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| Name | Class |
|---|---|
| Cyprus State Heath Organization Services | UNKNOWN |
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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:
Participants will be asked to:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care (Group A-Control) | Other | Participants in Group A will follow a Standard of Care Intervention. They 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 the general recommendation of "5-a-day" as part of their dietary healthier behaviour. Moreover, participants should stay well hydrated and get adequate of sleep (an average of 6 consecutive hours at night). Oral and written guidance for the management of MASLD will be administered. The duration of the intervention is 3 months. |
|
| Time-restricted eating (Group B-Intervention) | Experimental | Participants will have to adhere to an ad libitum TRE dietary pattern (8 hours eating, 16 hours fasting) with an additional dietary restriction regarding the "5-a-day" fruit and vegetable in which they will need to be consumed between 9am-4pm. Some more restrictions regarding first and last meal will be asked. 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). The duration of the intervention is 3 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Diet-Time-restricted eating (TRE) | Other | Ad libitum time-restricted scheme with a further time-restriction on fruit and vegetable consumption in participants with MASLD |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | From enrolment to the end of treatment at 3 months (with one in-between measurement) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in other pesticide biomarkers in urine | Change in Change in other pesticide biomarkers in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in any other measured pesticide metabolite 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. Levels in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in other pesticide biomarker 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. |
Inclusion Criteria:
Exclusion Criteria:
Night Shift worker
Fasting >12-h/day more than once a week or > once a week no food intake after 18:00
Co-existing causes of chronic liver disease according to standard diagnostic testing including, but not restricted to:
Medications which cause liver disease or secondary hepatic steatosis (Tamoxifen, systemic corticosteroids, methotrexate, tetracycline, estrogens, valproic acid, and statin (registration is possible if statin is delivered in a consistent dosage within 12 weeks)
Current or recent history (<5 years) of significant alcohol intake (>30g of alcohol/ day or >210g/week for men, >20g of alcohol/day or >140g/week for women)
Doctor diagnosed diabetes mellitus on insulin or sulfonylureas
Severe medical comorbidities [ischemic heart disease, 3rd degree atrioventricular block, chronic obstructive pulmonary disease, severe hypertension (blood pressure >200/120 mmHg)]
Unstable weight (>5% change in the last 2 months) or participation in a weight-loss program within the past 12 weeks
Sleep disorder (with a medical diagnosis) or individuals self-reporting sleep difficulties and poor sleep [average sleep less than 6 consecutive hours or patients who systematically experience sleep interruption for more than 2 times each night (waking up for toilet use is not to be considered sleep interruption)]
Individuals with food allergies (or hypersensitivity to the fruits and vegetables that will be selected for the study)
Systematic organic products consumers (defined as a self-reported usual consumption of more than 80% of their weekly fruits & vegetables being organic)
Pregnant or trying to become pregnant or lactating women
People not in position to communicate in Greek or English language
Having metallic parts in the body.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Konstantinos C. Makris, Professor | Contact | 0035725002398 | konstantinos.makris@cut.ac.cy | |
| Elina I Ioannou | Contact | elii.ioannou@edu.cut.ac.cy |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Limassol General Hospital | Limassol | 4159 | Cyprus |
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| Lifestyle Management | Other | 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. |
|
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | From enrolment to the end of treatment at 3 months (one measurement at the beginning and one measurement at the end of the intervention) |
| From first day o the intervention to the end of treatment at 3 months (with six in between measurements) |
| Changes in other biomarkers of oxidative stress in urine | Change in other biomarkers of oxidative stress in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in any other measured biomarkers of oxidative stress 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. Levels in Urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in other pesticide biomarker 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. | From first day o the intervention to the end of treatment at 3 months (with six in between measurements) |
| Changes in metabolome in saliva and urine | Change in metabolome profile in the 24-h in saliva or urine (in µg/L, corrected for creatinine levels) between the TRE and the SoC intervention. Percent change in metabolome profile between the last day samples of the TRE group (intervention period) and the last day samples of the SoC treatment period will be compared with an Exposome wide association analysis. | From first day o the intervention to the end of treatment at 3 months (with six in between measurements) |
| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D000093763 | Intermittent Fasting |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D005215 | Fasting |
| D005247 | Feeding Behavior |
| D001519 | Behavior |
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