Healthy VolunteersPhase 2NCT01950520
Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate
A Phase 2 study testing Propranolol, Pindolol and Dantrolene in people with Healthy Volunteers, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers
- What is being tested?
- Propranolol, Pindolol and Dantrolene
- Type of treatment
- Pill or oral medicine, Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 47 participants
- Where
- 1 siteUnited States
- Study dates
- 7 Feb 2014to 11 Jun 2024
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Generally healthy
- Males between the age 18-35 years
- Written informed consent.
Who cannot join
- 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
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- 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 treatment of overactive bladder.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: The Mechanism of Human Non-Shivering Thermogenesis and Basal Metabolic Rate
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.
Read more
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
Read the 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 (BAT) 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), 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.
The second phase of the study focuses on measuring of FDA-approved drugs (such as anti-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.
- Conditions
- Healthy Volunteers
- Being tested
- Propranolol, Pindolol, Dantrolene, Magnesium Sulfate, Caffeine
- Keywords
- Adipose Tissue, Adult, Resting Energy Expenditure, RESPIRATORY QUOTIENT, BASAL METABOLIC RATE
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PropranololDrug
Propanolol 160mg, oral, by mouth (Cohort 1 only)
PindololDrug
Pindolol 20mg, oral, by mouth (Cohort 1 only)
DantroleneDrug
Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium SulfateDrug
Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
CaffeineDrug
Caffeine 200mg, oral, by mouth (Cohort 2 only)
QsymiaDrug
Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
TopiramateDrug
Topiramate 200mg, oral, by mouth (Cohort 2 only)
PhentermineBehavioural
Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
NaltrexoneDrug
Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Mirabegron 50mgDrug
Mirabegron 50mg, oral, by mouth (Cohort 3 only)
Mirabegron 200mgDrug
Mirabegron 200mg, oral, by mouth (Cohort 3 only)
Placebo Cohort 1Drug
Placebo, oral, by mouth (Cohort 1 only)
Placebo Cohort 2Drug
Placebo, oral, by mouth (Cohort 2 only)
Placebo for MirabegronDrug
Placebo for Mirabegron, oral, by mouth (Cohort 3 only)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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) Receives: 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) Receives: Drug: Mirabegron 50mg; Drug: Mirabegron 200mg; Drug: Placebo for Mirabegron |
What is being measured
The primary outcome is the main question the study is designed to answer.
Resting Energy Expenditure at Low Temperature
Resting energy expenditure (REE) at a temperature just above the subject's placebo shivering threshold.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: Cohort 3: Four one-day overnight inpatient stays over a 12-week period.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Sep 2013 (estimated)
- Study start7 Feb 2014
- Primary completion17 Dec 2022
- Study completion11 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Kong Y Chen, Ph.D., Principal investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01950520
- Sponsor's protocol ID
- 130200
- Other IDs
- 13-DK-0200
- Status last verified
- 11 Jun 2024
- First submitted
- 21 Sep 2013
- Last updated
- 16 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: .All IPD that underlie results in a publication
Publications
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.
PubMed 21177944van 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.
PubMed 21490370Nedergaard 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.
PubMed 17473055Baskin 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.
PubMed 29980535