disease (based on non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS), with a score range of 0-3). | 4 years | 
| Cardiovascular risk assessment | CV risk assessment will be performed by the Systematic Coronary Risk Evaluation (SCORE) chart. | 4 years | 
| Coeliac disease-related symptoms | CD-related symptoms will be assessed by the Celiac Symptom Index (CSI). | 4 years | 
| Coeliac disease-specific quality of life | CD-specific quality of life questionnaire will be also used (Celiac Disease Quality of Life (CD-QoL). | 4 years | 
| Disease activity | Disease activity will be estimated by tissue transglutaminase (tTG) levels. | 4 years | 
| Sarcopenia | Sarcopenia will be assessed based on body composition and handgrip strength via handgrip dynamometer. | 4 years | 
| Triglyceride level | Triglyceride level in mmol/L. | 4 years | 
| Cholesterol level | Cholesterol (total, HDL and LDL lipoproteins) level in mmol/L. | 4 years | 
| Fasting glucose level | Fasting glucose level in mmol/L. | 4 years | 
| Fasting insulin level | Fasting insulin level in mmol/L. | 4 years | 
| Haemoglobin (Hb) A1c level | HbA1c level in percentage. | 4 years | 
| Homeostasis Model Assessment (HOMA) index | HOMA index | 4 years | 
| Bilirubin level | Bilirubin level in µmol/L. | 4 years | 
| Uric acid level | Uric acid µmol/L. | 4 years | 
| Urea level | Urea level in mmol/L. | 4 years | 
| Creatinine level | Creatinine level in µmol/L. | 4 years | 
| Sodium level | Sodium level in mmol/L. | 4 years | 
| Potassium level | Potassium level in mmol/L. | 4 years | 
| Calcium level | Calcium level in mmol/L. | 4 years | 
| Vitamin D | Vitamin D level in ng/mL. | 4 years | 
| Vitamin B12 | Vitamin B12 level in pg/mL. | 4 years | 
| Folic acid level | Folic acid level in µg/L. | 4 years | 
| Iron level | Iron level in µmol/L. | 4 years | 
| Ferritin level | Ferritin level in µg/L. | 4 years | 
| Transferrin level | Transferrin level in g/L. | 4 years | 
| Transferrin saturation | Transferrin saturation in percentage. | 4 years | 
| International Normalized Ratio (INR) | INR | 4 years | 
| Aspartate aminotransferase level | Aspartate aminotransferase level in U/L. | 4 years | 
| Alanine aminotransferase level | Alanine aminotransferase in U/L. | 4 years | 
| Fibrosis-4 (FIB-4) Index | FIB-4 Index for liver fibrosis. | 4 years | 
| Total protein level | Total protein level in g/L. | 4 years | 
| Albumin level | Albumin level in g/L. | 4 years | 
| Immunoglobulins | Immunoglobulins in U/mL. | 4 years | 
| High-sensitivity C-reactive protein (hs-CRP) level | hs-CRP level in mg/L. | 4 years | 
| Fibrinogen level | Fibrinogen level in g/L. | 4 years | 
| Blood counts | Blood counts in Giga/L. | 4 years | 
| Homocysteine levels | Homocysteine levels in µmol/L. | 4 years | 
| Interleukin-6 levels | Interleukin-6 levels in ng/L. | 4 years | 
| Leptin levels | Leptin levels in ng/mL. | 4 years | 
| Ghrelin levels | Ghrelin levels in pg/mL. | 4 years | 
| Adiponectin levels | Adiponectin levels in µg/mL. | 4 years | 
| Galectin-3 levels | Galectin-3 levels in ng/mL. | 4 years | 
| Dietary interview | Dietary adherence will be determined by dietary interview provided by an expertise dietitian. | 4 years | 
| Celiac Disease Adherence Test | Dietary adherence will be determined by the Celiac Disease Adherence Test (CDAT). | 4 years | 
| Coeliac-specific antibodies | Dietary adherence will be determined by coeliac-specific antibodies (tissue transglutaminase (tTG) immunoglobulin (Ig) A/IgG and endomysium antibody levels (EMA) IgA) in U/mL. | 4 years | 
| Urine gluten immunogenic peptide | Dietary adherence will be determined by urine gluten immunogenic peptide (GIP) measurement. | 4 years | 
| Diet composition | The composition of a GFD will be evaluated with the indicator of adherence to the Mediterranean diet, the Mediterranean Diet Score (MDS). | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coeliac disease, cardiovascular risk, body composition, dietary intervention