健康的な食事と相まって時間制限のある食事が肝臓がん患者に有益であるかどうかをテストする (TRE+HE)

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