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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Behavioral: Exercise training


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Morning exercise<br>Individuals will exercise train at 8 AM three times per week for 12 weeks. | Behavioral: Exercise training<br>* Mixed exercise training containing strength and endurance elements carried out under supervision<br>|
| Experimental: Evening exercise<br>Individuals will exercise train at 8 PM three times per week for 12 weeks. | Behavioral: Exercise training<br>* Mixed exercise training containing strength and endurance elements carried out under supervision<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver fat content | Liver fat content (in %) will be measured by MRI LiverMultiScan | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic fibrosis | Hepatic stiffness (in kPa) will be measured as a proxy for liver fibrosis by Fibroscan (transient elastography) | 12 weeks | 
| Body mass index (BMI) | Body weight (in kg) and height (in m) will be combined to report BMI in kg/m^2 | 12 weeks | 
| Fecal microbiota | Fecal microbiota composition assessed via microbial sequencing | 12 weeks | 
| Cardiorespiratory fitness | Peak workload (Wpeak) will be assessed with a the Steep Ramp Test (SRT) on a cycle ergometer | 12 weeks | 
| Waist circumference | Waist circumference (in cm) will be measured with a measuring tape | 12 weeks | 
| Blood pressure | Blood pressure (mmHg) will be measured using an arm cuff | 12 weeks | 
| 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 | 
| 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 | 
| 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 | 
| Blood lipid levels | Blood triglyceride, LDL-cholesterol and HDL-cholesterol levels (all in mmol/L) will be quantified in the laboratory | 12 weeks | 
| 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 | 
| 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 | 
| Food intake | Self-reported food intake (type of food, quantity, time of intake) will be assessed with 3-day food diaries | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Circadian rhythms