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

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.

Study Overview

• Status: Completed
• Conditions: Brown Adipose Tissue
• Intervention / Treatment: Drug: Glyceroltrinitrat

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • BS
    • Basel, BS, Switzerland, 4031
      • University Hospital Basel, Department of Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; 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.	Drug: Glyceroltrinitrat; transdermal patch
No Intervention: Control; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tissue biopsies of supraclavicular BAT and skeletal muscle musculus vastus lateralis	Analysis of the transcriptional changes both in BAT and muscle which are caused by the administration of glyceroltrinitrate (Nitroderm® TTS) as compared with no intervention	After 14 days treatment with glyceroltrinitrate or after 14 days control period respectively

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Matthias J Betz, MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Actual): June 11, 2025
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: January 24, 2023
• First Submitted That Met QC Criteria: January 24, 2023
• First Posted (Actual): February 2, 2023

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: energy expenditure; cold exposure; glyceroltrinitrate
• Additional Relevant MeSH Terms: Vasodilator Agents; Nitroglycerin
• Other Study ID Numbers: NEXT Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No