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出境医 / 临床实验 / Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients (LEPTOB)
Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients (LEPTOB)
Study Description
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.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 31 participants |
| Allocation: | N/A |
| 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 |
| Actual Study Start Date : | September 10, 2019 |
| Estimated Primary Completion Date : | August 31, 2021 |
| Estimated Study Completion Date : | May 31, 2022 |
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures :
- cerebrospinal fluid /plasma leptin ratio [ Time Frame: 3 months ]
Secondary Outcome Measures :
- cerebrospinal fluid /plasma glucose ratio [ Time Frame: at day 0, 3 months ]
- cerebrospinal fluid /plasma glucagon like peptide 1 (GLP1) ratio [ Time Frame: at day 0, 3 months ]
- cerebrospinal fluid /plasma insulin ratio [ Time Frame: 3 months ]
- cerebrospinal fluid /plasma ghrelin ratio [ Time Frame: at day 0, 3 months ]
- Cerebrospinal fluid levels of Agouti-Related Peptide (AgRP) [ Time Frame: at day 0, 3 months ]
- Plasma levels of Agouti-Related Peptide (AgRP) [ Time Frame: at day 0, 3 months ]
- Cerebrospinal fluid levels of proopiomelanocortin (POMC) [ Time Frame: at day 0, 3 months ]
- Plasma levels of proopiomelanocortin (POMC) [ Time Frame: at day 0, 3 months ]
- Cerebrospinal fluid levels of neuropeptide Y (NPY) [ Time Frame: at day 0, 3 months ]
- Plasma levels of neuropeptide Y (NPY) [ Time Frame: at day 0, 3 months ]
- Cerebrospinal fluid levels of leptin soluble receptor [ Time Frame: at day 0, 3 months ]
- Plasma levels of leptin soluble receptor [ Time Frame: at day 0, 3 months ]
- 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
- Hypothalamic concentration of N-acetyl-aspartate (NAA) [ Time Frame: at day 0, 3 months ]This concentration will be measure by spectroscopy
- Hypothalamic concentration of creatine [ Time Frame: at day 0, 3 months ]This concentration will be measure by spectroscopy
- Hypothalamic concentration of Choline [ Time Frame: 3 months ]This concentration will be measure by spectroscopy
- Hypothalamic concentration of Glutamine / glutamate [ Time Frame: at day 0, 3 months ]This concentration will be measure by spectroscopy
- Hypothalamic concentration of gamma-aminobutyric acid (GABA) [ Time Frame: at day 0, 3 months ]This concentration will be measure by spectroscopy
- Weight [ Time Frame: at day 0, 3 months ]
- Abdominal circumference [ Time Frame: 3 months ]
- 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.
- 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.
- Energy expenditure [ Time Frame: at day 0, 3 months ]This parameter will measure by indirect calorimetry (kCal / 24h)
- 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
- 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.
Eligibility Criteria
| 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
Contacts and Locations
Contacts
| Contact: Amélie Lansiaux, MD, PhD | 0033320225741 | lansiaux.amelie@ghcl.net | |
| Contact: Melody Plets, MSc | 0033320225733 | plets.melody@ghicl.net |
Locations
| France | |
| Centre hospitalier d'Arras | Recruiting |
| Arras, France, 62022 | |
| Contact: Vincent Florent, MD, MSc, PhD | |
Sponsors and Collaborators
Lille Catholic University
Centre Hospitalier Arras
Investigators
| 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 |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | May 28, 2019 | ||||||||
| First Posted Date ICMJE | June 4, 2019 | ||||||||
| Last Update Posted Date | February 17, 2021 | ||||||||
| Actual Study Start Date ICMJE | September 10, 2019 | ||||||||
| Estimated Primary Completion Date | August 31, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
cerebrospinal fluid /plasma leptin ratio [ Time Frame: 3 months ] | ||||||||
| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
|
||||||||
| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients | ||||||||
| Official Title ICMJE | 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 | ||||||||
| 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. | ||||||||
| 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. |
||||||||
| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Phase 2 | ||||||||
| Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Basic Science |
||||||||
| Condition ICMJE | Obesity Without Type 2 Diabetes, With BMI>30 | ||||||||
| Intervention ICMJE | 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
|
||||||||
| Study Arms ICMJE | Experimental: Obese patients
Patients with body mass index >30
Intervention: Drug: Metformin Oral Tablet
|
||||||||
| Publications * | Not Provided | ||||||||
|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
|||||||||
| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
31 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | May 31, 2022 | ||||||||
| Estimated Primary Completion Date | August 31, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
|
||||||||
| Sex/Gender ICMJE |
|
||||||||
| Ages ICMJE | 18 Years to 40 Years (Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | No | ||||||||
| Contacts ICMJE |
|
||||||||
| Listed Location Countries ICMJE | France | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT03974139 | ||||||||
| Other Study ID Numbers ICMJE | RC-P0054 | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
|
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| IPD Sharing Statement ICMJE |
|
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| Responsible Party | Lille Catholic University | ||||||||
| Study Sponsor ICMJE | Lille Catholic University | ||||||||
| Collaborators ICMJE | Centre Hospitalier Arras | ||||||||
| Investigators ICMJE |
|
||||||||
| PRS Account | Lille Catholic University | ||||||||
| Verification Date | February 2021 | ||||||||
|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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