Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate

NCT01950520 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 13020013-DK-0200
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Changes in how a person's body burns energy or calories can affect their weight over time. The lowest level of energy the body needs to function is called basal metabolic rate. In the cold, we burn extra energy, even before we start to shiver. This is called non-shivering thermogenesis and it occurs in different types of tissue such as muscle and fat. Researchers want to learn more about this type of energy burning and how it is regulated. They hope this will help treat obesity in the future. Objectives:

• Sub-study 1: to better understand how non-shivering thermogenesis works.
• Sub-study 2: to measure the effects of anti-obesity drugs on basal metabolic rate.
• Sub-study 3: to better understand the effects of mirabegron, a beta-3 adrenergic receptor agonist, on brown fat activity. Eligibility: \- Healthy, lean adult males ages 18 to 35. Design:
• Participants will be screened with medical history, physical exam, blood test, and EKG.
• For sub-studies 1 and 2:
• Participants will receive one X-ray scan.
• Each day, all participants will:
• Have height and weight measured, and have urine collected.
• Spend 4 hours in a temperature-controlled room with furniture, toilet area, phone, and computer. They will wear small non-invasive devices to monitor activity, heart rate, temperature, and shivering.
• Walk for 30 minutes.
• For sub-study 3:
• Participants will receive one DXA scan and up to 4 PET/CT scans and 4 MRIs
• Each stay, all participants will:
• Have height and weight measured, and have urine collected.
• Spend 6 hours in a temperature-controlled room with furniture, toilet area, phone, and computer. They will wear small non-invasive devices to monitor activity, heart rate, temperature, and shivering.
• Participants will be compensated for their time and participation at the end of the study

Conditions

Healthy Volunteers

Keywords

Adipose Tissue; Adult; Resting Energy Expenditure; RESPIRATORY QUOTIENT; BASAL METABOLIC RATE

Outcome Measures

Primary Outcomes (5)

• Resting Energy Expenditure at Low Temperature

  Resting energy expenditure (REE) at a temperature just above the subject's placebo shivering threshold.

  Cohort 1: Days 1-17

• Resting Energy Expenditure at Low Temperature

  Resting energy expenditure (REE) at a temperature just above the subject's placebo shivering threshold.

  Cohorts 2: Six one-day overnight inpatient stays over a six to twelve week period.

• Resting Energy Expenditure at Low Temperature

  Resting energy expenditure (REE) at a temperature just above the subject's placebo shivering threshold.

  Cohort 3: Four one-day overnight inpatient stays over a 12-week period.

• Basal Metabolic Rate

  Basal metabolic rate (BMR) is the resting energy expenditure (REE) at thermoneutrality (27c).

  Cohort 1: Days 1-17

• Brown Adipose Tissue Activity (Cohort 3 Only)

  Brown adipose tissue (BAT) activity is a quantification of tissue volume and metabolic activity per unit volume.

  Cohort 3: Four one-day overnight inpatient stays over a 12-week period.

Study Arms (3)

Cohort 1

EXPERIMENTAL

Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only) Within each block, the following five interventions will be repeated: Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only) Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only) Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only) Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only) Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)

Drug: Propranolol; Drug: Pindolol; Drug: Dantrolene; Drug: Magnesium Sulfate; Drug: Placebo Cohort 1

Cohort 2

EXPERIMENTAL

Interventions, in random order, will be administered during one of the six one-day stays Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only) Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only) Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only) Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only) Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only) Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)

Drug: Caffeine; Drug: Qsymia; Drug: Topiramate; Behavioral: Phentermine; Drug: Naltrexone; Drug: Placebo Cohort 2

Cohort 3

EXPERIMENTAL

Interventions, in random order, will be administered during one of the four overnight inpatient stays Mirabegron 50mg: Mirabegron 50mg, oral, by mouth (Cohort 3 only) Mirabegron 200mg: Mirabegron 200mg, oral, by mouth (Cohort 3 only) Placebo for Mirabegron: Placebo for Mirabegron, oral, by mouth (Cohort 3 only)

Drug: Mirabegron 50mg; Drug: Mirabegron 200mg; Drug: Placebo for Mirabegron

Interventions

Propranolol DRUG

Propanolol 160mg, oral, by mouth (Cohort 1 only)

Cohort 1

Pindolol DRUG

Pindolol 20mg, oral, by mouth (Cohort 1 only)

Cohort 1

Dantrolene DRUG

Dantrolene 100mg, oral, by mouth (Cohort 1 only)

Cohort 1

Magnesium Sulfate DRUG

Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)

Cohort 1

Caffeine DRUG

Caffeine 200mg, oral, by mouth (Cohort 2 only)

Cohort 2

Qsymia DRUG

Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)

Cohort 2

Topiramate DRUG

Topiramate 200mg, oral, by mouth (Cohort 2 only)

Cohort 2

Phentermine BEHAVIORAL

Phentermine 37.5mg, oral, by mouth (Cohort 2 only)

Cohort 2

Naltrexone DRUG

Naltrexone 100mg, oral, by mouth (Cohort 2 only)

Cohort 2

Mirabegron 50mg DRUG

Mirabegron 50mg, oral, by mouth (Cohort 3 only)

Cohort 3

Mirabegron 200mg DRUG

Mirabegron 200mg, oral, by mouth (Cohort 3 only)

Cohort 3

Placebo Cohort 1 DRUG

Placebo, oral, by mouth (Cohort 1 only)

Cohort 1

Placebo Cohort 2 DRUG

Placebo, oral, by mouth (Cohort 2 only)

Cohort 2

Placebo for Mirabegron DRUG

Placebo for Mirabegron, oral, by mouth (Cohort 3 only)

Cohort 3

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Generally healthy
• Males between the age 18-35 years
• Written informed consent.

You may not qualify if:

• BMI less than 18.5 or greater than 25.0 kg/M(2)
• History of cardiovascular disease such as congestive heart failure, heart block, clinically abnormal EKG as determined by investigators
• History of liver disease or ALT serum level greater than two times the laboratory upper limit of normal
• History of kidney diseases or renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min (MDRD equation)
• History of cancer or bariatric surgery
• History of diabetes mellitus or fasting serum glucose \> 126 mg/dL
• History of hypo- or hyper-thyroid or abnormal TSH, except minor deviations deemed to be of no clinical significance by the investigator.
• History of asthma, chronic obstructive pulmonary disease and glaucoma
• Psychological conditions, such as (but not limited to) claustrophobia, clinical depression, bipolar disorders, that would be incompatible with safe and successful participation in this study
• Weight change \>5 percent in the past 6 months or a trained athlete
• Blood pressure greater than 140/90 mmHg or current antihypertensive therapy
• Iron deficiency (Hemoglobin \<13.7 g/dL and Hematocrit \<40.1%)
• History of illicit drug, opioids, or alcohol abuse within the last 5 years; current use of drugs (by history) or alcohol (CAGE greater than or equal to 2) (95)
• Current use of medications/dietary supplements/alternative therapies known to alter energy metabolism
• Current medications that may have interactions with study drugs as determined by the investigators

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Cannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. 2011 Jan 15;214(Pt 2):242-53. doi: 10.1242/jeb.050989.

  PMID: 21177944 BACKGROUND

• van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R285-96. doi: 10.1152/ajpregu.00652.2010. Epub 2011 Apr 13.

  PMID: 21490370 BACKGROUND

• Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E444-52. doi: 10.1152/ajpendo.00691.2006. Epub 2007 May 1.

  PMID: 17473055 BACKGROUND

• Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, Johnson JW, O'Mara AE, Fletcher LA, Leitner BP, Duckworth CJ, Huang S, Cai H, Garraffo HM, Millo CM, Dieckmann W, Tolstikov V, Chen EY, Gao F, Narain NR, Kiebish MA, Walter PJ, Herscovitch P, Chen KY, Cypess AM. Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a beta3-Adrenergic Receptor Agonist. Diabetes. 2018 Oct;67(10):2113-2125. doi: 10.2337/db18-0462. Epub 2018 Jul 6.

  PMID: 29980535 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Propranolol; Pindolol; Dantrolene; Magnesium Sulfate; Caffeine; Qsymia; Topiramate; Phentermine; Naltrexone; mirabegron

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Hydantoins; Imidazolidines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Magnesium Compounds; Inorganic Chemicals; Sulfates; Sulfuric Acids; Sulfur Acids; Sulfur Compounds; Xanthines; Alkaloids; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Amphetamines; Phenethylamines; Ethylamines; Naloxone; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes

Results Point of Contact

• Title: Kong Chen, PhD, MSCI
• Organization: NIDDK

chenkong@niddk.nih.gov

301-451-1636

Study Officials

• Kong Y Chen, Ph.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2013
• First Posted: September 25, 2013
• Study Start: February 7, 2014
• Primary Completion: December 17, 2022
• Study Completion: June 11, 2024
• Last Updated: October 16, 2024
• Results First Posted: October 16, 2024

Record last verified: 2024-06-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: IPD will be available by request to the PI following publication of results
• Access Criteria: By request to PI with approved protocol to analyze IPD

Locations

US (1)