The goal of this clinical trial is to study the effect of a time-restricted eating (TRE) dietary pattern combined with a time of consumption restriction about the daily portions of fruits and vegetables in people diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). The protocol of the study is an intention to treat protocol. The main research questions are: 1. Does compliance in a TRE dietary scheme (positively) affect changes in body weight and body fat mass in people diagnosed with MASLD? 2. Does an additional time restriction on the consumption of fruits and vegetables within the "light-window" of the day affects the metabolism of food contaminants? Participants will be asked to: 1. Adhere to a TRE dietary pattern for 3 months. TRE consists of an 8-hour eating vs 16 hours fasting within the day. First meal of the day should not occur at least an hour after wake-up time and last meal of the day should occur not later than 2 hours before bed-time. 2. Adhere to a further time restricted consumption of a "5-a-day" portions of fruits and vegetables between the "light-window hours" between 9am to 4pm. 3. Visit the Nutrition \& Dietetics Clinic once every month for anthropometric measurements (on 4 time points). 4. Collect and deliver first morning urine samples (on 7 time points). 5. Collect and deliver saliva samples at baseline and at the end of the trial (Saliva collection should occur every 4-hours for 48-hours including fasting collection at baseline and at the end of three months) 5\) Complete a compliance and lifestyle questionnaire questionnaire via telephone interview to the research team every 2 weeks. 6\) Share photos to the research team with the use of an application on time of actual fruit and vegetables consumption, 3-4 times per week throughout the study protocol. Researchers will compare the designed intervention package of this TRE with the Standard of Care (SoC) protocol (based on the international guidelines) that is currently used in daily practice for the management of MASLD.
This parallel-arm, randomized controlled trial (RCT) will study the effects of an ad libitum TRE dietary pattern (8 hours eating, 16 hours fasting) with an additional restriction regarding the fruit and vegetable consumption on health parameters, pesticide metabolism and concomitant toxicity in MASLD patients compared with the Standard of Care (SoC) approach, that will serve as the control group. Participants will be asked to consume all meals/snacks during the 8 hours daily period that they will select for themselves without any further dietary advice regarding caloric or other macronutrient intake. However, participants will be instructed that their first meal of the day should not start for at least an hour after wake-up hour and will also be asked to have their last meal at least 2 hours earlier than bedtime (actual time of sleep). Additionally, participants will have to consume 5 portions (400g) of fruits and vegetables within time-window for fruit \& vegetable consumption earlier in the day; from 9am to 4pm. Non-caloric beverage consumption (water, black coffee, unsweetened tea, non-sweetened beverages) will be allowed within the restricted hours of the intervention. Participants allocated in the SoC group (control) will receive oral and written SoC lifestyle advice from a registered dietitian. The SoC advice is based on the EASL/EASD/EASO joint Clinical Practice Guidelines for the management of MASLD. Patients will receive guidance on a) energy restriction, b) weight reduction, c) the macronutrient composition of the diet, d) limitation of alcohol intake (below the risk threshold of 30g/d and 20g/day for men and women, respectively) and e) increase their physical activity levels. Additionally, in this study patients will be asked to consume standard "5-a-day" portions of fruits and vegetables daily, as part of their dietary healthier behaviour.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
150
Ad libitum time-restricted scheme with a further time-restriction on fruit and vegetable consumption in participants with MASLD
The SoC intervention refers to an adaptation of a healthier lifestyle in elements that have to do with weight management, adopting healthier dietary habits, alcohol intake reduction, increase physical activity levels, in people diagnosed with MASLD.
Limassol General Hospital
Limassol, Cyprus
Changes in body weight
Changes in body weight (in kilograms) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (with two in-between measurement)
Changes in body fat mass
Changes in body fat mass (expressed as % of the total body weight in kilograms) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included only if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (with one in-between measurement)
Changes in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine
Change in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in pesticide metabolite 3-phenoxybenzoic acid (3-PBA) levels between the last sample of the TRE group (intervention period) and the last sample of the SoC treatment period. The results of the linear-mixed effect models are the ones considered as they take into account the repeated measures for each participant and the TRE treatment duration adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From first day of the intervention to the end of treatment at 3 months (with six in between measurements)
Changes in Pesticide Metabolite 6-chloronicotininc Acid (6-CN) Levels in Urine
Change in Pesticide Metabolite 6-chloronicotininc Acid (6-CN) Levels in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in pesticide metabolite 6-chloronicotininc Acid (6-CN) levels between the last sample of the TRE group (intervention period) and the last sample of the SoC treatment period. The results of the linear-mixed effect models are the ones considered as they take into account the repeated measures for each participant and the TRE treatment duration adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From first day of the intervention to the end of treatment at 3 months (with six in between measurements)
Changes in waist circumference (WC)
Changes in waist circumference (in centimetres) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (with one in-between measurement)
Changes in 4-Hydroxynonenal (4HNE) Levels in Urine
Change in Urine levels of the biomarker of oxidative stress 4-Hydroxynonenal (4HNE) (in µg/L, corrected for creatinine levels), between the TRE and the SoC intervention. Percent change in metabolite of oxidative stress of 4-Hydroxynonenal (4HNE) levels between the last sample of the TRE group (intervention period) and the last sample of the SoC treatment period. The results of the linear-mixed effect models are the ones considered as they take into account the repeated measures for each participant and the TRE treatment duration adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From first day of the intervention to the end of treatment at 3 months (with six in between measurements)
Changes in Body Mass Index (BMI)
Changes in Body Mass Index (in kilograms divided by meters in square) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (with two in-between measurement)
Changes in glucose (Gluc) levels in blood
Changes on blood's glucose (Gluc) levels (in mg/dL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in total cholesterol (TC) levels in blood
Changes on blood's total cholesterol (TC) levels (in mg/dL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in high-density lipoprotein cholesterol (HDL) levels in blood
Changes on blood's high-density lipoprotein cholesterol (HDL) levels (in mg/dL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in low-density lipoprotein cholesterol (LDL) levels n blood
Changes on blood's low-density lipoprotein cholesterol (LDL) levels (in mg/dL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in alanine transaminase (ALT) levels n blood
Changes on blood's alanine transaminase (ALT) levels (in U/IL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in aspartate aminotransferase (AST) levels in blood
Changes on blood's aspartate aminotransferase (AST) levels (in U/IL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
Changes in C-Reactive Protein (CRP) levels n blood
Changes on blood's C-Reactive Protein (CRP) levels (in mg/dL) from baseline to the end of intervention in the TRE and the Soc group (intervention vs control, respectively). Depending on the data distribution, independent samples t-test or Wilcoxon Rank-Sum Test will be used If the changes do or do not follow a normal distribution between baseline and post-treatment are normally distributed, respectively. Mixed Effect Models will be used to assess the main and interaction (included if p\<0.05) effects between groups and time since study initiation adjusting for confounders, including circadian rhythm metrics such as melatonin and/or cortisol.
Time frame: From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention)
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