Time-restricted Eating Versus Daily Continuous Calorie Restriction on Body Weight and Colorectal Cancer Risk Markers

Study Overview
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Brief Summary
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Approximately 42% of American adults are obese, and this condition is strongly related to the development of colorectal cancer. Innovative lifestyle strategies to treat obesity and reduce colorectal cancer risk are critically needed. This research will demonstrate that time-restricted eating, a type of intermittent fasting, is an effective therapy to help obese individuals reduce and control their body weight and prevent the development of colorectal cancer.

Detailed Description
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Approximately 42% of the U.S. adult population is obese and data suggests that persons with obesity are at a 30% greater risk of developing colorectal cancer (CRC). Therefore, efficacious approaches to preventing and treating obesity will have significant effects on CRC incidence in the U.S. Although calorie restriction through lifestyle intervention is the most common approach to treat obesity, clinically meaningful weight loss is difficult to achieve via this method due to low adherence with calorie monitoring, indicating a need for innovation. Time-restricted eating, a type of intermittent fasting, has been shown in animals to impart cancer protective effects including lower body weight, decreased systemic inflammation, and improved glucose metabolism. Time-restricted eating is where individuals are asked to consume all their food for the day within a specified time frame, and water fast for the remaining hours of the day. We recently performed two short-term (≤12-weeks) pilot studies of time-restricted eating to evaluate its safety and preliminary efficacy on body weight and chronic disease risk markers in adults with obesity. Our results show the intervention is a safe and acceptable approach to weight loss among obese adults. Moreover, time-restricted eating produced approximately 3% weight loss from baseline and reductions in systolic blood pressure, oxidative stress and insulin resistance. Although these pilot findings show promise for time-restricted eating as an effective tool for CRC risk reduction among obese individuals, these data still require confirmation by a well powered longer-term clinical trial. The present proposal aims to implement a 12-month (6-month intervention, 6-month maintenance) controlled, parallel arm trial among 255 obese adults (45-70 years old) who have had a colonoscopy. Subjects will be randomized to 1 of 3 groups: 1) 8-hour time-restricted eating (daily ad libitum food intake from 12pm - 8pm), 2) Calorie restriction (daily 25% calorie restriction), or 3) Control (daily ad libitum food intake, no meal timing restrictions) to compare the effects on: (1) Body weight, body composition, and intervention adherence; (2) Circulating metabolic, inflammation, and oxidative stress-related biomarkers; (3) Colonic mucosal gene expression profiles and mucosal inflammation, DNA damage and cellular growth; and (4) maintenance of benefits on body weight/composition and CRC markers.

Official Title
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Effects of Time-restricted Eating Versus Daily Continuous Calorie Restriction on Body Weight and Colorectal Cancer Risk Markers Among Adults With Obesity

Conditions
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Time Restricted Eating, Obesity, Weight Loss, Colorectal Cancer

Intervention / Treatment
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* Behavioral: Time restricted eating
* Behavioral: Calorie Restriction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 45-70 years old, BMI 30-49.99 kg/m2 Are up to date with CRC screening. Exclusion Criteria: Have a history of renal disease, autoimmune disorders, immunodeficiency, malabsorptive disorder, significant gastrointestinal and hepatic disease, surgical change in gastrointestinal anatomy, severe ischemic heart disease, severe pulmonary disease, severe mental health disorder, eating disorder, or bariatric surgery; Abuse alcohol (> 50 grams/day), illicit drugs (other than self-reported marijuana use), or use combustible tobacco; Have controlled type 2 diabetes or undiagnosed uncontrolled diabetes based on hemoglobin A1c (HbA1c) > 9.0%; Have a history of cancer treatment within the past 12 months, CRC, genetic predisposition to CRC (e.g., Lynch syndrome); Have a baseline body weight > 450 lbs (weight limitation of the DXA); Are on a weight loss diet or actively involved in a formal weight loss program (e.g., Weight Watchers); Are not weight stable for 3 months prior to the study (weight gain or loss > 4 kg); Are unable to keep a food diary for 7 consecutive days during screening; Are night shift workers; Are pregnant or trying to get pregnant; Are taking drugs that influence study outcomes (weight loss medications); Are perimenopausal or have an irregular menstrual cycle (menses that does not appear every 27-32 days). Are non-English speaking Are taking anticoagulant medications or medications with endoscopic risk Are taking antivirals or immunosuppressant medications Don't have regular access to an email address and computer/smartphone/tablet Are currently following a diet that requires fasting on a weekly basis Currently eat for less than 10 hours of the day (determined by asking participants what time they start and stop eating on a usual day)

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Subjects will be randomized by the data manager, by way of a stratified random sample in 1:1:1 ratio. The sample frame will be divided into strata based on BMI, sex, and age. Subjects from each stratum, will then be randomized to 1 of 3 groups: 1) TRE, 2) Cal-R, or 3) Control.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Time Restricted Eating (TRE)<br>During the active weight loss period, the TRE group will be instructed to eat ad libitum from 12:00pm - 8:00pm daily and fast from 8:00pm - 12:00pm. During the 8-h eating window, there will be no restrictions on types or quantities of foods consumed. During the fasting period, participants will be encouraged to drink plenty of water and may consume energy-free beverages, such as black tea or coffee. TRE subjects will meet with the TRE dietitian for 30 minutes at the start of the intervention to review instructions and goals, and then every week throughout the active weight loss period to review intervention adherence. At the beginning of the maintenance phase, total energy needs will be reassessed. Subjects will be instructed to main their body weight by consuming meals in an extended 10-h eating window every day and water fast between 8pm and 10 am, respectively. | Behavioral: Time restricted eating<br>* daily ad libitum food intake, 8-h 12pm - 8pm, 6 m active weight loss phase; 10-h 10am-8pm, 6 m maintenance phase<br>|
| Active Comparator: Calorie Restriction (Cal-R)<br>Cal-R subjects will be instructed to restrict energy intake by 25% of their baseline total energy expenditure (TEE) daily. Subjects will meet with a study dietitian for a 60-min one-on-one session to develop individualized weight loss meal plans to help them adhere to their calorie restriction goal. Meal plans will include portion sizes and food lists that are consistent with their food preferences and prescribed calorie levels for weight loss. Food scales will be provided to help with food portioning. Cal-R subjects will meet with the dietitian every week throughout the weight loss period to review intervention adherence and modify the meal plans as needed. Subjects will be asked to maintain their baseline level of physical activity. At the beginning of the weight maintenance phase, total energy needs will be reassessed. | Behavioral: Calorie Restriction<br>* daily 25% calorie restriction, 6 m active weight loss phase; 100% energy needs, 6 m maintenance phase<br>|
| No Intervention: Control<br>Controls will be instructed to maintain their weight throughout the 12 m trial and to not change eating or physical activity habits. Controls will not receive dietary counseling. Controls will visit the research center monthly for outcome measurements. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight change (% kg) | Body weight in kg | Baseline to month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total and regional body fat composition and distribution | Total and regional body fat composition and distribution will be measured via whole body DEXA scan | Baseline, 6 month and 12 month | 
| Intervention adherence | Measured through electronic diet records and 24 hour dietary recalls | Monthly, through month 6 | 
| Fasting plasma glucose | From fasting venous blood measured by a commercial lab | Baseline, month 3, month 6, month 9, month 12 | 
| Plasma cytokines TNF-α, IL-6, IL1-β, and IL-10, % | Multiplex ELISA | Baseline, month 3, month 6, month 9, month 12 | 
| Plasma 8-isoprostane | ELISA | Baseline, month 3, month 6, month 9, month 12 | 
| Colonic mucosa gene expression profiling | Commercially available targeted transcriptomics platform | Baseline, month 6, month 12 | 
| Ki-67, proliferation | Healthy colonic mucosa, immunohistochemistry | Baseline, month 6, month 12 | 
| c-caspase-3, Bax, apoptosis | Healthy colonic mucosa, immunohistochemistry, | Baseline, month 6, month 12 | 
| CD3, CD163, pIKKa/b, tissue markers of inflammation | Healthy colonic mucosa, immunohistochemistry | Baseline, month 6, month 12 | 
| Weight maintenance (% kg) | Maintenance of weight loss | Month 6 to month 12 | 
| Fasting plasma insulin | From fasting venous blood measured at a commercial lab | Baseline, month 3, month 6, month 9, month 12 | 
| HOMA-IR | calculated from fasting glucose and insulin using a standard formula | Baseline, month 3, month 6, month 9, month 12 | 
| Gut Microbiome | Shotgun metagenomics | Baseline, month 3 and month 6 | 
| Fecal Metabolites | Untargeted Metabolomics | Baseline, month 3 and month 6 |