The Clock Thickens: Morning or Evening Training for the Treatment of NAFLD?

NCT ID: NCT05987748

Last Updated: 2023-08-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-09-01
• Study Completion Date: 2024-09-01

Brief Summary

The goal of this clinical trial is to investigate the different effect of morning and evening exercise training in individuals with non-alcoholic fatty liver disease (NAFLD). The main question it aims to answer is:

• Is morning or evening exercise better for the treatment of NAFLD?

Participants will follow a supervised exercise training program for three months with either morning or evening training and the effect on liver health will be assessed. Researchers will compare the morning to the evening exercise group to see if one training timepoint is more effective than the other in reducing the amount of fat in the liver and improving liver health.

Detailed Description

The aim of the study is to identify the effect of exercise timing on NAFLD. Additionally, we aim to increase the understanding of the exercise-related modulation of the metabolic and inflammatory processes causing NAFLD, including insulin resistance and dysbiosis of the gut microbiota. Forty obese patients with NAFLD will be enrolled by randomization to participate in an exercise training program over 12 weeks, either in the morning (n=20) or evening (n=20). Blood and stool samples will be collected before, during and after the intervention to monitor diagnostic markers such as liver enzymes (AST, ALT, GGT, etc.) and changes of the gut microbiota with exercise, respectively. Moreover, mixed meal tolerance tests will be performed before and after the intervention to monitor insulin sensitivity and hepatic fat content and cardiovascular parameters (e.g. arterial stiffness) will be monitored via MRI. Throughout the study, physical fitness will be assessed and monitored using steep ramp tests. Patients will be randomized for a supervised, standardized 50 min morning or evening training, with both progressive endurance and strength elements, in a frequency of 3 times a week for 12 weeks.

Conditions

Non-Alcoholic Fatty Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Morning exercise

Individuals will exercise train at 8 AM three times per week for 12 weeks.

Group Type: EXPERIMENTAL

Exercise training

Intervention Type: BEHAVIORAL

Mixed exercise training containing strength and endurance elements carried out under supervision

Evening exercise

Individuals will exercise train at 8 PM three times per week for 12 weeks.

Group Type: EXPERIMENTAL

Exercise training

Intervention Type: BEHAVIORAL

Mixed exercise training containing strength and endurance elements carried out under supervision

Interventions

Exercise training

Mixed exercise training containing strength and endurance elements carried out under supervision

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Age ≥ 45 years and ≤ 75
• Obese (BMI > 27 kg/m2)
• Males and postmenopausal females
• Caucasian
• Hepatic steatosis defined as increased hyperechogenicity of the liver on abdominal ultrasound, CAP score on Fibroscan > 280, and/or histological signs of steatosis
• Sedentary lifestyle (maximum of 20 minutes of moderate-to-vigorous physical activity per day on less than three days per week)
• Written informed consent

Exclusion Criteria

• Any other liver disease than NAFLD/NASH
• Present excessive alcohol use defined as > 2 units/day
• Recent use (< 3 months) of antibiotics
• Recent changes in dosages of regular medication (< 3 months)
• Recent (< 3 months) weight change (>5%)
• Recent (< 3 months) substantial diet changes
• Cardiovascular co-morbidity defined as heart failure, coronary insufficiency and hypertension in past history
• Comorbidity that contraindicates exercise training and exercise testing or that affects exercise response and exercise capacity
• Ongoing or recent use of glucocorticoids, oral/transdermal hormonal substitution, paclitaxel, theofyllin, amiodarone, myelosuppresive agents
• A psychiatric, addictive or any other disorder that compromises the subjects ability to understand the study content and to give written informed consent for participation in the study
• Working night or alternating shifts, known sleeping disorders such as narcolepsy or insomnia

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Maag Lever Darm Stichting

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Milena Schoenke

PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Milena Schönke, PhD

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Locations

Leiden University Medical Center

Leiden, South Holland, Netherlands

Countries

Netherlands

Central Contacts

Milena Schönke, PhD

Role: CONTACT

m.schoenke@lumc.nl

+31715268188

Maarten E Tushuizen, MD PhD

Role: CONTACT

m.e.tushuizen@lumc.nl

Facility Contacts

Milena Schönke, PhD

Role: primary

m.schoenke@lumc.nl

+31715268188

Maarten E Tushuizen, MD PhD

Role: backup

m.e.tushuizen@lumc.nl

References

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22.

Reference Type: BACKGROUND

PMID: 26707365 (View on PubMed)

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133. doi: 10.1002/hep.29466. Epub 2017 Dec 1.

Reference Type: BACKGROUND

PMID: 28802062 (View on PubMed)

Stols-Goncalves D, Hovingh GK, Nieuwdorp M, Holleboom AG. NAFLD and Atherosclerosis: Two Sides of the Same Dysmetabolic Coin? Trends Endocrinol Metab. 2019 Dec;30(12):891-902. doi: 10.1016/j.tem.2019.08.008. Epub 2019 Oct 17.

Reference Type: BACKGROUND

PMID: 31630897 (View on PubMed)

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. doi: 10.1038/nrgastro.2017.109. Epub 2017 Sep 20.

Reference Type: BACKGROUND

PMID: 28930295 (View on PubMed)

Ruissen MM, Mak AL, Beuers U, Tushuizen ME, Holleboom AG. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020 Sep;183(3):R57-R73. doi: 10.1530/EJE-20-0065.

Reference Type: BACKGROUND

PMID: 32508312 (View on PubMed)

Sato S, Basse AL, Schonke M, Chen S, Samad M, Altintas A, Laker RC, Dalbram E, Barres R, Baldi P, Treebak JT, Zierath JR, Sassone-Corsi P. Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis. Cell Metab. 2019 Jul 2;30(1):92-110.e4. doi: 10.1016/j.cmet.2019.03.013. Epub 2019 Apr 18.

Reference Type: BACKGROUND

PMID: 31006592 (View on PubMed)

Savikj M, Gabriel BM, Alm PS, Smith J, Caidahl K, Bjornholm M, Fritz T, Krook A, Zierath JR, Wallberg-Henriksson H. Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial. Diabetologia. 2019 Feb;62(2):233-237. doi: 10.1007/s00125-018-4767-z. Epub 2018 Nov 13.

Reference Type: BACKGROUND

PMID: 30426166 (View on PubMed)

Dalbram E, Basse AL, Zierath JR, Treebak JT. Voluntary wheel running in the late dark phase ameliorates diet-induced obesity in mice without altering insulin action. J Appl Physiol (1985). 2019 Apr 1;126(4):993-1005. doi: 10.1152/japplphysiol.00737.2018. Epub 2019 Feb 7.

Reference Type: BACKGROUND

PMID: 30730814 (View on PubMed)

Andersson A, Kelly M, Imajo K, Nakajima A, Fallowfield JA, Hirschfield G, Pavlides M, Sanyal AJ, Noureddin M, Banerjee R, Dennis A, Harrison S. Clinical Utility of Magnetic Resonance Imaging Biomarkers for Identifying Nonalcoholic Steatohepatitis Patients at High Risk of Progression: A Multicenter Pooled Data and Meta-Analysis. Clin Gastroenterol Hepatol. 2022 Nov;20(11):2451-2461.e3. doi: 10.1016/j.cgh.2021.09.041. Epub 2021 Oct 7.

Reference Type: BACKGROUND

PMID: 34626833 (View on PubMed)

Schaapman JJ, Tushuizen ME, Coenraad MJ, Lamb HJ. Multiparametric MRI in Patients With Nonalcoholic Fatty Liver Disease. J Magn Reson Imaging. 2021 Jun;53(6):1623-1631. doi: 10.1002/jmri.27292. Epub 2020 Aug 21.

Reference Type: BACKGROUND

PMID: 32822095 (View on PubMed)

Oeda S, Tanaka K, Oshima A, Matsumoto Y, Sueoka E, Takahashi H. Diagnostic Accuracy of FibroScan and Factors Affecting Measurements. Diagnostics (Basel). 2020 Nov 12;10(11):940. doi: 10.3390/diagnostics10110940.

Reference Type: BACKGROUND

PMID: 33198092 (View on PubMed)

Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan((R))) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand? World J Gastroenterol. 2016 Aug 28;22(32):7236-51. doi: 10.3748/wjg.v22.i32.7236.

Reference Type: BACKGROUND

PMID: 27621571 (View on PubMed)

van Lingen E, Tushuizen ME, Steenhuis MEJ, van Deynen T, Martens J, Morales DD, van der Meulen-de Jong AE, Molendijk I, van der Marel S, Maljaars PWJ. Disease activity in inflammatory bowel disease patients is associated with increased liver fat content and liver fibrosis during follow-up. Int J Colorectal Dis. 2022 Feb;37(2):349-356. doi: 10.1007/s00384-021-04065-8. Epub 2021 Nov 17.

Reference Type: BACKGROUND

PMID: 34791524 (View on PubMed)

Beyer C, Hutton C, Andersson A, Imajo K, Nakajima A, Kiker D, Banerjee R, Dennis A. Comparison between magnetic resonance and ultrasound-derived indicators of hepatic steatosis in a pooled NAFLD cohort. PLoS One. 2021 Apr 1;16(4):e0249491. doi: 10.1371/journal.pone.0249491. eCollection 2021.

Reference Type: BACKGROUND

PMID: 33793651 (View on PubMed)

Dennis A, Mouchti S, Kelly M, Fallowfield JA, Hirschfield G, Pavlides M, Banerjee R. A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis. Sci Rep. 2020 Sep 17;10(1):15308. doi: 10.1038/s41598-020-71995-8.

Reference Type: BACKGROUND

PMID: 32943694 (View on PubMed)

Amerikanou C, Kanoni S, Kaliora AC, Barone A, Bjelan M, D'Auria G, Gioxari A, Gosalbes MJ, Mouchti S, Stathopoulou MG, Soriano B, Stojanoski S, Banerjee R, Halabalaki M, Mikropoulou EV, Kannt A, Lamont J, Llorens C, Marascio F, Marascio M, Roig FJ, Smyrnioudis I, Varlamis I, Visvikis-Siest S, Vukic M, Milic N, Medic-Stojanoska M, Cesarini L, Campolo J, Gastaldelli A, Deloukas P, Trivella MG, Francino MP, Dedoussis GV; MAST4HEALTH consortium. Effect of Mastiha supplementation on NAFLD: The MAST4HEALTH Randomised, Controlled Trial. Mol Nutr Food Res. 2021 May;65(10):e2001178. doi: 10.1002/mnfr.202001178. Epub 2021 Apr 16.

Reference Type: BACKGROUND

PMID: 33629536 (View on PubMed)

Eilenberg M, Munda P, Stift J, Langer FB, Prager G, Trauner M, Staufer K. Accuracy of non-invasive liver stiffness measurement and steatosis quantification in patients with severe and morbid obesity. Hepatobiliary Surg Nutr. 2021 Oct;10(5):610-622. doi: 10.21037/hbsn-20-787.

Reference Type: BACKGROUND

PMID: 34760965 (View on PubMed)

Yang A, Nguyen M, Ju I, Brancatisano A, Ryan B, van der Poorten D. Utility of Fibroscan XL to assess the severity of non-alcoholic fatty liver disease in patients undergoing bariatric surgery. Sci Rep. 2021 Jul 7;11(1):14006. doi: 10.1038/s41598-021-93294-6.

Reference Type: BACKGROUND

PMID: 34234198 (View on PubMed)

Ciardullo S, Perseghin G. Statin use is associated with lower prevalence of advanced liver fibrosis in patients with type 2 diabetes. Metabolism. 2021 Aug;121:154752. doi: 10.1016/j.metabol.2021.154752. Epub 2021 Mar 11.

Reference Type: BACKGROUND

PMID: 33716004 (View on PubMed)

Kim D, Konyn P, Cholankeril G, Ahmed A. Physical Activity Is Associated With Nonalcoholic Fatty Liver Disease and Significant Fibrosis Measured by FibroScan. Clin Gastroenterol Hepatol. 2022 Jun;20(6):e1438-e1455. doi: 10.1016/j.cgh.2021.06.029. Epub 2021 Jun 29.

Reference Type: BACKGROUND

PMID: 34214678 (View on PubMed)

Albarazanji K, Nawrocki AR, Gao B, Wang X, Wang YJ, Xiao YF. Effects of mixed meal tolerance test on gastric emptying, glucose and lipid homeostasis in obese nonhuman primates. Sci Rep. 2021 Jun 4;11(1):11866. doi: 10.1038/s41598-021-91027-3.

Reference Type: BACKGROUND

PMID: 34088949 (View on PubMed)

Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.

Reference Type: BACKGROUND

PMID: 18628574 (View on PubMed)

Fujioka Y, Okura T, Sumi K, Matsumoto K, Shoji K, Nakamura R, Matsuzawa K, Izawa S, Kato M, Taniguchi S, Yamamoto K. Normal meal tolerance test is preferable to the glucagon stimulation test in patients with type 2 diabetes that are not in a hyperglycemic state: Comparison with the change of C-peptide immunoreactivity. J Diabetes Investig. 2018 Mar;9(2):274-278. doi: 10.1111/jdi.12692. Epub 2017 Jun 19.

Reference Type: BACKGROUND

PMID: 28494143 (View on PubMed)

Bacha F, Gungor N, Arslanian SA. Measures of beta-cell function during the oral glucose tolerance test, liquid mixed-meal test, and hyperglycemic clamp test. J Pediatr. 2008 May;152(5):618-21. doi: 10.1016/j.jpeds.2007.11.044. Epub 2008 Feb 4.

Reference Type: BACKGROUND

PMID: 18410762 (View on PubMed)

Hong Y, Dingemanse J, Sidharta P, Mager DE. Population pharmacodynamic modeling of hyperglycemic clamp and meal tolerance tests in patients with type 2 diabetes mellitus. AAPS J. 2013 Oct;15(4):1051-63. doi: 10.1208/s12248-013-9512-4. Epub 2013 Aug 1.

Reference Type: BACKGROUND

PMID: 23904152 (View on PubMed)

Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ, Deacon CF, Ahren B. Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab. 2010 Feb;95(2):872-8. doi: 10.1210/jc.2009-2054. Epub 2009 Dec 11.

Reference Type: BACKGROUND

PMID: 20008019 (View on PubMed)

Lages M, Barros R, Moreira P, Guarino MP. Metabolic Effects of an Oral Glucose Tolerance Test Compared to the Mixed Meal Tolerance Tests: A Narrative Review. Nutrients. 2022 May 12;14(10):2032. doi: 10.3390/nu14102032.

Reference Type: BACKGROUND

PMID: 35631171 (View on PubMed)

Wopereis S, Stroeve JHM, Stafleu A, Bakker GCM, Burggraaf J, van Erk MJ, Pellis L, Boessen R, Kardinaal AAF, van Ommen B. Multi-parameter comparison of a standardized mixed meal tolerance test in healthy and type 2 diabetic subjects: the PhenFlex challenge. Genes Nutr. 2017 Aug 29;12:21. doi: 10.1186/s12263-017-0570-6. eCollection 2017.

Reference Type: BACKGROUND

PMID: 28861127 (View on PubMed)

Meyer K, Samek L, Schwaibold M, Westbrook S, Hajric R, Beneke R, Lehmann M, Roskamm H. Interval training in patients with severe chronic heart failure: analysis and recommendations for exercise procedures. Med Sci Sports Exerc. 1997 Mar;29(3):306-12. doi: 10.1097/00005768-199703000-00004.

Reference Type: BACKGROUND

PMID: 9139168 (View on PubMed)

Other Identifiers

NL83431.058.22

Identifier Type: -

Identifier Source: org_study_id