Effect of Glyceroltrinitrate on Human Energy Expenditure and Brown Adipose Tissue Thermogenesis

Study Overview
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Brief Summary
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The aim of this study is to evaluate the efficacy of glyceroltrinitrate (Nitroderm® TTS) to activate and expand human BAT as compared to mild cold exposure.

Detailed Description
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The activation of brown adipose tissue in response to glyceroltrinitrate as compared to cold exposure will be studied in an open-label, cross-over trial in healthy volunteers with random sequence of the two study periods (treatment and control) seperated by a washout period of 7 days. In the treatment phase all participants will receive Nitroderm® TTS (glyceroltrinitrate) for a total of 15 days. For better tolerability, it will be will started with a lower dose of 5mg/24h (Nitroderm® TTS) the first 5 days and after that a change to Nitroderm® TTS 10mg/24h for another 10 days will be done. Each transdermal patch will be applied for 12 hours per day (overnight) to avoid development of nitrate tolerance. Energy expenditure will be measured by indirect calorimetry before and after a mild cold exposure by placing a medical cooling system around their midsection. Additionally brown adipose tissue activity will determined by 18F-FDG-PET/CT 30 min after injection of 75 MBq of 18F-FDG. To analyse changes in BAT and muscle which are caused by glyceroltrinitrate as compared with cold stimulus, a tissue biopsie of supraclavicular BAT and skeletal muscle (musculus vastus lateralis) will be performed. To measure changes in glucose tolerance and triglyceride levels a mixed meal test will be performed during control and treatment phase respectively. Additionally, a indirect calorimetry will be conducted before and after mixed meal test to assess diet-induced thermogenesis, i.e. the increase in REE due to ingestion of nutrients In control phase the same examinations will be performed, but without glyceroltrinitrat.

Official Title
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Effect of Glyceroltrinitrate on Human Energy Expenditure and Brown Adipose Tissue Thermogenesis

Conditions
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Brown Adipose Tissue

Intervention / Treatment
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* Drug: Glyceroltrinitrat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI 18.5 to 25 kg/m2 or 30 to 35kg/m2 Able to give informed consent as documented by signature Age 18 to 40 years Exclusion Criteria: Contraindications to glyceroltrinitrate, e.g. known hypersensitivity or allergy Concomitant medication: Non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, diuretics, antihypertensives, fibrates or statins, metformin, PDE-5-inhibitors Clinically significant concomitant disease states (e.g. renal failure, hepatic dysfunction, cardiovascular disease, diabetes mellitus) Hypersensitivity to cold (e.g. Raynaud Syndrome) Orthostatic hypotension: systolic blood pressure decreases min. 20mmHg or diastolic blood pressure decreases min 10mmHg within 3-5min after standing up (Schellong Test at screening visit) History of orthostatic syncope or pre-syncope Blood pressure values below 100 mmHg systolic and 60 mmHg diastolic Allergy to local anesthetic Hypothyroidism without sufficient substitution Hyperthyroidism Claustrophobia Smoker / habitual tobacco use Habitual excessive alcohol use Weight change of >5% within 3 months prior to inclusion Known or suspected non-compliance, drug or alcohol abuse Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant Enrolment of the investigator, his/her family members, employees and other dependent persons Enrolment into another study using ionizing radiation within the previous 12 months Pregnant or lactating women Lab parameters Hb below lower reference limit Glycated Hemoglobin (HbA1c): above 6.0% Random plasma glucose >11 mM

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Open-label, cross-over trial in healthy volunteers with random sequence of the two study interventions
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: normal weight<br>Treatment phase administration of glyceroltrinitrate (Nitroderm TTS) for 15 days. measurement of energy expenditure before and after cold exposure performing FDG-PET/CT and tissue biopsy (brown adipose tissue and muscle) measurement of glucose tolerance, triglyceride levels and energy expenditure before and after a mixed meal test. Control phase: measurement of energy expenditure before and after cold exposure performing FDG-PET/CT and tissue biopsy (brown adipose tissue and muscle) measurement of glucose tolerance, triglyceride levels and energy expenditure before and after a mixed meal test. | Drug: Glyceroltrinitrat<br>* transdermal patch<br>|
| Experimental: overweight<br>Treatment phase administration of glyceroltrinitrate (Nitroderm TTS) for 15 days. measurement of energy expenditure before and after cold exposure performing FDG-PET/CT and tissue biopsy (brown adipose tissue and muscle) measurement of glucose tolerance, triglyceride levels and energy expenditure before and after a mixed meal test. Control phase: measurement of energy expenditure before and after cold exposure performing FDG-PET/CT and tissue biopsy (brown adipose tissue and muscle) measurement of glucose tolerance, triglyceride levels and energy expenditure before and after a mixed meal test. | Drug: Glyceroltrinitrat<br>* transdermal patch<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BAT SUVmean | 18F-FDG uptake into the supra-clavicular brown adipose tissue as determined by 18F- | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| BAT SUVmax | maximum SUV in supraclavicular adipose tissue (according to BARCIST 1.0) | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BAT Volume | volume of supraclavicular adipose tissue (according to BARCIST 1.0) | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| BAT glycolytic volume | volume of supraclavicular adipose tissue x SUVmean (according to BARCIST 1.0) | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| Energy expenditure | Quantitative change in EE above resting metabolic rate in response to the respective study intervention. Measured by indirect calorimetry. | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| Cold induced thermogenesis | rise in energy expenditure above baseline occurring during mild cold exposure | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| Mixed meal test | Changes in glucose tolerance and triglyceride levels after a mixed meal test in the respective study visit. | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 
| Skin temperature | - Changes in skin temperature and body core temperature during treatment with glyceroltrinitrate (Nitroderm® TTS) compared to control. | After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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energy expenditure, glyceroltrinitrate, cold exposure