Efficacy and Feasibility of Time-restricted Eating on Cardiometabolic Health in Adults With Overweight/Obesity

Study Overview
=================
Brief Summary
-----------------
In Spain, obesity epidemic is one of the leading contributors of chronic disease and disability. Obesity is associated with higher morbidity and all-cause mortality risk especially when fat is stored in the abdominal area (i.e., increased visceral adipose tissue, VAT). Although current approaches such as energy restriction may be effective at reducing body fat and improving cardiometabolic health, their long-term adherences are limited. Time-restricted eating (TRE; e.g., 8 hours eating: 16 hours fasting on a daily basis) is a recently emerged intermittent fasting approach with promising cardiovascular benefits. Results from pioneering pilot studies in humans are promising and suggest that simply reducing the eating time window from ≥12 to ≤8-10 hours/day improves cardiometabolic health. However, currently, there is no consensus regarding whether the TRE eating window should be aligned to the early or middle to late part of the day. The EXTREME study will investigate the efficacy and feasibility of three different 8 hours TRE schedules (i.e., early, late and self-selected) over 12 weeks on VAT (main outcome) and cardiometabolic risk factors (secondary outcomes) in adults with overweight/obesity and abdominal obesity. The final goal of the EXTREME study is to demonstrate the health benefits of a novel and pragmatic intervention for the treatment of obesity and related cardiometabolic risk factors; an approach readily adaptable to real-world practice settings, easy for clinicians to deliver, and intuitive for patients to implement and maintain in their lives.

Official Title
-----------------
Efficacy and Feasibility of Time-restricted Eating on Cardiometabolic Health in Adults With Overweight/Obesity: The EXTREME Study

Conditions
-----------------
Time Restricted Feeding, Obesity, Abdominal, Cardiometabolic Syndrome

Intervention / Treatment
-----------------
* Behavioral: Early time-restricted eating
* Behavioral: Late time-restricted eating
* Behavioral: Self-selected time-restricted eating


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 30-60 years. Body mass index ≥25.0 and <40 kg/m2 Weight stability (within 3% of screening weight) for >3 months prior to study entry. Sedentary lifestyle (<150 min/week of moderate-vigorous intensity exercise) for >3 months prior to study entry. Habitual eating window ≥12 hours. At least one of the following metabolic impairments: High-density lipoprotein (HDL) cholesterol concentration <50 mg/dL for females and <40 mg/dL for males. Low-density lipoprotein (LDL) cholesterol levels >100 mg/dL (or on medication to treat elevated LDL cholesterol levels). Serum triglycerides concentration ≥150 mg/dL or on medication to treat elevated triglycerides. Systolic blood pressure >130 mm Hg and/or diastolic blood pressure >85 mm Hg or already being treated with anti-hypertension medications. Impaired glucose tolerance is defined as at least one of the following: Fasting plasma glucose (PG) >100 mg/dL and <125 mg/dL. Hemoglobin A1c between ≥5.7% and <6.5%. Insulin resistance as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA2-IR) >1.8. Exclusion Criteria: History of a major adverse cardiovascular event, clinically significant kidney, endocrine, or neurological disease, bariatric surgery, HIV/AIDS, known inflammatory and/or rheumatologic disease, cancer, or other medical condition in which fasting or exercise is contraindicated. Type 1 or Type 2 diabetes. Major psychiatric disorders, eating disorders, sleep disorders, or alcohol abuse. Regular use of medication or compounds that may affect study outcomes (e.g., antidiabetic, steroids, beta-blockers, antibiotics, prebiotics, probiotics and symbiotics). Participating in a weight loss or a weight-management program. Pregnancy and lactation or planned pregnancy (within the study period). Caregiver for a dependent requiring frequent nocturnal care/sleep interruptions. Shift workers with variable hours (e.g., nocturnal). Frequent travel over time zones during the study period. Fear of needles and claustrophobia to magnetic resonance imaging (MRI). Being unable to understand and to accept the instructions or the study objectives and protocol.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early time-restricted eating<br>Participants will eat ad libitum within an 8-hour early eating window. The first meal will be before 10 am (last meal before 18h). No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion | Behavioral: Early time-restricted eating<br>* Participants will eat ad libitum within an 8-hour early eating window starting not later than 10am. No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion<br>|
| Experimental: Late time-restricted eating<br>Participants will eat ad libitum within an 8-hour late eating window. The first meal will be at 13h or later (last meal not before 21h). No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion | Behavioral: Late time-restricted eating<br>* Participants will eat ad libitum within an 8-hour late eating window starting not earlier than 1pm. No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion<br>|
| Experimental: Self-selected time-restricted eating<br>Participants will self-selecte an 8-hour eating window to eat ad libitum. No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion | Behavioral: Self-selected time-restricted eating<br>* Participants will self-selected an 8-hour eating window to eat ad libitum. No calorie-containing food or beverage intake will be allowed outside the 8-hour eating window. Participants will also receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion<br>|
| No Intervention: Usual-care group<br>Participants will receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in visceral adipose tissue | Visceral adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatic fat content | Hepatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in Pancreatic fat content | Pancreatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in Intramuscular fat content | Intramuscular fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in Hepatic elasticity | Hepatic elasticity will be assessed by US elastography | Change from baseline to 12 weeks | 
| Change in Pancreatic elasticity | Pancreatic elasticity will be assessed by US elastography | Change from baseline to 12 weeks | 
| Change in Fasting glucose metabolism | Fasting blood samples will be used to analyse different biomarkers of glucose metabolism | Change from baseline to 12 weeks | 
| Change in Fasting lipid metabolism | Fasting blood samples will be used to analyse different biomarkers of lipid metabolism (e.g., triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) | Change from baseline to 12 weeks | 
| Change in Inflammatory profile | Fasting blood samples will be used to analyse inflammatory profile (e.g., C-reactive protein and interleukin 6) | Change from baseline to 12 weeks | 
| Change in Hepatic profile | Fasting blood samples will be used to analyse hepatic profile (e.g., alkaline phosphatase, bilirubin, alanine transaminase and gamma-glutamyl transferase) | Change from baseline to 12 weeks | 
| Change in Kidney profile | Fasting blood samples will be used to analyse kidney profile (e.g., creatinine and creatine kinase) | Change from baseline to 12 weeks | 
| Change in Glycemia (Continuous Glucose Monitoring) | Glycemia will be assessed by Continuous Glucose Monitoring during 2 weeks | Change from baseline to 12 weeks | 
| Change in Body weight | Body weight will be measured by a digital scale | Change from baseline to 12 weeks | 
| Change in Body composition (Fat mass and fat free mass) | Body composition will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from baseline to 12 weeks | 
| Change in Anthropometric measures | Neck, hip and waist circumferences will be assessed by standard procedures | Change from baseline to 12 weeks | 
| Change in Blood pressure | Systolic and Diastolic blood pressure will be assessed by standard procedures | Change from baseline to 12 weeks | 
| Change in energy intake | Energy intake (kcal/day) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in macronutrients intake | Macronutrients intake (g/day and percentage of energy intake) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in dietary habits | Dietary habits will be assessed by food frequency questionnaires | Change from baseline to 12 weeks | 
| Change in Food craving | Food craving will be assessed by the Food Craving Inventory (FCI) | Change from baseline to 12 weeks | 
| Change in Appetitive traits | Appetitive traits will be assessed by the Adult Eating Behavior Questionnaire (AEBQ) | Change from baseline to 12 weeks | 
| Change in Subjective sleep quality | Subjective sleep quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI) | Change from baseline to 12 weeks | 
| Change in Objectively sleep quality | Objectively sleep quality will be assessed by accelerometry | Change from baseline to 12 weeks | 
| Change in Chronotype | Chronotype will be assessed by the Munich Chronotype Questionnaire (MCTQ) | Change from baseline to 12 weeks | 
| Change in Morning-Evening type | Morning-Evening type will be assessed by the Morningness-Eveningness Questionnaire Self-Assessment Version. | Change from baseline to 12 weeks | 
| Change Subjective physical activity levels | Subjective physical activity levels will be assessed by the International Physical Activity Questionnaire short form | Change from baseline to 12 weeks | 
| Change Objectively physical activity levels | Objectively physical activity levels will be assessed by accelerometry | Change from baseline to 12 weeks | 
| Change in Depression aspects | Depression aspects will be assessed by the Beck Depression Inventory Fast Screen (BDI-FS) | Change from baseline to 12 weeks | 
| Change in Stress aspects | Stress aspects will be assessed by the Perceived Stress Scale (PSS) | Change from baseline to 12 weeks | 
| Change in Anxiety aspects | Anxiety aspects will be assessed by the State-Trait Anxiety Inventory (STAI) | Change from baseline to 12 weeks | 
| Change in General health | General health will be assessed by the EuroQol 5 dimensions 5 levels (EQ-5D-5L) | Change from baseline to 12 weeks | 
| Change in Quality of life | Quality of life will be assessed by the Rand Short Form 36 (SF-36) | Change from baseline to 12 weeks | 
| Change in Gut microbiota composition | DNA sequencing to determine gut microbiota composition (e.g., phylum and genera) | Change from baseline to 12 weeks | 
| Change in Gut microbiota diversity | DNA sequencing to determine gut microbiota diversity (e.g., beta and alpha) | Change from baseline to 12 weeks | 
| Feasibility of recruitment | Feasibility of recruitment (i.e., percent of response rate). | 12 weeks | 
| Feasibility of the intervention | Retention during the intervention (i.e., percent of attrition). | 12 weeks | 
| Adherence to the intervention | Adherence will be assessed by eating records | Every day during the intervention, up to 90 days | 
| Genetic variants in Clock genes | Genetic variantes in clock genes will be determined by Illumina sytem | Baseline |