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Completed

NCT Number: NCT02901496

Ectopic Adipose Tissue, Exercise Training and IL-6

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.

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Key information

Conditions

Adiposity Body Weight Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)

Copenhagen, 2100, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Endurance Exercise Training

Behavioral

Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max

Other names: Endurance exercise

Resistance Exercise Training

Behavioral

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.

Other names: Resistance exercise

No exercise

Behavioral

Control to exercise

Tocilizumab

Drug

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.

Other names: RoActemra

Placebo

Drug

Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.

Other names: Saline

Primary outcomes

  1. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    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.

Secondary outcomes

  1. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    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.

  2. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    • 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.

  3. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    • 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.

  4. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    • 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.

  5. Changes in visceral fat mass

    Time frame: 0, 12 weeks

    • 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.

  6. Epicardial adipose tissue

    Time frame: 0, 12 weeks

    Cardiac fat volume will be measured by a cardiac MRI scan before and after the interventions. All groups will be compared.

  7. Gastric emptying

    Time frame: 0, 12 weeks

    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.

Other outcomes

  1. Peri- and paracardial adipose tissue volume (measured by MRI)

    Time frame: 0, 12 weeks

  2. Body composition analysis (measured by Dual-energy X-ray absorptiometry)

    Time frame: 0, 4, 8 and 12 weeks

  3. Waist circumference (measured in cm)

    Time frame: 0, 4, 8 and 12 weeks

  4. BMI (kg/m^2, weight in kilograms, height in meters)

    Time frame: 0, 4, 8 and 12 weeks

  5. Resting blood pressure as a measure of cardiovascular function

    Time frame: 0, 12 weeks

  6. Maximal aerobic capacity (cardiovascular fitness) (VO2 peak)

    Time frame: 0, 12 weeks

  7. Muscle strength measured by one repetition maximum (1RM)

    Time frame: 0, 12 weeks

  8. Oral glucose tolerance test

    Time frame: 0, 12 weeks

  9. Glycemic control during mixed meal tolerance test

    Time frame: 0, 12 weeks

  10. Free-living glycemic control using continuous glucose monitoring

    Time frame: 0, 12 weeks

  11. Pro- and anti-inflammatory cytokines(Interleukin-6, Interleukin-1ra, Interleukin-1, Interleukin-18, Interleukin-15, Interleukin-10)

    Time frame: 0,4, 8 and 12 weeks

  12. soluble Interleukin-6 receptor (sIL-6R)

    Time frame: 0,4, 8 and 12 weeks

  13. soluble gp130

    Time frame: 0,4, 8 and 12 weeks

  14. Adipose characteristic by blood markers

    Time frame: 0,4, 8 and 12 weeks

    Blood sampling

  15. Cortisol

    Time frame: 0,4, 8 and 12 weeks

    Blood sampling

  16. Catecholamines (Epinephrine and norepinephrine)

    Time frame: 0,4, 8 and 12 weeks

  17. leukocytes

    Time frame: 0,4, 8 and 12 weeks, (Timepoints: 0, 22, 45, 01:45, 02:45, at week 0 and 12)

    Blood sampling

  18. Glucagon

    Time frame: 0,4, 8 and 12 weeks

    blood sampling

  19. Blood lipid

    Time frame: 0,4, 8 and 12 weeks

    Blood sampling

  20. Cardiovascular function assessed by blood markers

    Time frame: 0,4, 8 and 12 weeks

  21. Inflammation status assessed by blood markers

    Time frame: 0,4, 8 and 12 weeks

  22. Adipose biopsy to assess the adipokine expression signature

    Time frame: 0, 12 weeks

  23. Photo of subjects

    Time frame: 0, 12 weeks

    To asses if the visual appearance of the stomach is reflecting the amount of visceral fat mass and to see if there is a difference in the visual appearance before and after the intervention

  24. Faecal and urine samples to asses changes in the microbiome

    Time frame: 0, 12 weeks

  25. Change in sleepiness

    Time frame: 0, 12 weeks

    Self-report using the Epworth questionnaire

  26. Exercise factors during an acute exercise bout

    Time frame: Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)

    cortisol, il-6, epinephrine and norepinephrine

  27. Glucose metabolism during an acute exercise bout

    Time frame: Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)

    At each timepoint exercise factors: cortisol, il-6, epinephrine and norepinephrine will be measured. Furthermore pro anti-inflammatory cytokines, glucose, insulin, C-peptide, C-reactive protein will be reported.

  28. Whole blood stimulation with Lipopolysaccharide and phytohaemagglutinin

    Time frame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)

    in vitro stimulation of whole blood.

  29. Fibroblast growth factor 21

    Time frame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)

  30. oxidative burst in neutrophils

    Time frame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)

  31. gastrointestinal health

    Time frame: 0,12 weeks

    A questionnaire regarding gastrointestinal symptoms. A Visual Analog Score will be used.

  32. Physical activity

    Time frame: 0 weeks

    Self-report physical activity using The Minnesota Leisure Time Physical Activity Questionnaire

  33. Diet registration

    Time frame: 0,4,12

    Self-report diet registration for 3 days

  34. Satiety

    Time frame: 0,12

    self-report using a satiety questionnaire during mixed meal tolerance test

  35. Cardiac function measured by heart rate recovery

    Time frame: 0, 12 weeks

  36. Muscle biopsy to assess expression of exercise induced cytokines

    Time frame: 0, 12 weeks

  37. Coronary sinus flow reserve as a measure of global perfusion using MRI

    Time frame: 0, 12 weeks

  38. Insulin during mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  39. C-peptide during mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  40. Glucagon during mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  41. GLP-1 during mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  42. Insulin sensitivity index (Matsuda) based on mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  43. Insulin secretion index based on mixed meal tolerance test

    Time frame: Time Frame: 0, 12 weeks

  44. IL-6 released in respons to an exercise bout

    Time frame: one of the first 3 and one of the last 3 exercise bouts

    IL-6 in plasma measured before and after an exercise bout

Sponsors and collaborators

Lead sponsor

Rigshospitalet, Denmark

Other

Registry information

Official study title

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

Important dates

Study start
2016
Primary completion
2018
Study completion
2018
First posted
Sep 15, 2016
Registry last updated
Feb 26, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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