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Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients (LEPTOB)

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ClinicalTrials.gov Identifier: NCT03974139
Recruitment Status : Not yet recruiting
First Posted : June 4, 2019
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
Centre Hospitalier Arras
Information provided by (Responsible Party):
Lille Catholic University

Brief Summary:
Obesity, a major health problem, is gradually transforming into a global epidemic. The current obesity treatment with long term efficacy is the bariatric surgery, however, the operative risk of this procedure is high and the post-operative iotrogeny may be important. Obesity is most often associated to the feeding behavior which depends on hypothalamic integration of peripheral signals such as leptin and glucose. High levels of circulating leptin are detected in obese patients. These elevated leptin levels fail to reduce appetite or increase energy expenditure. The mechanism underlying this non-integration of peripheral signals remains to be identified. The ratio of leptin levels in the cereprospinal fluid (CSF) and in the periphery is drastically decreased in obese patients when compared to lean individuals, therefore a defective transport of circulating leptin into the brain via the CSF is maybe linked to obesity.

Condition or disease Intervention/treatment Phase
Obesity Without Type 2 Diabetes, With BMI>30 Drug: Metformin Oral Tablet Phase 2

Detailed Description:

We hypothesize that the alteration of leptin transport into the CSF of obese patients could be modulated by drugs such as metformin which is widely used worldwide to treat diabetes. This study is monocentric, prospective, one-arm type and interventional. The main objective isto evaluate the impact of metformin on the transport of leptin into the CSF of obese patients.

We propose to show a variation of CSF leptin / serum leptin before and after metformin treatment and study its association with changes in hypothalamic metabolic activity, cognitive and appetite-related behaviors and ratio of other metabolic signals. This would support the hypothesis of modulation of resistance to peripheral leptin by metformin and thus uncover a new indication for metformin treatment towards the management of obesity.

For this purpose, volunteers will be subjected to blood sampling via venipuncture, CSF collection via lumbar puncture, MRI assessments and questionnaires (cognitive tests, food survey and feeding behavior) before and after a 3-month metformin treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Study of the Communication of the Hypothalamus With the Periphery: Impact of Metformin on Leptin Transport in the Cerebrospinal Fluid of Obese Patients. A Monocentric Prospective Study
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Obese patients
Patients with body mass index >30
Drug: Metformin Oral Tablet
Day 1 to day 3: 500 mg/day Day 4 to day 6: 500 mg/twice a day Day 7 to day 9: 500 mg three times a day Day 10 until next lumbar puncture : 850 mg three times a day




Primary Outcome Measures :
  1. cerebrospinal fluid /plasma leptin ratio [ Time Frame: 3 months ]

Secondary Outcome Measures :
  1. cerebrospinal fluid /plasma glucose ratio [ Time Frame: at day 0, 3 months ]
  2. cerebrospinal fluid /plasma glucagon like peptide 1 (GLP1) ratio [ Time Frame: at day 0, 3 months ]
  3. cerebrospinal fluid /plasma insulin ratio [ Time Frame: 3 months ]
  4. cerebrospinal fluid /plasma ghrelin ratio [ Time Frame: at day 0, 3 months ]
  5. Cerebrospinal fluid levels of Agouti-Related Peptide (AgRP) [ Time Frame: at day 0, 3 months ]
  6. Plasma levels of Agouti-Related Peptide (AgRP) [ Time Frame: at day 0, 3 months ]
  7. Cerebrospinal fluid levels of proopiomelanocortin (POMC) [ Time Frame: at day 0, 3 months ]
  8. Plasma levels of proopiomelanocortin (POMC) [ Time Frame: at day 0, 3 months ]
  9. Cerebrospinal fluid levels of neuropeptide Y (NPY) [ Time Frame: at day 0, 3 months ]
  10. Plasma levels of neuropeptide Y (NPY) [ Time Frame: at day 0, 3 months ]
  11. Cerebrospinal fluid levels of leptin soluble receptor [ Time Frame: at day 0, 3 months ]
  12. Plasma levels of leptin soluble receptor [ Time Frame: at day 0, 3 months ]
  13. Apparent diffusion coefficient (ADC) [ Time Frame: at day 0, 3 months ]
    Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue, and is commonly clinically calculated using Magnetic resonance imaging (MRI). An ADC of a tissue is expressed in units of mm2/s

  14. Hypothalamic concentration of N-acetyl-aspartate (NAA) [ Time Frame: at day 0, 3 months ]
    This concentration will be measure by spectroscopy

  15. Hypothalamic concentration of creatine [ Time Frame: at day 0, 3 months ]
    This concentration will be measure by spectroscopy

  16. Hypothalamic concentration of Choline [ Time Frame: 3 months ]
    This concentration will be measure by spectroscopy

  17. Hypothalamic concentration of Glutamine / glutamate [ Time Frame: at day 0, 3 months ]
    This concentration will be measure by spectroscopy

  18. Hypothalamic concentration of gamma-aminobutyric acid (GABA) [ Time Frame: at day 0, 3 months ]
    This concentration will be measure by spectroscopy

  19. Weight [ Time Frame: at day 0, 3 months ]
  20. Abdominal circumference [ Time Frame: 3 months ]
  21. Percentage of body fat [ Time Frame: at day 0, 3 months ]
    This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body.

  22. Fat free mass (Kg) [ Time Frame: at day 0, 3 months ]
    This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body.

  23. Energy expenditure [ Time Frame: at day 0, 3 months ]
    This parameter will measure by indirect calorimetry (kCal / 24h)

  24. Score of the Three Factor Eating Questionnaire (TFEQ) [ Time Frame: 3 months ]

    The TFEQ contains 51 items and measures three dimensions of eating behavior:

    • cognitive restraint of eating' (Factor I - 21 items)
    • disinhibition (Factor II - 16 items)
    • hunger (Factor III - 14 items)

    Each item scores either 0 or 1 point. The minimum score for factors I-II-III is therefore 0-0-0, the possible maximum score 21-16-14


  25. Score of the Dutch Eating Behaviour Questionnaire (DEBQ) [ Time Frame: at day 0, 3 months ]
    This is a 33-item self-report questionnaire to assess three distinct eating behaviors in adults: (1) emotional eating, (2) external eating, and (3) restrained eating. Items on the DEBQ range from 1 (never) to 5 (very often), with higher scores indicating greater endorsement of the eating behavior.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults between 18 and 40 years old
  • Body mass index >30
  • For childbearing age women: use of an effective contraceptive method for the duration of the study
  • Patients willing to participate in the study and who have signed the informed consent form
  • Patients with health insurance

Exclusion Criteria:

  • Genetic obesity
  • Patients already treated with metformin
  • Type 2 diabetes defined by 2 fasting blood glucose >1,26g/L or blood glucose >2 g/L at 120 min of oral glucose tolerance test with 75 g of glucose
  • Glucose intolerance (fasting blood glucose between 1,10 g/L and 1,26 g/L or blood glucose between 1,40 g/L and 2g/L at 120 minutes of oral glucose tolerance test with 75 g of glucose)Active neoplastic pathology, diagnosed < 5 years, or in treatment
  • Neurological pathology (demyelinating, tumor, vascular)
  • Adipose tissue pathology (lipodystrophy)
  • History of bariatric surgery
  • Contraindication to metformin
  • Lumbar puncture contraindication
  • MRI contraindication
  • Person unable to consent, or benefiting from a legal protection regime (guardianship/curatorship/guardianship of justice)
  • Pregnant or breastfeeding woman
  • Contra-indication to impedance measurement
  • Contraindication to indirect calorimetry: claustrophobia
  • Taking a psychotropic drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03974139


Contacts
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Contact: Amélie Lansiaux, MD, PhD 0033320225741 lansiaux.amelie@ghcl.net
Contact: Melody Plets, MSc 0033320225733 plets.melody@ghicl.net

Locations
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France
Centre hospitalier d'Arras Not yet recruiting
Arras, France, 62022
Contact: Vincent Florent, MD, MSc, PhD         
Sponsors and Collaborators
Lille Catholic University
Centre Hospitalier Arras
Investigators
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Study Director: Vincent Prévot, PhD Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator: Vincent Florent, MD, MSc, PhD Centre Hospitalier d'Arras, INSERM

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Responsible Party: Lille Catholic University
ClinicalTrials.gov Identifier: NCT03974139     History of Changes
Other Study ID Numbers: RC-P0054
First Posted: June 4, 2019    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lille Catholic University:
metformin
leptin
cerebrospinal fluid

Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs