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Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate

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ClinicalTrials.gov Identifier: NCT01950520
Recruitment Status : Recruiting
First Posted : September 25, 2013
Last Update Posted : November 23, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

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:

<TAB>- 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.

<TAB>- 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:

<TAB>- 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

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Propranolol 160 mg Drug: Pindolol 20 mg Drug: Dantrolene 100 mg Drug: Magnesium Sulfate Drug: Caffeine 200 mg Drug: Qsymia (topiramate 92 mg CR,phentermine 15 mgPO) Drug: Topiramate 200 mg Drug: Phentermine 37.5 mg Behavioral: Naltrexone 100 mg Drug: Mirabegron 50 mg Drug: Mirabgron 200 mg Other: Placebo Phase 4

Detailed Description:

The balance between energy expenditure (EE) and energy intake ultimately determines body weight. Resting EE is the major component (60-75%) of total EE in an adult human being. Resting EE dynamically adapts to environmental changes such as ambient temperature. In our on-going study of environmental temperature changes within and around the thermoneutral zone, we observed that healthy young men can increase EE by 17 % of the basal metabolic rate through the process of non-shivering thermogenesis (NST). This capacity for NST is unexpectedly large as compared to prior reports of mild cold-induced thermogenesis (3 to 11%) and suggests that increasing NST could be explored as an intervention to combat obesity.

The aim of this study is to better understand the physiology of NST and to develop improved assays for evaluating the effect of drugs that alter EE. For example, only recently has it been realized that brown adipose tissue is functional in adult humans and that white adipose tissue can be converted to brown-adipose-like tissue to increase heat production during cold exposures. Moreover, skeletal muscle likely also plays a role in cold-induced thermogenesis even before overt shivering occurs. It is plausible that the mechanisms governing heat production for NST contribute to regulation of body weight and thus may be contributing to the current obesity epidemic: even small changes in EE, if not compensated by changes in food intake, can have long-term effects on body weight.

This protocol has two phases. The first uses a pharmacologic approach to investigate the mechanism of NST in young healthy lean males. Since the principal physiologic stimulus to BAT (and possibly muscle for NST) is via the sympathetic nervous system (SNS), b-adrenergic receptors may hold key roles in regulating human EE. We hypothesize that, by careful measurements of NST (at an individually-titrated cool environmental temperature, between 18-21 C vs. at thermoneutrality of 27 C) and using b-adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST.

The second phase of the study focuses on measuring of FDA-approved drugs (such as aitu-obesity drugs) potential effect on basal metabolic rate (BMR) under thermoneutral conditions. The rationale is that previous studies of drug effect on EE in humans have not always rigorously enforced the use of thermoneutral conditions, thus may have increased variability and underestimated the effect, contributing to inconclusive findings.

It is envisioned that this study will further our knowledge of the mechanisms that regulate the acute adaptive changes in resting energy expenditure and the effects of drug therapy targeting obesity in humans.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 134 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
Official Title: The Mechanism of Human Non-Shivering Thermogenesis and Basal Metabolic Rate
Actual Study Start Date : February 15, 2014
Estimated Primary Completion Date : October 19, 2029
Estimated Study Completion Date : October 19, 2029

Arm Intervention/treatment
Placebo Comparator: Cohort 1, The Mechanism of Human Nonshivering Thermogenesis
Cohort 1 is a singleblind, fixed order (for drug treatment), partially randomized (for temperature), crossover study. Cohort 1 uses a pharmacologicapproach to investigate the mechanism of NST in young healthy lean males.
Drug: Propranolol 160 mg
Cohort 1

Drug: Pindolol 20 mg
Cohort 1

Drug: Dantrolene 100 mg
Cohort 1

Drug: Magnesium Sulfate
Cohort 1

Other: Placebo
Placebo

Placebo Comparator: Cohort 2, Pharmacologic Perturbations of Resting Energy Expend
Cohort 2 is a randomized, doubleblind, placebocontrolled, 6-period cross-over study, with data analysisperformed in a blinded manner. Focus is on measuring of FDAapproved drugs (such as anti-obesitydrugs) potential effect on basal metabolic rate(BMR) under thermoneutral conditions.
Drug: Caffeine 200 mg
Cohort 2

Drug: Qsymia (topiramate 92 mg CR,phentermine 15 mgPO)
Cohort 2

Drug: Topiramate 200 mg
Cohort 2

Drug: Phentermine 37.5 mg
Cohort 2

Behavioral: Naltrexone 100 mg
Cohort 2

Other: Placebo
Placebo

Placebo Comparator: Cohort 3, (SqrRoot) 3- Adrenergic Receptor Agonist (mirabegron) Studies
Cohort 3 is a randomized, singleblind, placebocontrolled study, with the quantifier of BAT activity blinded to the four different interventions.Volunteers will undergo up to four experiments tostudy the effects of mirabegron on BMR and BAT activity.
Drug: Mirabegron 50 mg
Cohort 3, IND # 116246

Drug: Mirabgron 200 mg
Cohort 3, IND # 116246




Primary Outcome Measures :
  1. Cohort 1 interventions Cohort 1 interventions (propranolol 160 mg, pindolol 20 mg, dantrolene 100 mg, and magnesium sulfate (50mg/kg bolus followed by maintenance infusion at 2 g /h), resting energy expenditure, shivering threshold temps, the... [ Time Frame: 12 months ]
    Effect of interventions on resting energy expenditure at temperature just above placebo shivering threshold.

  2. Cohort 2 interventions (caffeine (300 mg PO), Qsymia (topiramate 92 mg CR, phentermine 15 mg PO), phentermine (37.5 mg PO),topiramate (200 mg PO), naltrexone (100 mg PO), resting energy expenditure, BMR (basal metabolic rate), thermoneutralit... [ Time Frame: Six one-day overnight inpatient stays over a six to twelve week period. ]
    Evaluate effect of interventions on BMR (=REE27 (Infinite)C).

  3. Cohort 3 interventions: mirabegron at 0mg, 50mg, and 200mg, resting energy expenditure, BMR (basal metabolic rate), BATMetabolic activity measured by 18FDG PET/CT, thermoneutrality, coolenvironmental temperature [ Time Frame: 4 study visits: one-day overnight inpatient stays, completed within a 12-week time window ]
    Effects of interventions on BAT metabolic activity and BMR.


Secondary Outcome Measures :
  1. Shivering thresholds [ Time Frame: 12 months ]
    We hypothesize that, by careful measurements of NST (at an individually-titrated cool environmental temperature, between 18-21 C vs. at thermoneutrality of 27 C) and using b-adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST.

  2. To compare the effects of mirabegron at 0mg, 50mg, and 200mg on BAT metabolic activity. [ Time Frame: 12 months ]
    Since the principal physiologic stimulus to BAT (and possibly muscle for NST) is via the sympathetic nervous system (SNS), beta adrenergic receptors may hold key roles in regulating human EE. We hypothesize that, by careful measurements of NST (at an individually-titrated cool environmental temperature, between 18-21 degrees C vs. at thermoneutrality of 27 degrees C) and using beta- adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST as well as further evaluation of the pharmacological activation of human BAT.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:
  • Generally healthy
  • Males between the age 18-35 years
  • Written informed consent.

EXCLUSION CRITERIA:

  • 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
  • History of adverse or allergic reactions to the study drugs
  • Daily caffeine intake >500 mg (about 4 cups) and have withdrawal symptoms
  • Current smoker or user of tobacco products
  • Cannot commit to the schedule of visits to the Clinical Research Center (CRC) as required by the study timeline
  • Have had previous radiation exposure within the last year (X-rays, PET scans, etc.) that would exceed research limits (please let us know if you have received radiation for research purposes)
  • Have inflexible dietary restrictions
  • Any other reason that the investigator thinks would make interpretation of the study results difficult.
  • For subjects having an MRD (cOHORT 3), history of pacemaker, metallic heart valves, aneurysm clip, pedicle screws, metallic foreign body in eye, or other metallic implant.
  • For subjects receiving mirabegron (Cohort 3), a diagnosis of bladder outlet obstruction or the use of antimuscarinic medications for the treatement of overactive bladder.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01950520


Contacts
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Contact: Margaret S McGehee, C.R.N.P. (301) 594-6799 mcgeheems@mail.nih.gov
Contact: Kong Y Chen, Ph.D. (301) 451-1636 chenkong@niddk.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Layout table for investigator information
Principal Investigator: Kong Y Chen, Ph.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01950520    
Other Study ID Numbers: 130200
13-DK-0200
First Posted: September 25, 2013    Key Record Dates
Last Update Posted: November 23, 2020
Last Verified: November 18, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Adipose Tissue
Adult
Resting Energy Expenditure
RESPIRATORY QUOTIENT
BASAL METABOLIC RATE
Additional relevant MeSH terms:
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Topiramate
Phentermine
Propranolol
Magnesium Sulfate
Pindolol
Naltrexone
Caffeine
Dantrolene
Mirabegron
Alcohol Deterrents
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents
Anticonvulsants
Hypoglycemic Agents