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

Non-Alcoholic Fatty Liver Disease Clinical Trial

— TikTac  

Official title:

The Clock Thickens: Morning or Evening Training for the Treatment of NAFLD? (TikTac Study)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05987748
• Other study ID #: NL83431.058.22
• Status: Not yet recruiting
• Phase: N/A
• Start date: September 1, 2023
• Est. completion date: September 1, 2024

Study information

• Verified date: August 2023
• Source: Leiden University Medical Center
• Contact: Milena Schönke, PhD
• Phone: +31715268188
• Email: m.schoenke[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: September 1, 2024
• Est. primary completion date: September 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 75 Years

Eligibility

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:

• Exclusion criteria for MRI (claustrophobia, pacemaker, metal implants, etc.)

• 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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Behavioral:
• Exercise training
Mixed exercise training containing strength and endurance elements carried out under supervision

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Center	Leiden	South Holland

Sponsors (2)

Lead Sponsor	Collaborator
Leiden University Medical Center	Maag Lever Darm Stichting

Country where clinical trial is conducted

Netherlands, 

References & Publications (29)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Liver fat content	Liver fat content (in %) will be measured by MRI LiverMultiScan	12 weeks
Secondary	Hepatic fibrosis	Hepatic stiffness (in kPa) will be measured as a proxy for liver fibrosis by Fibroscan (transient elastography)	12 weeks
Secondary	Body mass index (BMI)	Body weight (in kg) and height (in m) will be combined to report BMI in kg/m^2	12 weeks
Secondary	Fecal microbiota	Fecal microbiota composition assessed via microbial sequencing	12 weeks
Secondary	Cardiorespiratory fitness	Peak workload (Wpeak) will be assessed with a the Steep Ramp Test (SRT) on a cycle ergometer	12 weeks
Secondary	Waist circumference	Waist circumference (in cm) will be measured with a measuring tape	12 weeks
Secondary	Blood pressure	Blood pressure (mmHg) will be measured using an arm cuff	12 weeks
Secondary	Plasma levels of liver enzymes	Plasma levels of aspartate transaminase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) (all in units/L) and bilirubin (in umol/L) will be quantified in the laboratory	12 weeks
Secondary	Plasma insulin levels	Plasma insulin (in pmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal	12 weeks
Secondary	Plasma glucose levels	Plasma glucose (in mmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal	12 weeks
Secondary	Blood lipid levels	Blood triglyceride, LDL-cholesterol and HDL-cholesterol levels (all in mmol/L) will be quantified in the laboratory	12 weeks
Secondary	Physical activity	Self-reported physical activity (minutes of moderate-intensity activity per week) will be assessed with the International Physical Activity Questionnaire (IPAQ)	12 weeks
Secondary	Sleep	Sleeping habits (bedtime, time of falling asleep, time of waking up, sleep duration) will be assessed via the Munich Chronotype Questionnaire (MCTQs 5.0).	12 weeks
Secondary	Food intake	Self-reported food intake (type of food, quantity, time of intake) will be assessed with 3-day food diaries	12 weeks