Combined Effects of GLP-1 Analogue and Exercise on Maintenance of Weight Loss and Health After Very-low Calorie Diet

NCT04122716 | Unknown Phase 4 DMC

• 3 other identifiers: U 1111-1173-3104 (UTN)2015-005585-32H-16027082
• Study Type: interventional
• Target: 215
• Locations: 1 country
• Sites: 1

Brief Summary

Introduction: The success rate of weight loss maintenance is limited. Therefore, the purpose of this study is to investigate the maintenance of weight loss and immunometabolic health outcomes after diet-induced weight loss followed by one-year treatment with a glucagon-like peptide-1 receptor agonist (liraglutide), physical exercise, or the combination of both treatments as compared with placebo in individuals with obesity. Methods and analysis: This is an investigator-initiated, randomized, placebo-controlled, parallel group trial. The investigators will enroll women and men (age 18 to 65 years) with obesity (body mass index 32 to 43 kg/m2) to adhere to a very low-calorie diet (800 kcal/day) for eight weeks in order to lose at least 5 % of body weight. Subsequently, participants will be randomized in a 1:1:1:1 ratio to one of four study groups for 52 weeks: 1) placebo, 2) exercise 150 min/week + placebo, 3) liraglutide 3.0 mg/day, and 4) exercise 150 min/week + liraglutide 3.0 mg/day. Re-screening is allowed within the recruitment period. The primary endpoint is change in body weight from randomization to end-of-treatment. Ethics and dissemination: The trial has been approved by the ethical committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT 2015-005585-32). The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.

Conditions

Obesity

Keywords

Weight loss maintenance; Immunometabolic health; Exercise intervention; GLP-1 receptor agonist (liraglutide)

Outcome Measures

Primary Outcomes (1)

• Body weight change (kg)

  Weight will be measured to the nearest 0.1 kg. The same set of scales should ideally be used throughout the trial. Weight should be measured in a fasting state without shoes and wearing light clothes.

  Change from baseline to end-of-treatment (52 weeks)

Secondary Outcomes (10)

• Body composition (fat percentage)

  Change from baseline to end-of-treatment (52 weeks)

• Body composition (fat mass and fat free mass)

  Change from baseline to end-of-treatment (52 weeks)

• Waist and hip circumference

  Change from baseline to end-of-treatment (52 weeks)

• HOMA-IR

  Change from baseline to end-of-treatment (52 weeks)

• Matsuda Index

  Change from baseline to end-of-treatment (52 weeks)

Other Outcomes (17)

• Physical fitness (ml/min/min)

  Change from baseline to end-of-treatment (52 weeks)

• Quality of life score

  Change from baseline to end-of-treatment (52 weeks)

• Heart rate

  Change from screening to baseline to end-of-treatment (52 weeks)

Study Arms (4)

Liraglutide + exercise

ACTIVE COMPARATOR

Liraglutide: 3 mg/day sc. The GLP-1 RA, liraglutide (3.0 mg), or placebo, will be administrated once daily as subcutaneous injections in the abdomen or thigh. The starting dose is 0.6 mg with weekly increments of 0.6 mg until 3.0 mg is achieved. The titration procedure will be prolonged for participants who do not tolerate fast up-titration. Participants who do not tolerate the 3.0 mg dose may in special circumstances stay at lower dose (2.4 mg). However, the aim is to reach 3.0 mg for all study participants. Exercise: 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations.

Drug: Liraglutide; Behavioral: Exercise

Liraglutide + non-exercise

OTHER

Liraglutide: 3 mg/day sc. The GLP-1 RA, liraglutide (3.0 mg), or placebo, will be administrated once daily as subcutaneous injections in the abdomen or thigh. The starting dose is 0.6 mg with weekly increments of 0.6 mg until 3.0 mg is achieved. The titration procedure will be prolonged for participants who do not tolerate fast up-titration. Participants who do not tolerate the 3.0 mg dose may in special circumstances stay at lower dose (2.4 mg). However, the aim is to reach 3.0 mg for all study participants. Non-exercise: Participants should stay at same physical activity level (i.e. max. 2 h of vigorous endurance training/week) as when the participant was included in the study.

Drug: Liraglutide

Placebo + exercise

OTHER

Placebo: 3mg/day sc. Exercise: 150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations.

Behavioral: Exercise

Placebo + non-exercise

NO INTERVENTION

Placebo: 3mg/day sc. Non-exercise: Participants should stay at same physical activity level (i.e. max. 2 h of vigorous endurance training/week) as when the participant was included in the study.

Interventions

Liraglutide DRUG

Daily injections (3mg) with weight consultations starting at dose of 0.6 mg injections with 0.6 mg increments weekly until 3.0 mg is achieved. For subjects who do not tolerate the fast weekly up-titration of 0.6 mg study drug until the 3mg, the titration procedure can be prolonged with up to three weeks for each up-titration. Subjects who do not tolerate the 3mg dose may in special circumstances stay at 2.4 mg, however the overall aim is to reach 3 mg for all study subjects. The dosage and up-titration follow the recommendations from the summary of product characteristics.

Also known as: Saxenda

Liraglutide + exercise; Liraglutide + non-exercise

Exercise BEHAVIORAL

150 min of moderate intensity, 75 min of vigorous intensity, or an equivalent combination of moderate and vigorous intensity exercise per week in accordance with WHO recommendations. Exercise prescription will be performed under strict control of the scientific personnel. There will be aerobic exercise and will include 4 sessions per week after the ramp-in period. 2 sessions per week will be performed under supervision of the staff and 2 sessions will be performed individually but monitored by the staff. Supervised sessions include structured exercise with a duration of 45 min. Of this 30 min will comprise of interval-based spinning session and 15 min circuit training program focusing on large muscle groups. Individual exercise includes aerobic exercise and general physical activity (e.g brisk walking and cycling to work). Participants will use heart rate monitors during sessions.

Liraglutide + exercise; Placebo + exercise

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• BMI \> 32 and \< 43 (kg/m2)
• Age \>18 and \<65 years
• Safe contraceptive method

You may not qualify if:

• Patients diagnosed with known serious chronic illness including type 1 or 2 diabetes (or a randomly measured fasting plasma glucose \> 7 mmol/l)
• Angina pectoris, coronary heart disease, congestive heart failure (NYHA III-IV)
• Severe renal impairment (creatinine clearance (GFR) \<30 mL/min)
• Severe hepatic impairment
• Inflammatory bowel disease
• Gastroparesis
• Cancer
• Chronic obstructive lung disease
• Psychiatric disease, a history of major depressive or other severe psychiatric disorders
• The use of medications that cause clinically significant weight gain or loss
• Previous bariatric surgery
• A history of idiopathic acute pancreatitis
• A family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma
• Osteoarthritis which is judged to be too severe to manage the exercise programme. As intended per study design the intervention will include a 5% weight loss prior to randomization, thus it is expected that possible participants with mild form of osteoarthritis will be able to manage exercise prescriptions.
• Pregnancy, expecting pregnancy or breast feeding. If a study participant is in doubt whether she could be pregnant, a urine pregnancy test is performed. Females of childbearing potential who are not using adequate contraceptive methods (as required by local law or practice). Adequate contraception must be used throughout the study period and at least 65 hours after discontinuation of trial medication (65 hours corresponds to 5 times the half-life of Saxenda). Allergy to any of the ingredients/excipients.

Sponsors & Collaborators

• Signe Torekov: lead
• Hvidovre University Hospital: collaborator
• University of Oxford: collaborator
• Karolinska Institutet: collaborator

Study Sites (1)

University of Copenhagen, Department of Biomedical Sciences

Copenhagen, 2200, Denmark

Location

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• Jensen SBK, Blond MB, Sandsdal RM, Olsen LM, Juhl CR, Lundgren JR, Janus C, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. EClinicalMedicine. 2024 Feb 19;69:102475. doi: 10.1016/j.eclinm.2024.102475. eCollection 2024 Mar.

  PMID: 38544798 DERIVED

• Sandsdal RM, Juhl CR, Jensen SBK, Lundgren JR, Janus C, Blond MB, Rosenkilde M, Bogh AF, Gliemann L, Jensen JB, Antoniades C, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial. Cardiovasc Diabetol. 2023 Feb 25;22(1):41. doi: 10.1186/s12933-023-01765-z.

  PMID: 36841762 DERIVED

• Bogh AF, Jensen SBK, Juhl CR, Janus C, Sandsdal RM, Lundgren JR, Noer MH, Vu NQ, Fiorenza M, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Insufficient sleep predicts poor weight loss maintenance after 1 year. Sleep. 2023 May 10;46(5):zsac295. doi: 10.1093/sleep/zsac295.

  PMID: 36472579 DERIVED

• Jensen SBK, Janus C, Lundgren JR, Juhl CR, Sandsdal RM, Olsen LM, Andresen A, Borg SA, Jacobsen IC, Finlayson G, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment. Nat Commun. 2022 Aug 15;13(1):4770. doi: 10.1038/s41467-022-32307-y.

  PMID: 35970829 DERIVED

• Andersen E, Juhl CR, Kjoller ET, Lundgren JR, Janus C, Dehestani Y, Saupstad M, Ingerslev LR, Duun OM, Jensen SBK, Holst JJ, Stallknecht BM, Madsbad S, Torekov SS, Barres R. Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial. Hum Reprod. 2022 Jun 30;37(7):1414-1422. doi: 10.1093/humrep/deac096.

  PMID: 35580859 DERIVED

• Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, Svane MS, Bandholm T, Bojsen-Moller KN, Blond MB, Jensen JB, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730. doi: 10.1056/NEJMoa2028198.

  PMID: 33951361 DERIVED

MeSH Terms

Conditions

Obesity

Interventions

Liraglutide; Exercise

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Signe S Torekov, Prof, PhD

  University of Copenhagen

  STUDY DIRECTOR

• Sten Madsbad, Prof, MD

  Hvidovre University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The above-mentioned are masked in terms of Liraglutide/placebo, not in terms of exercise/non-exercise. Statistical analysis of primary outcome will be blinded to the assessor.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: After 8 weeks of weight loss the participants are randomized to receive a) Liraglutide 3mg/day sc or b) placebo sc or c) Exercise + placebo sc or d) Exercise + Liraglutide 3mg/d sc for 52 weeks.

Study Record Dates

• First Submitted: July 20, 2018
• First Posted: October 10, 2019
• Study Start: September 1, 2016
• Primary Completion: November 1, 2019
• Study Completion: November 1, 2021
• Last Updated: November 2, 2020

Record last verified: 2020-10

Locations

DK (1)