Clinical trial NCT05711199: Effect of Glyceroltrinitrate on Human Energy Expenditure and Brown Adipose Tissue Thermogenesis
Official title: Effect of Glyceroltrinitrate on Human Energy Expenditure and Brown Adipose Tissue Thermogenesis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Brown Adipose Tissue
Keywords: energy expenditure
glyceroltrinitrate
cold exposure
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2023-02-02
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Open-label, cross-over trial in healthy volunteers with random sequence of the two study interventions
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: BAT SUVmean
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: BAT SUVmax
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
Secondary outcomes:
measure: BAT Volume
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: BAT glycolytic volume
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: Energy expenditure
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: Cold induced thermogenesis
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: Mixed meal test
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
measure: Skin temperature
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
Other outcomes:
measure: Tissue biopsies of supraclavicular BAT and skeletal muscle musculus vastus lateralis
timeFrame: After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel, Department of Endocrinology
state: BS
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Matthias J Betz, MD
role: PRINCIPAL_INVESTIGATOR
References: