Time-restricted Eating and Healthy Eating in Patients With Metabolic Liver Disease or Cancer (TRE+HE)

Feasibility Study of Time Restricted Eating and a Healthy Diet in Patients Receiving Liver-Directed Therapy for Hepatocellular Carcinoma

This is a feasibility study that will collect data to assess the potential effect of nutritional intervention. This prospective single-site trial will enroll adult patients with liver diseases such as metabolic-dysfunction associated steatotic liver disease (MASLD), metabolic-dysfunction associated steatohepatitis (MASH), cirrhosis and/or hepatocellular carcinoma (HCC). Eligible individuals who are randomized to the intervention group will be enrolled in a six-month nutritional change program consisting of time-restricted eating plus targeted healthy changes in what they eat (TR-HE). The intervention includes dietary counseling visits with a study registered dietitian (RD) and motivational phone calls with a study Certified Health and Wellness Coach (HC). Individuals who are randomized to the control group or who elect to join the control group will be enrolled in a six-month period of observation and phlebotomy only. The main questions it aims to answer are:

Is a prolonged nightly fast coupled with a healthy diet safe and feasible for patients with liver disease or cancer? Does the intervention improve liver metabolism?

Study Overview

• Status: Recruiting
• Conditions: Liver Cancer, Adult; Obesity and Overweight; MASH - Metabolic Dysfunction-Associated Steatohepatitis
• Intervention / Treatment: Behavioral: Time-restricted eating plus healthy diet

Detailed Description

We are proposing a feasibility study that will collect data to assess the potential effect of nutritional intervention in adult patients with liver disease. We hypothesize that a time-restricted, healthy eating intervention is feasible and safe;will improve metabolic and inflammatory biomarkers, and quality of life.

Primary endpoint is to assess feasibility and safety. Feasibility assessment includes recruitment, retention, and satisfaction of subject; data collection efficiency; adherence to TR+HE protocols by dietary logs and/or dietary recalls. Safety assessment includes liver function tests, hypoglycemic episodes, nausea, disrupted sleep, decreased quality of life or other patient reported events from surveys. Secondary endpoint is to assess clinical parameters including quality of Life (SF-36 questionnaire), sleep disturbance (PROMIS-8b), anthropometrics and vitals, food frequency questionnaire, adiposity by dual-energy X-ray absorptiometry (DEXA), physical activity by accelerometer, glucose levels by continuous glucose monitoring, plasma metabolic markers by fasting glucose, insulin, beta-hydroxy-butyrate, Hemoglobin A1C, leptin, and inflammatory cytokines.

This prospective, single-site, open-label controlled clinical trial will enroll up to 70 overweight or obese adults (BMI at least 27, aged 18 years or more) diagnosed with metabolic liver disease up to and including HCC (BCLC early to intermediate stage), and whose usual nightly fasting interval is less than 12 hours.

The trial will have two arms: the Time Restricted + Healthy Eating (TR+HE) group (14-16 h fast with no energy intake after 7 pm), and the Control (CTL) Group. We will randomize the subjects 2:1 to the intervention group versus the control group. Once the intervention group is full, we will direct any new subjects to the control group. The control group is monitoring plus blood draws. If we have difficulty filling the control group we can use historical SOC data. Participants will be assigned to the TR+HE or the CTL group based on the baseline assessment of the usual nightly fasting and subjects willingness to adhere to the intervention.

All subjects will receive standard of care (SOC) treatment, with additional study-related visits for DXA, accelerometry and CGM instructions, blood draws for metabolic and inflammatory panels, and other clinical assessments. Participants will be provided with mail-in stool samplers.

The active intervention arm will start with a nutritional counseling session by the study registered dietician (RD) lasting about 60 minutes. After that, participants will receive up to 3 follow-up sessions by the study RD and brief support phone calls every week from health coach (HC) for the first 3 months of the study. For the following 3 months, the intervention arm will receive daily support prompts provided by a guava-based app and/or bi-weekly phone calls.

The control arm will have the same guava-based app to monitor their eating habits, but will follow their usual eating patterns and diet.

Study Schedule and Assessments

Month 0 Enrollment/Baseline Assessment:

The study coordinator will schedule an in-person or virtual visit to administer the informed consent form and to enroll participants. This visit will include collection of demographics and baseline questionnaires (FFQ, SF-36 and PROMIS-8B). Participants will also be asked to complete a 3-day dietary journal to assess their usual diet and estimate their usual nightly fasting duration and food frequency questionnaire (VioScreen).

The study coordinator will then schedule an in-person visit at the Exercise and Physical Activity Resource Center for a pregnancy test, a DXA scan, vitals and anthropometrics measures, and a blood draw for biomarkers. During this visit, participants will receive an accelerometer and continuous glucose monitor (CGM) to be worn for 7 days. The continuous glucose monitoring will be used to check for hypoglycemic events before starting the intervention. LFT standard-of-care labs may be extracted from the medical chart. Participants will also be provided with mail-in stool collection kits and will be provided with and enrolled in the Guava Health app.

Guava is a phone app that allows individuals to monitor their health data, physical activity and nutrition. Guava can connect to health and fitness devices like CGMs and Fitbits and can interface with the patients EMR. This allows individuals to log food consumed using the smart phone camera or text input, medications, weight, exercise, and blood pressure. The data synching with the EMR also allows individuals to monitor relevant health information, up coming visits, lab results etc. The app will provide reminders, and other engagement levers, to encourage subjects to follow their recommended eating intervals and diets. The study team will monitor the Guava Dashboard for compliance and will reach out to participants as needed. At the end of the study, consented data will be exported from the app to the research team as a spreadsheet for analysis. Subjects will be provided with a contact should they need help with the app.

The Guava team have developed a Dashboard that the study team can access at any time during the trial. Study team will monitor Guava Dashboard for compliance and will reach out to participants as needed. At the end of the study, consented data will be exported back to the research team for analysis.

The study coordinator will then schedule a virtual visit with the study RD, and a virtual visit with the study HC. Participants in the intervention group will receive instruction on achieving and maintaining a healthy diet with prolonged nightly fasting of 14-16 h.

Intervention starts after completion of baseline visit including the CGM and accelerometer reporting. Intervention will continue up to 6 months.

During the first three months, participants in the nutritional intervention group will be followed up monthly by the study RD through virtual visits to perform the dietary intake and schedule collection and diet course corrections, and weekly by the study HC to reinforce the change, address challenges, and encourage accomplishments.

Month 3 Visit: Participants will complete study questionnaires (FFQ, SF-36, PROMIS-8B, and diet journal) and meet with the study coordinator for anthropometrics (BMI, WC) measures and stool and blood samples collection. Blood will be used for measuring insulin, glucose, liver enzymes, and a panel of inflammatory cytokines; stool will be used to isolate microbial DNA. LFT standard-of-care labs may be extracted from the medical chart.

Month 6 Visit:

The study coordinator will schedule a visit to collect study questionnaires (FFQ, SF-36, PROMIS-8B, and diet journal) and samples; measure anthropometrics and vitals; perform a DXA scan and provide participants with an accelerometer and glucose monitor to be worn for 7 days. LFT standard-of-care labs may be extracted from the medical chart. The 6-month visit marks the end of the active intervention.

Month 12 Visit: Participants will complete study questionnaires (FFQ, SF-36, PROMIS-8B, and diet journal) and meet with the study coordinator for anthropometrics (BMI, WC), a blood draw and collection of stool samples. LFT standard-of-care labs may be extracted from the medical chart.

Collection of Data Identifier: participant name, DOB, MRN Demographics: gender, age, race, contact information, tobacco and alcohol use, marital status, education, employment status, household income Clinical: SF-36, PROMIS-8B, DXA, standard-of-care liver images and liver function tests, vitals in EPIC Nutritional: FFQ, Diet journals and/or food recalls, continuous glucose monitoring data Physical activity: accelerometry data Specimens: plasma metabolic and inflammatory biomarkers, stool samples

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nick Webster, PhD; Phone Number: 858-534-6275; Email: nwebster@health.ucsd.edu
• Study Contact Backup: Name: Tanya Shekhtman; Email: tshekhtman@health.ucsd.edu

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • University of California San Diego
      • Contact: Nick Webster; Phone Number: 8585346275; Email: nwebster@health.ucsd.edu
      • Principal Investigator: Nick Webster, Ph.D., M.A.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Overweight or obese (BMI 27-45 kg/m2)
2. Diagnosed with metabolic-dysfunction associated steatitic liver disease (MASLD/NAFLD), metabolic-dysfunction associated steatohepatitis, cirrhosis or liver cancer (BCLC early to intermediate stage HCC)
3. English or Spanish speaking over the age of 18.
4. ECOG Performance Status ≤ 2.
5. Usual nightly fasting <12 hours
6. Willing to comply with all study procedures
7. Life expectancy of > 12 months

Exclusion Criteria:

1. Advanced HCC, progression, and/or associated comorbidities
2. Metastatic disease, tumor in vein, or ascites
3. Advanced Cirrhosis (hypoalbuminemia/Child-Pugh B+C).
4. Poorly controlled or refractory (grade 3-4) hepatic encephalopathy
5. Type 1 diabetes or self-reported hypoglycemia or hypoglycemic events by CGM
6. Participation in another conflicting study that requires modification of diet or food timing.
7. Patients on GLP-1 receptor agonists
8. Uncontrollable eating pattern (e.g., wasting, Night Eating Syndrome, disordered eating habits, food insecurity)
9. Medications that markedly impact metabolic study biomarkers.
10. Other cancer in last 10 years (other than nonmelanoma skin cancer or carcinoma of the cervix in situ)
11. Serious medical conditions such as chronic kidney disease, congestive heart failure, or any condition that would interfere with participation in the trial.
12. Unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy
13. Active alcohol abuse or less than 6 months of sobriety
14. Participation in a trial of an investigational agent within the prior 30 days
15. Pregnancy or lactating, positive hCG urine test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Intervention group will follow time-restricted consumption of a healthy diet.	Behavioral: Time-restricted eating plus healthy diet; Subjects will restrict calorie consumption to 8-10 hours during the day plus will follow a healthy plant-based diet.
No Intervention: Control; Control observational arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence to protocol	Participant adherence to and comprehension of the protocol as an indicator of intervention delivery by staff. Adherence will be assessed by the number of participants who complete the study, the percentage of days with fasting >14 h, and the number of days that food was logged into the app.	6 months
Safety from adverse events	Safety assessed by adverse events and liver function tests. Reports on adverse events will include hypoglycemic epidoes, nausea, disrupted sleep, decreased quality of life or other patient reported events from surveys. Liver function tests (AST and ALT) as well ss platelet count and total protein are monitored under SOC. AST and ALT elevation will be considered mild if 2-5 times upper limit normal (ULN), moderate if 5-15 times ULN, and severe if >15 times ULN.	6 months
Ability to recruit	Ability to recruit our target population will be assessed by the number of eligible individuals in the patient population, and the number who enroll in the trial.	6 months
Satisfaction and self-motivation	We will determine the degree to which participants liked the intervention through satisfaction surveys at the end of the study and the number of participants who demonstrate self-motivation to continue the intervention protocol during 6-month follow-up.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of intervention on Quality of Life	Quality of Life will be assessed using the EORTC QLQ C-30 questionnaire for Cancer patients	6 months
Effect of interventions on fasting glucose	Fasting glucose will be measured at baseline and 6 months	6-months
Sleep disturbance	Sleep disturbance as reported by the PROMIS-8b survey	6 months
Effect of intervention on body weight	Body weight will be measured prior to and during intervention	6 months
Effect of intervention on food frequency	Participants will complete a Food frequency questionnaire at Baseline, 3 months and 6 months	6 months
Effect of intervention on Adiposity	Adiposity will be measured by Dual-energy X-ray Absorptiometry (DXA) at baseline and at 6 months	6 months
Effect of interventions on Physical activity	Physical activity will be measured by Accelerometer mounted at the waist at baseline and at 6 months	6 months
Effect of intervention on Glucose levels	Glucose levels will be monitored by Continuous Glucose Monitoring at baseline and at 6 months	6 months
Effect of intervention on fasting insulin	Fasting insulin levels will be measured at baseline and at 6 months	6 months
Effect of intervention on ketone production	Fasting beta-hydroxybutyrate levels will be measured at baseline and 6 months	6 months
Effect of interventions on hemoglobin A1c	Hemoglobin A1c will be measured at baseline and 6 months	6 months
Effect of intervention on plasma leptin	Leptin levels will be measured at baseline and 6 months	6 months
Effect of intervention on inflammatory cytokines	Inflammatory cytokines will be measured at baseline and 6 months	6 months
Effect of intervention on fecal microbiome	7S sequencing will be performed on fecal samples at baseline and 6 months	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease progression as a Tertiary/Exploratory outcome	Tumor regression or recurrence will be assessed using LI-RADS-TR.	12-months

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Investigators: Principal Investigator: Nick Webster, PhD, Universoty of California San Diego

Publications and helpful links

General Publications

• Das M, Kumar D, Sauceda C, Oberg A, Ellies LG, Zeng L, Jih LJ, Newton IG, Webster NJG. Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice. Cancers (Basel). 2024 Apr 16;16(8):1513. doi: 10.3390/cancers16081513.
• Das M, Webster NJG. Obesity, cancer risk, and time-restricted eating. Cancer Metastasis Rev. 2022 Sep;41(3):697-717. doi: 10.1007/s10555-022-10061-3. Epub 2022 Aug 19.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 4, 2025
• First Submitted That Met QC Criteria: February 7, 2025
• First Posted (Actual): February 13, 2025

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 22, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: healthy diet; Time-restricted eating
• Additional Relevant MeSH Terms: Nutrition Disorders; Neoplasms by Site; Neoplasms; Overnutrition; Body Weight; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Feeding Behavior; Fasting; Overweight; Obesity; Carcinoma, Hepatocellular; Intermittent Fasting; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet; Diet, Healthy
• Other Study ID Numbers: #808859

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No