Nonalcoholic Fatty Liver Disease - Intermittent Calorie Restriction (FLICR) Study

Study Overview
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Brief Summary
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Several diets have been proposed to reduce liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD), and various effects on liver steatosis have been observed. The objective of this trial is to compare the effects of intermittent calorie restriction (ICR) (5:2 diet) and standard-of-care (SoC) on reduction of hepatic steatosis.

Detailed Description
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This is an open-label randomised controlled trial of patients with NAFLD. Patients are recruited in the Liver Outpatient Clinic of the Ewha Womans University Mokdong Hospital. The department of Nutritional Science and Food Management, Ewha Womans University will collaborate for this study. About 72 patients (36 patients with body mass index [BMI] ≥25 kg/m2 and 36 patients with BMI <25 kg/m2) will be enrolled in a 1:1 ratio to 12 weeks treatment with either 5:2 diet (ICR group, 18 patients in each BMI group), or general lifestyle advice from a hepatologist (standard of care; SoC group, 18 patients in each BMI group). Beginning in week 3 (Visit 2), an ICR group and a SoC group are generated through randomisation. Both arms will be accompanied for a duration of 12 weeks. After 12 weeks from the completion of the experimental phase (wash-out period), there will be the end of follow up visit. The whole duration of the study is 26 weeks (2 weeks lead-in, 12 weeks intervention and 12 weeks post-intervention investigation). Magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) and MR-Elastography are conducted at the screening visit and at weeks 12. There will be 5 visits at the study center (screening, randomization, week 8, end of treatment and end of study) and 10 phone visits (week 4, 5, 6, 7, 8, 10, 11, 12, 13, 14). At each visit clinical events, anthropometric index and standard laboratory parameters will be collected. Participants will fill in questionnaires capturing quality of life. Adverse events will be recorded. Phone visits are used to survey the safety of patients. Non-adherence to ICR for 20% of the total study period has been selected as cut off to define treatment failure at per-protocol analysis.

Official Title
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Effect of 12-week Intermittent Calorie Restriction on Liver Fat Content in Comparison With Standard-of-care in Patients With Nonalcoholic Fatty Liver Disease: a Randomized Controlled Trial

Conditions
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Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Behavioral: Intermittent calorie restriction
* Behavioral: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NAFLD diagnosed by (1) Histologic assessment with a fat accumulation of more than 5% of the liver's weight in a biopsy, or (2) Radiologic assessment with a MRI-PDFF ≥8%. Age between 19 and 75 years Capability to understand the study and the individual consequences of participation Signed and dated declaration of agreement in the forefront of the study Exclusion Criteria: Daily alcohol consumption >30 g in men and >20 g in women Other causes of chronic liver disease (HBV, HCV, HDV, HEV, HIV), autoimmune diseases or chronic cholestatic liver disease, drug induced liver injury, hereditary haemochromatosis, Wilson disease, α-1-Antitrypsin deficiency Liver cirrhosis Hepatocellular carcinoma Medications which cause liver disease or secondary NAFLD (e.g. Tamoxifen, systemic Corticosteroids, Methotrexate, Tetracycline, Estrogens, Valproic acid) Changes in body weight > 5% in the last 3 months Intake of medical treatment for NAFLD/NASH in the last 6 months (except for vitamin E) Diabetes Pregnancy Patients after organ transplantations Missing or lacking consent capability

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomly allocated two groups; ICR (intermittent calorie restriction) group and SoC (standard-of-care) group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ICR Arm<br>On 2 non-consecutive days per week, participants in the ICR (5:2 diet) group will be instructed to consume 500 kcal/day for women and 600 kcal/day for men. | Behavioral: Intermittent calorie restriction<br>* Recipes will be provided with suggestions of meals that would not exceed the calorie restriction. For the remaining 5 days of the week, they will receive instructions and recipes that follows the Korean Dietary Reference Intakes (KDRIs), with an intake limit of 2,000 kcal/day for women and 2,500 kcal/day for men. The percentage of energy (E%) from different macronutrients in the recipes will be 45-60 E% carbohydrates, 25 E% fat and 10-20 E% protein.<br>|
| Placebo Comparator: Soc Arm<br>The SoC group will receive 80% of standard calorie (1,200-1,500 kcal/day or reducing 500-1000 kcal/day from standard calorie). | Behavioral: Standard of care<br>* They will receive individualized guidance from a hepatologist on how to choose a healthy diet, to reduce the intake of sweets and saturated fatty acids, increase sources of unsaturated fat, avoid large portions, and to regularly eat 3 meals per day. Each participant will be provided a written summary of the dietary advice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of ICR on liver steatosis by MRI-PDFF | The primary outcome of interest is a change in MRI-PDFF value of a least 30% with ICR | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in liver fibrosis by MR-Elastography | Measure the change of liver fibrosis with MR-Elastography | Baseline, 12 weeks | 
| Changes in anthropometrics | BMI (kg/m2) | Baseline, 12, and 24 weeks | 
| Changes in body composition analysis (BCA) | Measure the change of BCA with Inbody | Baseline, 12, and 24 weeks | 
| Changes in visceral adipose tissue (VAT) | Measure the change of VAT with fat CT | Baseline, 12, and 24 weeks | 
| Changes in quality of life score | Measure the change of Quality of Life score with Chronic Liver Disease-NAFLD questionnaire (CLDQ). The CLDQ uses 29 items in four domains, each scored on a Likert scale from 1 (all of the time) to 7 (none of the time) representing the frequency of clinical symptoms and emotional problems in the last two weeks. Results are reported in the six subscale scores (abdominal symptoms, fatigue, systemic symptoms, activity, emotional functioning, worry) and a CLDQ overall score. | Baseline, 12, and 24 weeks | 
| Genetic analysis | Polymorphism of PNPLA3, TM6SF2, TM4SF5, SREBF2, MBOAT7-TMC4, HSD17B13 and adenine insertion (A-INS) will be analyzed by NGS (Next Generation Sequencing) | Baseline | 
| Changes in hormone | Measure the change of leptin, adiponectin, ghrelin, GLP-1, apelin, and osteopontin | Baseline, 12 weeks | 
| Changes in liver metabolite | Measure the change of diglycerides (DG), FA, phosphatidylethanolamines (PE), phosphatidylcholines (PC), methionine, SAMe, and methylthioadenosine | Baseline, 12 weeks | 
| Changes in gut microbiota | Evaluation of 16S rRNA gene sequencing | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis, MRI-PDFF, MR-Elastography, Intermittent Calorie Restriction, Liver metabolite, Gut microbiome