Effect of Liraglutide on Microbiome in Obesity

NCT ID: NCT04046822

Last Updated: 2019-08-20

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-09
• Study Completion Date: 2020-04-30

Brief Summary

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.

Detailed 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.

Conditions

Obesity; Weight Loss; Microbiome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active drug

Liraglutide is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the liraglutide dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Group Type: ACTIVE_COMPARATOR

Liraglutide 6 MG/ML [Saxenda]

Intervention Type: DRUG

Liraglutide is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the liraglutide dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Placebo

Placebo is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Interventions

Liraglutide 6 MG/ML [Saxenda]

Liraglutide is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the liraglutide dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Intervention Type: DRUG

Placebo

Placebo is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Intervention Type: DRUG

Other Intervention Names

Saxenda; Saline Injection

Eligibility Criteria

Inclusion Criteria

1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial;

2. Age ≥ 18 years and < 65 years at the time of signing informed consent;

3. Body mass index (BMI) ≥ 30 kg/m2

4. Stable body weight during the previous 3 months (< 5 kg self-reported weight change).

Exclusion Criteria

General Safety

1. Current or history of treatment with medications that may cause significant weight gain for at least 3 months before this trial;

2. Current use or use within three months before this trial of GLP-1 receptor agonist, pramlintide, sibutramine, orlistat, zonisamide, topiramate or phentermine;

3. Type 1 diabetes;

4. Type 2 diabetes;

5. Obesity related to endocrine diseases;

6. Hepatic Failure (AST and/or ALT >3 times upper limit of normal and/or Total Bilirubin >1.7 upper limit of normal)

7. End stage renal disease (eGFR < 30 ml/min/1.73 m2 ) or chronic or intermittent haemodialysis or peritoneal dialysis

8. History or presence of chronic pancreatitis

9. Presence of acute pancreatitis within the past 180 days prior to the day of screening

10. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma

11. Presence or history of malignant neoplasms within the past 5 years prior to the day of screening

12. Severe psychiatric disorder which in the investigator's opinion could compromise compliance with the protocol

13. Known or suspected hypersensitivity to trial product(s) or related products

14. Previous participation in this trial. Participation is defined as randomisation

15. Receipt of any investigational medicinal product within 30 days before screening

16. 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.:

• patients who use combined hormonal contraceptives (containing estreogen and progesterone) associated with inhibition of ovulation or oral, intravaginal that transdermal;
• patients who use hormonal contraceptives based only progesterone that inhibit ovulation, whether oral, injectable or implantable
• patients with placement of IUD (intrauterine device)
• patients with positioning of hormone releasing intrauterine systems
• patients with bilateral tubal occlusion
• patients with vasectomized partner
• patients who practice sexual abstinence

17. Any disorder, unwillingness or inability, which in the investigator's opinion, might jeopardise the subject's safety or compliance with the protocol

18. 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

• Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening;
• Presently classified as being in New York Heart Association (NYHA) Class IV heart failure

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Federico II University

OTHER

Sponsor Role: lead

Responsible Party

Annamaria Colao

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

"Federico II" University of Naples, Department of Clinical and Molecular Endocrinology and Oncology

Naples, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Annamaria Colao, MD

Role: CONTACT

colao@unina.it

00390817462132

Facility Contacts

Annamaria Colao

Role: primary

colao@unina.it

00390817462132

References

Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591. Epub 2005 Apr 14.

Reference Type: BACKGROUND

PMID: 15831718 (View on PubMed)

Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, Stanton C. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016 May;92(1087):286-300. doi: 10.1136/postgradmedj-2015-133285. Epub 2016 Feb 24.

Reference Type: BACKGROUND

PMID: 26912499 (View on PubMed)

Dinan TG, Cryan JF. Mood by microbe: towards clinical translation. Genome Med. 2016 Apr 6;8(1):36. doi: 10.1186/s13073-016-0292-1.

Reference Type: BACKGROUND

PMID: 27048547 (View on PubMed)

Nakatani Y, Maeda M, Matsumura M, Shimizu R, Banba N, Aso Y, Yasu T, Harasawa H. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. Diabetes Metab. 2017 Oct;43(5):430-437. doi: 10.1016/j.diabet.2017.05.009. Epub 2017 Jun 23.

Reference Type: BACKGROUND

PMID: 28648835 (View on PubMed)

Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23. doi: 10.1073/pnas.0407076101. Epub 2004 Oct 25.

Reference Type: BACKGROUND

PMID: 15505215 (View on PubMed)

Other Identifiers

Microbiome 1

Identifier Type: -

Identifier Source: org_study_id