A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: A high-dose study

International Journal of Obesity

Volumn 34, Issue 5, 2010, Pages 919-935

  Aronne, L J ^a   Tonstad, S ^b   Moreno, M ^c   Gantz, I ^d   Erondu, N ^d   Suryawanshi, S ^d   Molony, C ^d   Sieberts, S ^d   Nayee, J ^d   Meehan, A G ^d   Shapiro, D ^d   Heymsfield, S B ^d   Kaufman, K D ^d   Amatruda, J M ^d  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b ULLEVÅL UNIVERSITY HOSPITAL   (Norway)

^c PONTIFICIA UNIVERSIDAD CATÓLICA DE CHILE   (Chile)

^d MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Cannabinoid 1 receptor; Endocannabinoid; Randomized clinical trial

Indexed keywords

PLACEBO; TARANABANT; AMIDE; ANTIOBESITY AGENT; CANNABINOID 1 RECEPTOR; N-(3-(4-CHLOROPHENYL)-2-(3-CYANOPHENYL)-1-METHYLPROPYL)-2-METHYL-2-((5-(TRIFLUOROMETHYL)PYRIDIN-2-YL)OXY)PROPANAMIDE; PYRIDINE DERIVATIVE;

ADULT; AGED; AGGRESSION; ANXIETY; ANXIETY DISORDER; ARTHRALGIA; ARTICLE; BACKACHE; BODY MASS; BODY WEIGHT; BREAST DISEASE; CLINICAL TRIAL; CONFUSION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DEPRESSION; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EPILEPSY; EYE DISEASE; FATIGUE; FEMALE; GLYCEMIC CONTROL; HEADACHE; HICCUP; HOT FLUSH; HUMAN; HYPERHIDROSIS; HYPERTENSION; HYPESTHESIA; INCIDENCE; INFLUENZA; INJURY; INSOMNIA; INTESTINAL DYSMOTILITY; INTOXICATION; IRRITABILITY; LIPID ANALYSIS; MAJOR CLINICAL STUDY; MALE; MEASUREMENT; MEDIASTINUM DISEASE; METABOLIC DISORDER; METABOLIC SYNDROME X; MOOD DISORDER; MOTOR DYSFUNCTION; NAUSEA; NERVOUSNESS; NUTRITIONAL DISORDER; OBESITY; PAIN; PANIC; PRIORITY JOURNAL; PROCEDURAL SITE REACTION; PRURITUS; RESPIRATORY TRACT DISEASE; RHINOPHARYNGITIS; RISK ASSESSMENT; RISK BENEFIT ANALYSIS; SENSORY DYSFUNCTION; SIDE EFFECT; SINGLE BLIND PROCEDURE; SINUSITIS; STROKE; SUICIDAL IDEATION; SYNCOPE; THORAX DISEASE; TREATMENT DURATION; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT DISEASE; VERTIGO; VOMITING; WAIST CIRCUMFERENCE; AGONISTS; DRUG EFFECTS; LOW CALORY DIET; MIDDLE AGED; MULTICENTER STUDY; PATHOPHYSIOLOGY; PHYSIOLOGY; RANDOMIZED CONTROLLED TRIAL; TREATMENT OUTCOME; VERY ELDERLY; YOUNG ADULT;

ADULT; AGED; AGED, 80 AND OVER; AMIDES; ANTI-OBESITY AGENTS; BODY MASS INDEX; BODY WEIGHT; DIET, REDUCING; DOUBLE-BLIND METHOD; FEMALE; HUMANS; MALE; METABOLIC SYNDROME X; MIDDLE AGED; OBESITY; PYRIDINES; RECEPTOR, CANNABINOID, CB1; RISK ASSESSMENT; TREATMENT OUTCOME; YOUNG ADULT;

EID: 77952290161     PISSN: 03070565     EISSN: 14765497     Source Type: Journal    
DOI: 10.1038/ijo.2010.21     Document Type: Article

References (54)

1. Bray GA. Medical management of obesity. In: Bray GA, Bouchard C (eds). Handbook of Obesity: Clinical Applications 3rd edn. Informa Healthcare: New York, NY, 2008. pp. 227-484.
2. NICE. Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. pp. 1-84. 2006. NICE clinical guidelines 43, NHS: London, available at http://www.nice.org.uk/ Guidance/CG43.
3. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142: 532-546.
4. Osei-Hyiaman D, Harvey-White J, Batkai S, Kunos G. The role of the endocannabinoid system in the control of energy homeostasis. IntJ Obes (Lond) 2006; 30 (Suppl 1): S33-S38.
5. Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 2005; 81: 263-284.
6. Cota D, Marsicano G, Tschop M, Grübler Y, Flachskamm C, Schubert M et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003; 112: 423-431.
7. Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F et al. The cannabinoid CB1 receptor antagonist SR141716 increases acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003; 63: 908-914.
8. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-1305.
9. Matias I, Gonthier M, Orlando P, Martiadis V, De Petrocellis L, Cervino C et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and 6-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 2006; 91: 3171-3180.
10. Lin LS, Ha S, Ball RG, Tsou NN, Castonguay LA, Doss GA et al. Conformational analysis and receptor docking of N-[(1S,2S)-3-(4-chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2-\{[5-(trifluoromethyl)pyridin-2-yl] oxy\}propanamide (taranabant, MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist. JMed Chem 2008; 51: 2108-2114.
11. Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 2008; 7: 68-78.
12. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16: 606-613.
13. Addy C, Cote J, Li S, Agrawal N, Majumdar A, Li H et al. Taranabant plasma concentrations increased when co-administered with ketoconazole or diltiazem. Obes Program Abstract Suppl 2007; 15: A147.
14. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85: 2402-2410.
15. Keller SD, Bayliss MS, Ware Jr JE, Hsu MA, Damiano AM, Goss TF. Comparison of responses to SF-36 Health Survey questions with one-week and four-week recall periods. Health Serv Res 1997; 32: 367-384.
16. Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief measure to assess quality of life in obesity. Obes Res 2001; 9: 102-111.
17. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol group. Ann Med Med 2001; 33: 337-343.
18. Wechsler D. WAIS-III Technical Manual. The Psychological Corporation, Harcourt Brace & Co: San Antonio, 1997.
19. McNair DM, Lorr M, Droppleman LF. Manual for the Profile of Mood States (POMS). Educational and Industrial Testing Service: San Diego, CA, 1971.
20. Spitzer RL, Kroenke K, Williams JBW. Validation and utility of a self-report of PRIME-MDFthe PHQ primary care study. JAMA 1999; 282: 1737-1744.
21. Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Memorandum. November 2006: Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). Appendix 2: Request to SponsorsFAdvice for the pharmaceutical industry in exploring their placebo-controlled clinical trials databases for suicidality and preparing data sets for analysis by FDA http://www.fda.gov/ ohrms/dockets/ac/06/brief-ing/2006-4272b1-01-FDA.pdf pp. 128-137.
22. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 2007; 164: 1035-1043.
23. Van Gaal LF, Scheen AJ, Rissanen AM, Rossner S, Hanotin C, Ziegler O. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur Heart J 2008; 29: 1761-1771.
24. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389-1397. (Pubitemid 40523733)
25. Després JP, Golay A, Sjöström L. Rimonabant in obesity-lipids study group. N Engl J Med 2005; 353: 2121-2134.
26. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006; 295: 761-775.
27. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 2000; 356: 2119-2125.
28. McMahon FG, Fujioka K, Singh BN, Mendel CM, Rowe E, Rolston K et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med 2000; 160: 2185-2191.
29. McMahon FG, Weinstein SP, Rowe E, Ernst KR, Johnson F, Fujioka K. Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors. J Hum Hypertens 2002; 16: 5-11.
30. Smith IG, Goulder MA. Sibutramine Clinical Study 1047 Team. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001; 50: 505-512.
31. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194-1199.
32. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281: 235-242.
33. Klein S, Allison DB, Heymsfield SB, Kelley DE, Leibel RL, Nonas C et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Obesity 2007; 15: 1061-1067. (Pubitemid 46932459)
34. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001; 285: 2486-2497.
35. Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433-438.
36. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new worldwide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006; 23: 469-480.
37. Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005; 365: 1363-1364.
38. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660-1672.
39. Tonstad S. Is rimonabant a safe and effective therapy for sustained weight loss and improved cardiometabolic risk factors? Nat Clin Pract Cardiovasc Med 2006; 3: 364-365.
40. Fong TM, Heymsfield SB. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int J Obes (Lond) 2009; 33: 947-955.
41. Coutts AA, Izzo AA. The gastrointestinal pharmacology of cannabinoids: an update. Curr Opin Pharmacol 2004; 4: 572-579.
42. Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998; 83: 393-411.
43. Pettit DA, Harrison MP, Olson JM, Spencer RF, Cabral GA. Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J Neurosci Res 1998; 51: 391-402.
44. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradio-graphic study in the fetal, neonatal and adult human brain. Neuroscience 1997; 77: 299-318.
45. Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S et al. A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int J Obes (in press).
46. Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N et al. A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes Metab 2010, e-pub ahead of print; doi:10/1111/j.1463-1326.2009.01188.xx.
47. Chen RZ, Huang RR, Shen CP, MacNeil DJ, Fong TM. Synergistic effects of cannabinoid inverse agonist AM251 and opioid antagonist nalmefene on food intake in mice. Brain Res 2004; 999: 227-230.
48. Tallett AJ, Blundell JE, Rodgers RJ. Effects of acute low-dose combined treatment with naloxone and AM 251 on food intake, feeding behaviour and weight gain in rats. Pharmacol Biochem Behav 2009; 91: 358-366.
49. Verty AN, McFarlane JR, McGregor IS, Mallet PE. Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake. Endocrinology 2004; 145: 3224-3231.
50. Ständer S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 2005; 38: 177-188.
51. Lee HK, Choi EB, Pak CS. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents. Curr Top Med Chem 2009; 9: 482-503.
52. Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J Pharmacol 1997; 334: R1-R2.
53. Gómez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002; 22: 9612-9617.
54. Pavón FJ, Serrano A, Pérez-Valero V, Jagerovic N, Hernández-Folgado L, Bermúdez-Silva FJ et al. Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J Neuroendocrinol 2008; 20 (Suppl 1): 116-123.