Ectopic Adipose Tissue, Exercise Training and IL-6

NCT ID: NCT02901496

Last Updated: 2024-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 83 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2018-04-30

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.

Conditions

Adiposity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Endurance exercise + infusion of Tocilizumab

Endurance exercise training + monthly infusion of Tocilizumab

Group Type: EXPERIMENTAL

Endurance Exercise Training

Intervention Type: 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

Tocilizumab

Intervention Type: 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.

Endurance exercise + infusion of placebo

Endurance exercise training + monthly infusion of placebo

Group Type: EXPERIMENTAL

Endurance Exercise Training

Intervention Type: 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

Placebo

Intervention Type: DRUG

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

No exercise + infusion of Tocilizumab

No exercise + monthly infusion of Tocilizumab

Group Type: EXPERIMENTAL

No Exercise

Intervention Type: BEHAVIORAL

Control to exercise

Tocilizumab

Intervention Type: 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.

No exercise + infusion of placebo

No exercise training + monthly infusion of placebo

Group Type: PLACEBO_COMPARATOR

No Exercise

Intervention Type: BEHAVIORAL

Control to exercise

Placebo

Intervention Type: DRUG

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

Resistance exercise + infusion of placebo

Resistance exercise training + monthly infusion of placebo

Group Type: EXPERIMENTAL

Resistance Exercise Training

Intervention Type: 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.

Placebo

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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.

Intervention Type: BEHAVIORAL

No Exercise

Control to exercise

Intervention Type: BEHAVIORAL

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Endurance exercise; Resistance exercise; RoActemra; Saline

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Louise Lang Lehrskov

MD, PhD student

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bente K Pedersen, Professor

Role: STUDY_DIRECTOR

Rigshospitalet, Denmark

Locations

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

Copenhagen, , Denmark

Countries

Denmark

References

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.

Reference Type: RESULT

PMID: 30595477 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31268469 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29720225 (View on PubMed)

Other Identifiers

H-16018062

Identifier Type: -

Identifier Source: org_study_id