Ectopic Adipose Tissue, Exercise Training and IL-6

Study Overview
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Brief Summary
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Aim: Exercise training improves the risk of cardiometabolic diseases; yet the underlying mechanisms are unclear. Exercise induces release of IL-6 from skeletal muscle. Acute elevations in IL-6 improve lipid and glucose metabolism, the latter partly through a delayed gastric emptying. Physical inactivity causes accumulation of visceral fat (VAT). Visceral and epicardial adipose tissue (EAT) is more inflamed than subcutaneous adipose tissue. Thus, the investigators hypothesize that exercise-induced IL-6 mediates the exercise-induced reduction in EAT and VAT. Secondly, the investigators hypothesize that exercise-induced adaptations in glucose metabolism and gastric motility are dependent on IL-6. Finally the investigators hypothesise that both endurance and resistance exercise training reduce VAT and EAT. Primary aim: To investigate the effects of exercise training on VAT and to determine to what extend IL-6 mediates this effect. Secondary aims: 1) To determine whether 12 weeks of endurance and strength training can reduce the amount of EAT. 2) To study whether the effects of exercise on glucose metabolism and gastric emptying are dependent on IL-6. Methods: Inclusion: 70 inactive men and women, >18 years, waist to height ratio > 0.5 and/or waist circumference ≥ 88 cm (women); waist circumference ≥ 102 cm (men) Design: A 12-week, double-blinded randomised, placebo-controlled exercise intervention study. Intervention: Subjects will be randomised to one of five groups: i) Tocilizumab (IL-6 receptor antibody) and endurance training, ii) Placebo to Tocilizumab and endurance training, iii) Tocilizumab, no exercise iv) Placebo to Tocilizumab and no training, and v) Placebo to Tocilizumab, and resistance training. Tocilizumab/placebo dose will be administered (according to standard recommendations) before the first training session, and maintained during the 12-week training program. Training will be supervised to ensure intensity and compliance. Subjects will be instructed not to change eating habits and informed that this study does not aim for a weight loss. Statistical considerations: Study investigators are blinded to treatment allocation. Dropouts will be replaced. A sample size of 70 subjects is needed to detect a 10% change in visceral adipose, with a power of 80% and a significance level of 0.05.

Official Title
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The Role of Exercise Training Combined With Tocilizumab on Visceral and Epicardial Adipose Tissue and Gastric Emptying in a High Risk Population: an Exploratory Double-blind, Placebo-controlled Randomised Trial

Conditions
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Adiposity

Intervention / Treatment
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* Behavioral: Endurance Exercise Training
* Behavioral: Resistance Exercise Training
* Behavioral: No Exercise
* Drug: Tocilizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women Sedentary Waist to height ratio ≥ ½ and/or waist circumference ≥ 88 cm (women); waist circumference ≥ 102 cm (men) Age ≥ 18 y Exclusion Criteria: Pregnancy Diagnosed with diabetes (HbA1c ≥ 48 mmol/mol or fasting glucose ≥ 7.0 mmol/l) Diagnosed with ischemic heart disease Atrial fibrillation Treatment with biologic rheumatic drugs, systemic prednisolone or other immunosuppressive treatments Health conditions that prevents individuals from participating in the exercise training intervention e.g. severe obesity Patients who cannot undergo MRI scans (e.g. kidney disease, metallic implants or claustrophobia)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endurance exercise + infusion of Tocilizumab<br>Endurance exercise training + monthly infusion of Tocilizumab | Behavioral: Endurance Exercise Training<br>* Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max<br>* Other names: Endurance exercise;Drug: Tocilizumab<br>* Tocilizumab infusion will be administered monthly (8 mg/kg body weight i.v., maximun 800 mg). Each subject will receive 3 infusions during the study period.<br>* Other names: RoActemra;|
| Experimental: Endurance exercise + infusion of placebo<br>Endurance exercise training + monthly infusion of placebo | Behavioral: Endurance Exercise Training<br>* Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max<br>* Other names: Endurance exercise;Drug: Placebo<br>* Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.<br>* Other names: Saline;|
| Experimental: No exercise + infusion of Tocilizumab<br>No exercise + monthly infusion of Tocilizumab | Behavioral: No Exercise<br>* Control to exercise<br>Drug: Tocilizumab<br>* Tocilizumab infusion will be administered monthly (8 mg/kg body weight i.v., maximun 800 mg). Each subject will receive 3 infusions during the study period.<br>* Other names: RoActemra;|
| Placebo Comparator: No exercise + infusion of placebo<br>No exercise training + monthly infusion of placebo | Behavioral: No Exercise<br>* Control to exercise<br>Drug: Placebo<br>* Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.<br>* Other names: Saline;|
| Experimental: Resistance exercise + infusion of placebo<br>Resistance exercise training + monthly infusion of placebo | Behavioral: Resistance Exercise Training<br>* Three months of supervised resistance training. Subjects will perform 3 weekly sessions of 45 min. The intensity will be kept at minimum 60% of 1RM.<br>* Other names: Resistance exercise;Drug: Placebo<br>* Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in visceral fat mass | Visceral fat mass will be measured by MRI before and after the intervention. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo. | 0, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in visceral fat mass | Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: no training + placebo. | 0, 12 weeks | 
| Changes in visceral fat mass | 2. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: resistance training + placebo. | 0, 12 weeks | 
| Changes in visceral fat mass | 3. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: no training + tocilizumab. | 0, 12 weeks | 
| Changes in visceral fat mass | 4. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: resistance training + placebo and group: no training + placebo. | 0, 12 weeks | 
| Changes in visceral fat mass | 5. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: no training + placebo and group: no training + tocilizumab. | 0, 12 weeks | 
| Epicardial adipose tissue | Cardiac fat volume will be measured by a cardiac MRI scan before and after the interventions. All groups will be compared. | 0, 12 weeks | 
| Gastric emptying | Gastric emptying will be measured by paracetamol blood levels (mmol/l) before and after the interventions. The paracetamol levels will be compared between groups as follows. Group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo. Group: Endurancetraining + placebo and group: no training + placebo. Group: Endurancetraining + tocilizumab and group: no training + tocilizumab. Group: No training + placebo and group: no training + tocilizumab. | 0, 12 weeks |