Effect on Energy Metabolism at Cellular Level of Diet Plus Treatment With Ephedrine and Caffeine in Obesity

NCT02048215 | Completed Phase 3

• 1 other identifier: THERMODIET
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

Brief Summary This trial was part of a sub-project targeted to diet, thermogenesis and obesity of a larger multicentre study named "Interaction between nutritional, social-behavioral and metabolic factors for prevention of cardiovascular disease: development of nutritional strategies on general population". Ephedrine and caffeine (EC) combination has been widely used in human obesity treatment. It is known that this drug increases the metabolic rate in both animals and humans. Ephedrine is an agonist of both α and β-adrenoceptors; moreover, it induces norepinephrine release from sympathetic neurons. Caffeine increases both norepinephrine and dopamine release and stimulates the neuronal activity in several brain regions. We hypothesize that EC treatment might exert a specific effect on lipolysis and thermogenesis by stimulation of beta-3 adrenoreceptors on adipose tissue and by stimulating uncoupling of oxidative phosphorylation, i.e. energy being dissipated as heat rather than being converted to adenosine triphosphate (ATP) Our study is a double-blind, placebo-controlled, 4-week trial to investigate the effect of hypocaloric diet alone or coupled to EC treatment of morbidly obese women on thermogenesis, expression of UCP 3 (in muscle tissue) and of beta-3 adrenoreceptors (in adipose tissue). Subjects are randomly assigned to EC (200/20 mg) or to placebo administered three times a day orally together with a energy-deficit diet (70% of resting energy expenditure), starting one month before undergoing bariatric surgery. Primary study endpoints are weight change analysed by intention to treat, changes in resting energy expenditure, UCP3 (long and short isoform), messenger ribonucleic acid (mRNA) levels in rectus abdominis and immunostaining for beta-3 adrenoreceptors in subcutaneous and omental adipose tissue. Also plasma epinephrine, norepinephrine, triglycerides, free fatty acids, glycerol, TSH, free thyroxine (fT4), free triiodothyronine (fT3) fasting glucose, insulin and homeostasis model assessment (HOMA) index, are measured at baseline and at the end of treatments.

Conditions

Obesity

Keywords

thermogenesis; low-calorie diet; uncoupling-protein 3; beta-3 adrenoceptors; thermogenic drugs

Outcome Measures

Primary Outcomes (1)

• Change in resting energy expenditure

  Resting energy expenditure is measured by indirect calorimetry

  Baseline and 1 month

Secondary Outcomes (12)

• Blood pressure monitoring

  Baseline and daily for 30 days (t.i.d.)

• Electrocardiograpic monitoring

  Baseline and at week 2,3,4

• Cardiac ultrasound monitoring

  Baseline and at week 2,3,4

• Changes in fasting glucose

  Baseline and at one month

• Changes in fasting insulin

  baseline and one month

Study Arms (2)

Ephedrine + Caffeine + diet

ACTIVE COMPARATOR

Ephedrine 20 mg + Caffeine 200 mg capsule t.i.d. for one month plus hypocaloric diet

Drug: Caffeine; Drug: Ephedrine; Other: Hypocaloric diet

Placebo + diet

PLACEBO COMPARATOR

Similarly-looking placebo capsule t.i.d. for one month plus hypocaloric diet

Drug: Placebo; Other: Hypocaloric diet

Interventions

Caffeine DRUG

Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, Italy). During the treatment period all patients are fed a hypocaloric diet (total energy content of \~70% of energy expenditure, as measured by indirect calorimetry), and containing 20% proteins, 55% carbohydrates, 25% fat half of which was monounsaturated, and 35 g/day fibres.

Also known as: Randomization number 2, 4, 5, 6, 8, 11

Ephedrine + Caffeine + diet

Placebo DRUG

Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, Italy). During the treatment period all patients are fed a hypocaloric diet (total energy content of \~70% of energy expenditure, as measured by indirect calorimetry), and containing 20% proteins, 55% carbohydrates, 25% fat half of which was monounsaturated, and 35 g/day fibres.

Also known as: Randomization number 1, 3, 7, 9, 10, 12, 13

Placebo + diet

Ephedrine DRUG

Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, Italy). During the treatment period all patients are fed a hypocaloric diet (total energy content of \~70% of energy expenditure, as measured by indirect calorimetry), and containing 20% proteins, 55% carbohydrates, 25% fat half of which was monounsaturated, and 35 g/day fibres.

Also known as: Randomization number 2, 4, 5, 6, 8, 11

Ephedrine + Caffeine + diet

Hypocaloric diet OTHER

Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, Italy). During the treatment period all patients are fed a hypocaloric diet (total energy content of \~70% of energy expenditure, as measured by indirect calorimetry), and containing 20% proteins, 55% carbohydrates, 25% fat half of which was monounsaturated, and 35 g/day fibres.

Also known as: Low-calorie diet 70% of measured energy expenditure

Ephedrine + Caffeine + diet; Placebo + diet

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• pre-menopausal females
• body mass index ≥ 40 kg/m2
• with stable weight in the three month before the study
• scheduled for bariatric surgery
• in whom weight loss was clinically advisable before surgery to reduce surgical risk
• non-smokers or smoking less than 5 cigarettes per day

You may not qualify if:

• pregnancy
• ischaemic heart disease
• cardiac failure
• high blood pressure requiring drug treatment
• tachyarrhythmia
• sick sinus syndrome
• atrioventricular block
• two-bundle ventricular block
• cerebrovascular diseases
• occlusive peripheral artery disease
• renal failure
• current treatment with drugs that might affect metabolic rate (e.g. β-adrenergic blockers, thyroid hormones).

Sponsors & Collaborators

• Istituto Auxologico Italiano: lead
• University of Milan: collaborator
• Università Politecnica delle Marche: collaborator

Study Sites (1)

Istituto Auxologico Italiano -Ospedale San Giuseppe

Verbania, VB, 28824, Italy

Location

Related Publications (16)

• Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: human studies. Int J Obes. 1986;10(6):467-81.

  PMID: 3804564 BACKGROUND

• Astrup A, Breum L, Toubro S. Pharmacological and clinical studies of ephedrine and other thermogenic agonists. Obes Res. 1995 Nov;3 Suppl 4:537S-540S. doi: 10.1002/j.1550-8528.1995.tb00224.x.

  PMID: 8697055 BACKGROUND

• Miller DS, Stock MJ, Stuart JA. Proceedings: The effects of caffeine and carnitine on the oxygen consumption of fed and fasted subjects. Proc Nutr Soc. 1974 Sep;33(2):28A-29A. No abstract available.

  PMID: 4456386 BACKGROUND

• Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jequier E. Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals. Am J Clin Nutr. 1980 May;33(5):989-97. doi: 10.1093/ajcn/33.5.989.

  PMID: 7369170 BACKGROUND

• Astrup A, Toubro S, Christensen NJ, Quaade F. Pharmacology of thermogenic drugs. Am J Clin Nutr. 1992 Jan;55(1 Suppl):246S-248S. doi: 10.1093/ajcn/55.1.246s.

  PMID: 1345887 BACKGROUND

• Bellet S, Roman L, DeCastro O, Kim KE, Kershbaum A. Effect of coffee ingestion on catecholamine release. Metabolism. 1969 Apr;18(4):288-91. doi: 10.1016/0026-0495(69)90049-3. No abstract available.

  PMID: 5777013 BACKGROUND

• Berkowitz BA, Spector S. Effect of caffeine and theophylline on peripheral catecholamines. Eur J Pharmacol. 1971 Jan;13(2):193-6. doi: 10.1016/0014-2999(71)90150-6. No abstract available.

  PMID: 5544072 BACKGROUND

• Klaus S, Casteilla L, Bouillaud F, Ricquier D. The uncoupling protein UCP: a membraneous mitochondrial ion carrier exclusively expressed in brown adipose tissue. Int J Biochem. 1991;23(9):791-801. doi: 10.1016/0020-711x(91)90062-r. No abstract available.

  PMID: 1773883 BACKGROUND

• Garruti G, Ricquier D. Analysis of uncoupling protein and its mRNA in adipose tissue deposits of adult humans. Int J Obes Relat Metab Disord. 1992 May;16(5):383-90.

  PMID: 1319974 BACKGROUND

• Lean ME, James WP, Jennings G, Trayhurn P. Brown adipose tissue in patients with phaeochromocytoma. Int J Obes. 1986;10(3):219-27.

  PMID: 3019909 BACKGROUND

• Oberkofler H, Dallinger G, Liu YM, Hell E, Krempler F, Patsch W. Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans. J Lipid Res. 1997 Oct;38(10):2125-33.

  PMID: 9374134 BACKGROUND

• Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB. Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem. 1997 Jul 11;272(28):17686-93. doi: 10.1074/jbc.272.28.17686.

  PMID: 9211919 BACKGROUND

• Solanes G, Vidal-Puig A, Grujic D, Flier JS, Lowell BB. The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J Biol Chem. 1997 Oct 10;272(41):25433-6. doi: 10.1074/jbc.272.41.25433.

  PMID: 9325252 BACKGROUND

• Millet L, Vidal H, Andreelli F, Larrouy D, Riou JP, Ricquier D, Laville M, Langin D. Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest. 1997 Dec 1;100(11):2665-70. doi: 10.1172/JCI119811.

  PMID: 9389729 BACKGROUND

• De Matteis R, Arch JR, Petroni ML, Ferrari D, Cinti S, Stock MJ. Immunohistochemical identification of the beta(3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int J Obes Relat Metab Disord. 2002 Nov;26(11):1442-50. doi: 10.1038/sj.ijo.0802148.

  PMID: 12439645 RESULT

• Bracale R, Petroni ML, Davinelli S, Bracale U, Scapagnini G, Carruba MO, Nisoli E. Muscle uncoupling protein 3 expression is unchanged by chronic ephedrine/caffeine treatment: results of a double blind, randomised clinical trial in morbidly obese females. PLoS One. 2014 Jun 6;9(6):e98244. doi: 10.1371/journal.pone.0098244. eCollection 2014.

  PMID: 24905629 DERIVED

MeSH Terms

Conditions

Obesity

Interventions

Caffeine; Ephedrine; Caloric Restriction

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Phenethylamines; Ethylamines; Diet Therapy; Nutrition Therapy; Therapeutics; Energy Intake; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Study Officials

• Maria L Petroni, MD

  Istituto Auxologico Italiano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2014
• First Posted: January 29, 2014
• Study Start: February 1, 2000
• Primary Completion: January 1, 2001
• Study Completion: November 1, 2007
• Last Updated: January 29, 2014

Record last verified: 2014-01

Locations

IT (1)