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About
The purpose of the trial is to assess whether the beneficial effect of liraglutide on weight is mediated by changes in the composition of the intestinal Microbiome. The main mechanisms of action of liraglutide were traced to a reduction in the secretion of glucagon and slowing gastric emptying resulting in decreased appetite and body weight. It also seems that liraglutide is capable of increasing the satiety signals thanks to a dual mechanism of stimulation and inhibition induced by medication. Pomc neurons (opiomelacortin) present in hypothalamic arcuate nuclei, stimulated by liraglutide, glucagon-like peptide- 1 (GLP-1) receptor expressed by inhibiting intensely appetite. At the same time through the GABAergic neuronal activity is inhibited neuropeptide Y(NPY) deputies to the production of orexins that are powerful promoters of appetite. Alterations in the composition of the human gut microbiome occur in metabolic disorders such as obesity, diabetes. Liraglutide has been reported to switch microbiome composition towards lean-related bacterial phylotypes in animal studies. This leads to hypothesize that the switch of microbiome by liraglutide may be one of the mechanisms through which liraglutide may exert its effect. In particular the investigators hypothesize that liraglutide could restore a healthy microbiome or at least improve the microbiome composition through slowing gastrointestinal motility. Moreover, the liraglutide-related change of microbiome could be an additional mechanism that contribute to the beneficial metabolic effect of liraglutide. To test this hypothesis the investigators will investigate if there will be any change of gut microbiome assessed as Firmicutes-to-Bacteroidetes ratio after liraglutide treatment. In order to understand if the change of gut microbiome after liraglutide treatment occurs as an association or contributes to the effect of liraglutide ,the investigators will correlate the Firmicutes-to-Bacteroidetes ratios with the changes of Body Mass Index, Body Composition, appetite parameters, chronic inflammation parameters, lipid profile and insulin resistance. All the subjects will follow the same diet in order to avoid any bias.
Full description
This is a randomized, double-blind, parallel group, placebo-controlled trial comparing liraglutide 3.0 mg with placebo both administered subcutaneously once-daily in subjects with established obesity. Subjects will be randomised in a 1:1 ratio to receive either liraglutide 3.0 mg or placebo as an adjunct to standard-of-care.All baseline assessments will be done prior to administration of the first dose of trial product while all the follow up assessments will be done at the end of the trial. Dose escalation of liraglutide/placebo will take place during the first 4 weeks after randomisation as described. All subjects will aim at reaching the recommended target dose of 3.0 mg liraglutide once-daily or the corresponding volume of placebo. In this trial approximately 70 subjects will be randomly assigned to trial product.
Enrollment
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Volunteers
Inclusion criteria
Exclusion criteria
General Safety
Current or history of treatment with medications that may cause significant weight gain for at least 3 months before this trial;
Current use or use within three months before this trial of GLP-1 receptor agonist, pramlintide, sibutramine, orlistat, zonisamide, topiramate or phentermine;
Type 1 diabetes;
Type 2 diabetes;
Obesity related to endocrine diseases;
Hepatic Failure (AST and/or ALT >3 times upper limit of normal and/or Total Bilirubin >1.7 upper limit of normal)
End stage renal disease (eGFR < 30 ml/min/1.73 m2 ) or chronic or intermittent haemodialysis or peritoneal dialysis
History or presence of chronic pancreatitis
Presence of acute pancreatitis within the past 180 days prior to the day of screening
Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
Presence or history of malignant neoplasms within the past 5 years prior to the day of screening
Severe psychiatric disorder which in the investigator's opinion could compromise compliance with the protocol
Known or suspected hypersensitivity to trial product(s) or related products
Previous participation in this trial. Participation is defined as randomisation
Receipt of any investigational medicinal product within 30 days before screening
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method i.e.:
Any disorder, unwillingness or inability, which in the investigator's opinion, might jeopardise the subject's safety or compliance with the protocol
Previous surgical treatment for obesity (excluding liposuction >1 year before trial entry); 19 ) Inflammatory bowel diseases; 20 ) recent antibiotic therapy ( within 30 days before screening)
Cardiovascular- related
Primary purpose
Allocation
Interventional model
Masking
70 participants in 2 patient groups, including a placebo group
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Central trial contact
Annamaria Colao, MD
Data sourced from clinicaltrials.gov
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