CAlorie and Protein REstriction PROgram in Barrett's Esophagus Patients (CARE-PRO).

Study Overview
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Brief Summary
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The increasing incidence of Esophageal Adenocarcinoma (EAC) in several Western countries can be primarily ascribed to risk factors such as obesity, chronic gastroesophageal reflux, dietary habits and alcohol intake. Nevertheless, Barrett's Esophagus (BE), remains the main risk factor for EAC. Several studies supports the role played by the gut microbiota on the modulation of metabolic and immunological pathways. An abnormal state of the microbial ecosystem seems to be involved in the promotion and onset of various diseases, including cancer. Recent studies have shown that diet and lifestyle have an important modulatory role as protective or risk factors for oncological diseases. The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) released a review of the evidence that emerged from published studies in the field of nutrition and cancer prevention and summarized their findings into 10 recommendations. Several studies have also shown that a moderate caloric and/or protein restriction seems to be able to reduce the risk of neoplastic disease development. The primary aim of this study is to evaluate the impact of a lifestyle-oriented intervention on body weight, waist circumference, biomarkers associated with cancer risk, esophageal microbiota composition and adherence to cancer prevention recommendations after 24 months in overweight or obese BE patients. Methods and analysis: Patients are randomly divided into two arms, a control arm (CA) and an interventional arm (IA). The CA receives information about a correct lifestyle to prevent cancer. The IA is involved in the two-year program of moderate caloric and protein restriction. At the time of enrollment, anthropometric measurements will be recorded for each patient and they will be randomized to IA or CA. Blood samples will be obtained from each patient and blood glucose will be determined. Serum metabolic biomarkers will be measured in each serum sample and total proteins will be extracted from fresh frozen esophageal biopsy and will be analyzed to evaluate the insulin signal pathway. To assess esophageal microbiota profiling, total genomic DNA (gDNA) will be extracted from matched fresh frozen biopsy. In order to determine a score of adherence to cancer prevention recommendations, participants will be asked to complete a self-administrated questionnaire reflecting WCRF/AICR recommendations. All the measurements will also occur at the end point, after two years from the enrollment.

Official Title
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The Impact of a Moderate CAlorie and Protein REstriction PROgram (CARE-PRO) as an Efficient and Affordable Therapeutic Strategy in Patients With Barrett's Esophagus.

Conditions
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Barrett's Esophagus, Overweight and Obesity

Intervention / Treatment
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* Behavioral: Calorie and protein restriction diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of Barrett's esophagus without dysplasia or cancer aged ≥ 18 years with BMI ≥ 25.0 kg/m^2 Willingness and ability to perform supervised Nordic walking session twice a month and self-planned physical activity at least 3 times a week Signed informed consent Exclusion Criteria: No histological confirmation of Barrett's esophagus Cancer diagnosis within one year before trial begins Presence of insulin-dependent diabetes Denied informed 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm (IA)<br>Patients randomized in the Intervention Arm (IA) will be given personalized diet based on calorie and protein restriction. Calorie restriction will be up to 600 kcal below patients' energy requirements and the amount of protein will be 0.8g of protein/Kg body weight mostly form plant-origin food. | Behavioral: Calorie and protein restriction diet<br>* Patient in intervention arm will be given individualized dietary advice on the basis of WCRF/AICR recommendations. The aim of healthy dietary advice will be the reduction of patient's total daily calorie intake up to 600 kcal below their energy requirements and 0.8g of protein/Kg body weight mostly form plant-origin food. Patients, periodically, will meet the dietitian for a 45-minute nutritional counselling session and a trained nurse for a 15-minute health coaching session. Each patient in the IA will be involved in at least three 4-hour cooking classes. Patients in the IA, after a medical/cardiac evaluation to assure their physical ability for exercise, will attend Nordic walking sessions of moderate intensity two times per month during the 24 months of intervention.<br>|
| No Intervention: Control Arm (CA)<br>Participants in the CA will be given information about the importance of a healthy lifestyle in reducing the risk of cancer and will receive a leaflet based on WCRF/AICR recommendations. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight change | A 7% weight loss | Baseline and after 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic serum biomarkers | Fasting glucose (mg/dl) | Baseline and after 24 months | 
| Metabolic serum biomarkers | Insulin (pg/ml) and C-peptide (pg/ml), tumor necrosis factor-alpha -TNF-alpha (pg/ml) and Interleukin-6 - IL-6 (pg/ml). | Baseline and after 24 months | 
| Metabolic serum biomarkers | Insulin-like growth factor - IGF1 (nmol/ml), insulin-like growth factor binding protein 1 and 3 - IGFBP1 (nmol/ml) and IGFBP3 (nmol/ml) | Baseline and after 24 months | 
| Metabolic serum biomarkers | Leptin (ng/ml) | Baseline and after 24 months | 
| Metabolic serum biomarkers | Adiponectin (µg/ml) | Baseline and after 24 months | 
| Insulin resistance index (HOMA-IR) | HOMA-IR index [fasting plasma glucose (mg/dl) × fasting serum insulin(μU/ml)/405] | Baseline and after 24 months | 
| Expression of proteins involved on insulin and IGF1 receptors signal transduction | Phosphoinositide 3-kinases (PI3K)/Protein kinase B(Akt) pathway; mitogenic (ERK/MAPK) pathway | Baseline and after 24 months | 
| Esophageal microbiota composition | To assess esophageal microbiota profiling, total gDNA will be extracted from fresh frozen biopsy. Specific primers for the bacterial V3-V4 hypervariable regions of 16S ribosomal ribonucleic acid (rRNA) will be used to amplify bacterial DNA [≈ 500 bases pair (bp)] to be sequenced by Illumina Miseq platform with 300 bp paired-end approach. | Baseline and after 24 months | 
| Adherence score to World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) recommendations for cancer prevention. | In order to determine a score of adherence to cancer prevention recommendations, participants will be asked to complete a 6-item self-administrated questionnaire reflecting six recommendations provided by the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR). A score of 1 will be assigned when the item is met and a score of 0 will be assigned when it is not. An answer that partially satisfies the item will be assigned a score of 0.5. Some recommendation (item) have sub-item (item 3,4 and 5). Even for sub-item the score will be 1-0 with 0.5 for partially satisfied item. For total score of item presenting sub-item, we will consider the score obtained by calculating the average score between the sub-item. The final adherence score will derive from the mathematical sum of the individual scores obtained for each item. The maximum expected score will be equal to 6 (full adherence). | Baseline and after 24 months | 
| Waist circumference reduction | Waist circumference (cm) | Baseline and after 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal adenocarcinoma, Diet, Physical activity, Microbiota