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Ectopic Adipose Tissue, Exercise Training and IL-6

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ClinicalTrials.gov Identifier: NCT02901496
Recruitment Status : Unknown
Verified October 2017 by Louise Lang Lehrskov, Rigshospitalet, Denmark.
Recruitment status was:  Recruiting
First Posted : September 15, 2016
Last Update Posted : October 13, 2017
Sponsor:
Information provided by (Responsible Party):
Louise Lang Lehrskov, Rigshospitalet, Denmark

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Adiposity Behavioral: Endurance Exercise Training Behavioral: Resistance Exercise Training Behavioral: No Exercise Drug: Tocilizumab Drug: Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Other
Official Title: Ectopic Adipose Tissue, Exercise Training and IL-6 - A Human Intervention Study Investigating the Role of Exercise Training on Ectopic Adipose Tissue and Gastric Emptying - Mechanisms of Action.
Study Start Date : August 2016
Estimated Primary Completion Date : November 2017
Estimated Study Completion Date : November 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Endurance exercise + infusion of Tocilizumab
Endurance exercise training + monthly infusion of Tocilizumab
Behavioral: Endurance Exercise Training
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 Name: Endurance exercise

Drug: Tocilizumab
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 Name: RoActemra

Experimental: Endurance exercise + infusion of placebo
Endurance exercise training + monthly infusion of placebo
Behavioral: Endurance Exercise Training
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 Name: Endurance exercise

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

Experimental: No exercise + infusion of Tocilizumab
No exercise + monthly infusion of Tocilizumab
Behavioral: No Exercise
Control to exercise

Drug: Tocilizumab
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 Name: RoActemra

Placebo Comparator: No exercise + infusion of placebo
No exercise training + monthly infusion of placebo
Behavioral: No Exercise
Control to exercise

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

Experimental: Resistance exercise + infusion of placebo
Resistance exercise training + monthly infusion of placebo
Behavioral: Resistance Exercise Training
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 Name: Resistance exercise

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




Primary Outcome Measures :
  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 Outcome Measures :
  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 ]
    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.

  3. Changes in visceral fat mass [ Time Frame: 0, 12 weeks ]
    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.

  4. Changes in visceral fat mass [ Time Frame: 0, 12 weeks ]
    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.

  5. Changes in visceral fat mass [ Time Frame: 0, 12 weeks ]
    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.

  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 Outcome Measures:
  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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02901496


Contacts
Layout table for location contacts
Contact: Louise L Lehrskov, MD +45 35457190 louise.lang.lehrskov@regionh.dk
Contact: Anne-Sophie wedel-Neergaard, MD +45 35457190 anne-sophie.wedell-neergaard.02@regionh.dk

Locations
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Denmark
Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS) Recruiting
Copenhagen, Denmark, 2100
Contact: Louise L Lehrskov, MD    +45 35457190    louise.lang.lehrskov@regionh.dk   
Principal Investigator: Louise L Lehrskov, MD         
Principal Investigator: Regitse H Christensen, MD         
Principal Investigator: Anne-Sophie Wedel-Neergard, MD         
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
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Study Director: Bente K Pedersen, Professor Rigshospitalet, Denmark

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Louise Lang Lehrskov, MD, PhD student, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02901496     History of Changes
Other Study ID Numbers: H-16018062
First Posted: September 15, 2016    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Cardiac Complexes, Premature
Obesity
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Pathologic Processes