Activation of Brown Adipose Tissue Thermogenesis in Humans Using Formoterol Fumarate (GB10)

NCT05553184 | Completed

• 1 other identifier: GB10-2021-3873
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

One emerging, highly modifiable homeostatic mechanism for energy expenditure in humans is brown adipose tissue (BAT) thermogenesis. BAT is currently considered a prime target for the treatment of obesity and Type 2 diabetes (T2D). Using acetate and fluorodeoxyglucose (FDG) positron emission tomography (PET) , It has been demonstrated that BAT thermogenesis is inducible by chronic cold exposure. BAT activation through cold exposure is associated with improved glucose homeostasis and insulin sensitivity. A pharmaceutical approach, which seemed to be very promising to stimulate the activation of BAT, was the use of a selective beta 3-adrenergic receptor agonist, mirabegron. Nevertheless, in a later study, It has been demonstrated that human BAT thermogenesis is under the control of beta-2, not beta-3, adrenergic receptor. The most selective beta-2 adrenergic receptor agonist approved for clinical use in Canada is formoterol fumarate, given in inhalation for the treatment of asthma (Oxeze®). In summary, BAT contributes to cold-induced thermogenesis and is recruited by chronic cold exposure as well as by a growing number of food supplements and drugs. Intracellular triglyceride (TG) is the primary source of fuel for BAT thermogenesis under normal physiological conditions, as blocking intracellular TG lipolysis using nicotinic acid abolishes BAT thermogenesis. Beta-2 adrenergic stimulation is the pharmacological target to activate BAT thermogenesis in humans and may also lead to white adipose tissue lipolysis. Using a highly-selective beta-2 receptor agonist with and without administration of nicotinic acid would thus give the opportunity to quantify more precisely energy expenditure accounted by BAT thermogenesis and white adipose tissue metabolism in humans.

Conditions

Type 2 Diabetes; Obesity

Keywords

Brown adipose tissue; formoterol fumarate; Thermogenesis

Outcome Measures

Primary Outcomes (1)

• Change in Brown Adipose Tissue thermogenesis (formoterol induced, cold-induced and effect of nicotinic acid)

  determined using \[11C\]-acetate PET

  measured 60 minutes before and 90 minutes after cold exposure (A) and 30 minutes after inhalation of Fumarate Formoterol (B and C)

Secondary Outcomes (10)

• Brown Adipose Tissue (BAT) glucose uptake

  measured 150 minutes after the start of acute cold exposure (A), and 90 minutes after inhalation of Fumarate Formoterol (B and C)

• Brown Adipose Tissue nonesterified fatty acid (NEFA) metabolism (uptake, oxidation, esterification and release rates)

  measured 120 minutes after the start of acute cold exposure (A), and 60 minutes after inhalation of Fumarate Formoterol (B and C)

• Change in systemic plasma NEFA turnover.

  measured at baseline and every 60 minutes after the start of acute cold exposure (A) and every 60 minutes after inhalation of fumarate formoterol (B and C), for 4 hours

• Change in systemic plasma glycerol turnover.

  measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 4 hours.

• Change in systemic plasma glucose turnover.

  measured at baseline and every hour after the start of acute cold exposure (A) and every hour after inhalation of fumarate formoterol (B and C), for 5.50 hours

Study Arms (3)

Acute Cold Exposure

ACTIVE COMPARATOR

3h-acute cold exposure.

Other: Acute Cold Exposure; Diagnostic Test: Positron Emission Tomography (PET); Diagnostic Test: Indirect calorimetry; Diagnostic Test: dual-energy x-ray absorptiometry (DEXA scan); Procedure: Biopsy; Procedure: iv lines; Procedure: Electromyogram (EMG)

Formoterol with nicotinic acid

EXPERIMENTAL

Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg). Nicotinic acid or Niacin: repeated doses of 150 MG every 30 minutes, for 3 hours.

Drug: Formoterol Fumarate 12 micrograms Inhalation Powder; Drug: Nicotinic Acid 50 MG Oral Tablet; Diagnostic Test: Positron Emission Tomography (PET); Diagnostic Test: Indirect calorimetry; Procedure: Biopsy; Procedure: iv lines

Formoterol without nicotinic acid

EXPERIMENTAL

Formoterol fumarate or Oxeze® Turbuhaler®: 48 µg (4 inhalations of 12 µg).

Drug: Formoterol Fumarate 12 micrograms Inhalation Powder; Diagnostic Test: Positron Emission Tomography (PET); Diagnostic Test: Indirect calorimetry; Procedure: Biopsy; Procedure: iv lines

Interventions

Formoterol Fumarate 12 micrograms Inhalation Powder DRUG

At time 60 minutes, a total of 48 micrograms will be inhaled within 3 minutes: 4 inhalations of 12 micrograms of fumarate formoterol (Oxeze® Turbuhaler®).

Also known as: Oxeze Turbuhaler

Formoterol with nicotinic acid; Formoterol without nicotinic acid

Nicotinic Acid 50 MG Oral Tablet DRUG

a total dose of 1050 MG will be ingested. From time 0 to 180 minutes, doses of 150 MG will be repeated every 30 minutes.

Also known as: Niacin 50 MG

Formoterol with nicotinic acid

Acute Cold Exposure OTHER

Participants will be fitted with a liquid-conditioned tube suit. The liquid-conditioned tube suit will be perfused with 18°C water using a temperature- and flow-controlled circulation bath from time 0 to 180 min.

Acute Cold Exposure

Positron Emission Tomography (PET) DIAGNOSTIC_TEST

PET imaging using C11-palmitate (time 90), C11-acetate (time 120) and F18-Fluorodeoxyglucose (FDG) (time 150)

Acute Cold Exposure; Formoterol with nicotinic acid; Formoterol without nicotinic acid

Indirect calorimetry DIAGNOSTIC_TEST

will be repeated every hour, for 20 minutes, using Vmax29n.

Acute Cold Exposure; Formoterol with nicotinic acid; Formoterol without nicotinic acid

dual-energy x-ray absorptiometry (DEXA scan) DIAGNOSTIC_TEST

Whole body scan

Acute Cold Exposure

Biopsy PROCEDURE

After local anesthesia with 2% xylocaine without epinephrine, 100-200 mg of subcutaneous adipose tissue will be sampled by needle (14G) biopsy

Acute Cold Exposure; Formoterol with nicotinic acid; Formoterol without nicotinic acid

iv lines PROCEDURE

for stable tracer perfusion and blood sampling

Acute Cold Exposure; Formoterol with nicotinic acid; Formoterol without nicotinic acid

Electromyogram (EMG) PROCEDURE

Surface electrodes will be used to measure skeletal muscle activity and shivering intensity

Acute Cold Exposure

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI of 18 to 30 kg/m2.

You may not qualify if:

• Change in weight of more than 2 kg over the past 3 months or recent changes in lifestyle;
• The presence of any chronic medical condition requiring any pharmacological treatment;
• Previous intolerance or allergy to lactose, formoterol, nicotinic acid or local anesthetic agent;
• Any previous cardiac arrhythmia, long QT syndrome or hypokalemia;
• Chronic treatment with any medication other than contraceptives;
• Acute use of any drug other that acetaminophen or non-steroidal anti-inflammatory without decongestant or other stimulants;
• Smoking or consumption of more than 2 alcoholic beverages per day;
• Having participated to a research study with exposure to radiation in the last two years before the start of the study.

Sponsors & Collaborators

• Université de Sherbrooke: lead

Study Sites (1)

Centre de recherche du CHUS

Sherbrooke, Quebec, J1H 5N4, Canada

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Interventions

Niacin; Tablets; Positron-Emission Tomography; Absorptiometry, Photon; Biopsy

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Dosage Forms; Pharmaceutical Preparations; Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Image Enhancement; Photography; Radionuclide Imaging; Tomography; Diagnostic Techniques, Radioisotope; Radiography; Densitometry; Photometry; Chemistry Techniques, Analytical; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• André C. Carpentier, M.D.

  Université de Sherbrooke

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Tenure professor

Model Details: The protocol will be carried out as a within-subject, randomized, cross-over study in which each subject will serve as his/her own control

Study Record Dates

• First Submitted: August 25, 2022
• First Posted: September 23, 2022
• Study Start: July 5, 2022
• Primary Completion: May 29, 2023
• Study Completion: May 29, 2023
• Last Updated: November 28, 2023

Record last verified: 2023-11

Locations

CA (1)