Clinical trial NCT05309642: Nonalcoholic Fatty Liver Disease - Intermittent Calorie Restriction (FLICR) Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Nonalcoholic Fatty Liver
Nonalcoholic Steatohepatitis
Keywords: Nonalcoholic Fatty Liver
Nonalcoholic Steatohepatitis
MRI-PDFF
MR-Elastography
Intermittent Calorie Restriction
Liver metabolite
Gut microbiome
Lead sponsor: Ewha Womans University Mokdong Hospital
Sponsor class: OTHER
First posted: 2022-04-04
Enrollment: 72
Sex: ALL
Minimum age (years): 19
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomly allocated two groups; ICR (intermittent calorie restriction) group and SoC (standard-of-care) group
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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, α-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

Primary outcomes:
measure: Impact of ICR on liver steatosis by MRI-PDFF
timeFrame: Baseline, 12 weeks
Secondary outcomes:
measure: Changes in liver fibrosis by MR-Elastography
timeFrame: Baseline, 12 weeks
measure: Changes in anthropometrics
timeFrame: Baseline, 12, and 24 weeks
measure: Changes in body composition analysis (BCA)
timeFrame: Baseline, 12, and 24 weeks
measure: Changes in visceral adipose tissue (VAT)
timeFrame: Baseline, 12, and 24 weeks
measure: Changes in quality of life score
timeFrame: Baseline, 12, and 24 weeks
measure: Genetic analysis
timeFrame: Baseline
measure: Changes in hormone
timeFrame: Baseline, 12 weeks
measure: Changes in liver metabolite
timeFrame: Baseline, 12 weeks
measure: Changes in gut microbiota
timeFrame: Baseline, 12 weeks
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University College of Medicine
state: Yangcheon-gu
Study officials:
affiliation: Ewha Womans University College of Medicine
name: Hwi Young Kim, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
citation: 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.
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.
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.