Clinical trial NCT02901496: Ectopic Adipose Tissue, Exercise Training and IL-6
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Adiposity
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2016-09-15
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


Eligibility 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)

Primary outcomes:
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
Secondary outcomes:
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
measure: Changes in visceral fat mass
timeFrame: 0, 12 weeks
measure: Epicardial adipose tissue
timeFrame: 0, 12 weeks
measure: Gastric emptying
timeFrame: 0, 12 weeks
Other outcomes:
measure: Peri- and paracardial adipose tissue volume (measured by MRI)
timeFrame: 0, 12 weeks
measure: Body composition analysis (measured by Dual-energy X-ray absorptiometry)
timeFrame: 0, 4, 8 and 12 weeks
measure: Waist circumference (measured in cm)
timeFrame: 0, 4, 8 and 12 weeks
measure: BMI (kg/m^2, weight in kilograms, height in meters)
timeFrame: 0, 4, 8 and 12 weeks
measure: Resting blood pressure as a measure of cardiovascular function
timeFrame: 0, 12 weeks
measure: Maximal aerobic capacity (cardiovascular fitness) (VO2 peak)
timeFrame: 0, 12 weeks
measure: Muscle strength measured by one repetition maximum (1RM)
timeFrame: 0, 12 weeks
measure: Oral glucose tolerance test
timeFrame: 0, 12 weeks
measure: Glycemic control during mixed meal tolerance test
timeFrame: 0, 12 weeks
measure: Free-living glycemic control using continuous glucose monitoring
timeFrame: 0, 12 weeks
measure: Pro- and anti-inflammatory cytokines(Interleukin-6, Interleukin-1ra, Interleukin-1, Interleukin-18, Interleukin-15, Interleukin-10)
timeFrame: 0,4, 8 and 12 weeks
measure: soluble Interleukin-6 receptor (sIL-6R)
timeFrame: 0,4, 8 and 12 weeks
measure: soluble gp130
timeFrame: 0,4, 8 and 12 weeks
measure: Adipose characteristic by blood markers
timeFrame: 0,4, 8 and 12 weeks
measure: Cortisol
timeFrame: 0,4, 8 and 12 weeks
measure: Catecholamines (Epinephrine and norepinephrine)
timeFrame: 0,4, 8 and 12 weeks
measure: leukocytes
timeFrame: 0,4, 8 and 12 weeks, (Timepoints: 0, 22, 45, 01:45, 02:45, at week 0 and 12)
measure: Glucagon
timeFrame: 0,4, 8 and 12 weeks
measure: Blood lipid
timeFrame: 0,4, 8 and 12 weeks
measure: Cardiovascular function assessed by blood markers
timeFrame: 0,4, 8 and 12 weeks
measure: Inflammation status assessed by blood markers
timeFrame: 0,4, 8 and 12 weeks
measure: Adipose biopsy to assess the adipokine expression signature
timeFrame: 0, 12 weeks
measure: Photo of subjects
timeFrame: 0, 12 weeks
measure: Faecal and urine samples to asses changes in the microbiome
timeFrame: 0, 12 weeks
measure: Change in sleepiness
timeFrame: 0, 12 weeks
measure: Exercise factors during an acute exercise bout
timeFrame: Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
measure: Glucose metabolism during an acute exercise bout
timeFrame: Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
measure: Whole blood stimulation with Lipopolysaccharide and phytohaemagglutinin
timeFrame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
measure: Fibroblast growth factor 21
timeFrame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
measure: oxidative burst in neutrophils
timeFrame: During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks)
measure: gastrointestinal health
timeFrame: 0,12 weeks
measure: Physical activity
timeFrame: 0 weeks
measure: Diet registration
timeFrame: 0,4,12
measure: Satiety
timeFrame: 0,12
measure: Cardiac function measured by heart rate recovery
timeFrame: 0, 12 weeks
measure: Muscle biopsy to assess expression of exercise induced cytokines
timeFrame: 0, 12 weeks
measure: Coronary sinus flow reserve as a measure of global perfusion using MRI
timeFrame: 0, 12 weeks
measure: Insulin during mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: C-peptide during mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: Glucagon during mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: GLP-1 during mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: Insulin sensitivity index (Matsuda) based on mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: Insulin secretion index based on mixed meal tolerance test
timeFrame: Time Frame: 0, 12 weeks
measure: IL-6 released in respons to an exercise bout
timeFrame: one of the first 3 and one of the last 3 exercise bouts
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)
Study officials:
affiliation: Rigshospitalet, Denmark
name: Bente K Pedersen, Professor
role: STUDY_DIRECTOR
References:
citation: Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum N, Dahl CN, Henneberg M, Ried-Larsen M, Nybing JD, Christensen R, Rosenmeier JB, Karstoft K, Pedersen BK, Ellingsgaard H, Krogh-Madsen R. Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial. Cell Metab. 2019 Apr 2;29(4):844-855.e3. doi: 10.1016/j.cmet.2018.12.007. Epub 2018 Dec 27.
citation: Christensen RH, Wedell-Neergaard AS, Lehrskov LL, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum NB, Dahl CN, Henneberg M, Ried-Larsen M, Boesen MP, Christensen R, Karstoft K, Krogh-Madsen R, Rosenmeier JB, Pedersen BK, Ellingsgaard H. Effect of Aerobic and Resistance Exercise on Cardiac Adipose Tissues: Secondary Analyses From a Randomized Clinical Trial. JAMA Cardiol. 2019 Aug 1;4(8):778-787. doi: 10.1001/jamacardio.2019.2074.
citation: Christensen RH, Wedell-Neergaard AS, Lehrskov LL, Legard GE, Dorph EB, Nymand S, Ball MK, Zacho M, Christensen R, Ellingsgaard H, Rosenmeier JB, Krogh-Madsen R, Pedersen BK, Karstoft K. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. 2018 May 2;19(1):266. doi: 10.1186/s13063-018-2637-0.