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

Nonalcoholic Steatohepatitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05309642
• Other study ID #: FLICR
• Status: Completed
• Phase: N/A
• Start date: March 7, 2022
• Est. completion date: December 6, 2023

Study information

• Verified date: February 2024
• Source: Ewha Womans University Mokdong Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: December 6, 2023
• Est. primary completion date: December 6, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 75 Years

Eligibility

Inclusion Criteria:

1. 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%.

2. Age between 19 and 75 years

3. Capability to understand the study and the individual consequences of participation

4. Signed and dated declaration of agreement in the forefront of the study

Exclusion Criteria:

1. Daily alcohol consumption >30 g in men and >20 g in women

2. 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, a-1-Antitrypsin deficiency

3. Liver cirrhosis

4. Hepatocellular carcinoma

5. Medications which cause liver disease or secondary NAFLD (e.g. Tamoxifen, systemic Corticosteroids, Methotrexate, Tetracycline, Estrogens, Valproic acid)

6. Changes in body weight > 5% in the last 3 months

7. Intake of medical treatment for NAFLD/NASH in the last 6 months (except for vitamin E)

8. Diabetes

9. Pregnancy

10. Patients after organ transplantations

11. Missing or lacking consent capability

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver
• Nonalcoholic Steatohepatitis

Intervention

Behavioral:
• Intermittent calorie restriction
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.
• Standard of care
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.

Locations

Country	Name	City	State
Korea, Republic of	Ewha Womans University College of Medicine	Seoul	Yangcheon-gu

Sponsors (1)

Lead Sponsor	Collaborator
Ewha Womans University Mokdong Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (8)

Cai H, Qin YL, Shi ZY, Chen JH, Zeng MJ, Zhou W, Chen RQ, Chen ZY. Effects of alternate-day fasting on body weight and dyslipidaemia in patients with non-alcoholic fatty liver disease: a randomised controlled trial. BMC Gastroenterol. 2019 Dec 18;19(1):219. doi: 10.1186/s12876-019-1132-8. — View Citation

Carter S, Clifton PM, Keogh JB. Effect of Intermittent Compared With Continuous Energy Restricted Diet on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Noninferiority Trial. JAMA Netw Open. 2018 Jul 6;1(3):e180756. doi: 10.1001/jamanetworkopen.2018.0756. — View Citation

Holmer M, Lindqvist C, Petersson S, Moshtaghi-Svensson J, Tillander V, Brismar TB, Hagstrom H, Stal P. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. JHEP Rep. 2021 Feb 17;3(3):100256. doi: 10.1016/j.jhepr.2021.100256. eCollection 2021 Jun. — View Citation

Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF, Varady KA. Intermittent fasting combined with calorie restriction is effective for weight loss and cardio-protection in obese women. Nutr J. 2012 Nov 21;11:98. doi: 10.1186/1475-2891-11-98. — View Citation

Retterstol K, Svendsen M, Narverud I, Holven KB. Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study. Atherosclerosis. 2018 Dec;279:52-61. doi: 10.1016/j.atherosclerosis.2018.10.013. Epub 2018 Oct 17. — View Citation

Schubel R, Nattenmuller J, Sookthai D, Nonnenmacher T, Graf ME, Riedl L, Schlett CL, von Stackelberg O, Johnson T, Nabers D, Kirsten R, Kratz M, Kauczor HU, Ulrich CM, Kaaks R, Kuhn T. Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial. Am J Clin Nutr. 2018 Nov 1;108(5):933-945. doi: 10.1093/ajcn/nqy196. — View Citation

Wong VW, Wong GL, Chan RS, Shu SS, Cheung BH, Li LS, Chim AM, Chan CK, Leung JK, Chu WC, Woo J, Chan HL. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol. 2018 Dec;69(6):1349-1356. doi: 10.1016/j.jhep.2018.08.011. Epub 2018 Aug 22. — View Citation

Younossi ZM, Corey KE, Lim JK. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology. 2021 Feb;160(3):912-918. doi: 10.1053/j.gastro.2020.11.051. Epub 2020 Dec 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Changes in liver fibrosis by MR-Elastography	Measure the change of liver fibrosis with MR-Elastography	Baseline, 12 weeks
Secondary	Changes in anthropometrics	BMI (kg/m2)	Baseline, 12, and 24 weeks
Secondary	Changes in body composition analysis (BCA)	Measure the change of BCA with Inbody	Baseline, 12, and 24 weeks
Secondary	Changes in visceral adipose tissue (VAT)	Measure the change of VAT with fat CT	Baseline, 12, and 24 weeks
Secondary	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
Secondary	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
Secondary	Changes in hormone	Measure the change of leptin, adiponectin, ghrelin, GLP-1, apelin, and osteopontin	Baseline, 12 weeks
Secondary	Changes in liver metabolite	Measure the change of diglycerides (DG), FA, phosphatidylethanolamines (PE), phosphatidylcholines (PC), methionine, SAMe, and methylthioadenosine	Baseline, 12 weeks
Secondary	Changes in gut microbiota	Evaluation of 16S rRNA gene sequencing	Baseline, 12 weeks