Planning of clinical trial programmes for medicines for the treatment of obesity

Scientific relevance. Obesity is a significant public health problem. Currently, the Russian Federation and the other Member States of the Eurasian Economic Union (EAEU) do not have regulatory documents and recommendations for planning clinical trials (CTs) of new (original) medicines for the treatment of obesity.

Aim. The study aimed to provide recommendations on the basic principles of planning and conducting CTs of medicines for the treatment of obesity.

Discussion. The authors reviewed the requirements for conducting CTs of medicines for the treatment of obesity set forth by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). In addition, the authors analysed approaches to CTs providing for a reliable evaluation of the efficacy and safety of medicines for the treatment of obesity. The primary endpoint of such CTs is a statistically significant loss of at least 5% of the baseline weight after 12 months of treatment. Secondary endpoints include assessments of abdominal obesity reduction, subcutaneous and visceral fat reduction, and the medicinal product’s effect on maintaining a reduced body weight.

Conclusions. In addition, CTs should investigate the effects of treatment on cardiovascular risk factors and cardiovascular morbidity/mortality. A CT protocol should define the intercurrent events that should be considered in the analysis of trial results. When investigating the safety of medicines for the treatment of obesity, studies should focus on neuropsychiatric safety, the potential for abuse/addiction and withdrawal reactions, and the development of valvulopathy and pulmonary hypertension. These recommendations may be of use to experts evaluating clinical development programmes or marketing authorisation submissions for medicines for the treatment of obesity.

1. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88. https://doi.org/10.1186/1471-2458-9-88

2. Lenz M, Richter T, Mühlhauser I. The morbidity and mortality associated with overweight and obesity in adulthood. Dtsch Arztebl Int. 2009;106(40):641–8. https://doi.org/10.3238/arztebl.2009.0641

3. Alberti K, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome a new worldwide definition. Lancet. 2005;366(9491):1059–62. https://doi.org/10.1016/s0140-6736(05)67402-8

4. Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist. 2010;15(6):556–65. https://doi.org/10.1634/theoncologist.2009-0285

5. Peto R, Whitlock G, Jha P. Effects of obesity and smoking on US life expectancy. N Engl J Med. 2010;362(9):855–7. https://doi.org/10.1056/NEJMc1000079

6. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Uberto Pagotto U, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62. https://doi.org/10.1210/jc.2014-3415

7. Tepaeva AI. Quality of life of overweight and obese patients: results of sociological analysis. Bulletin of Medical Internet Conferences. 2013;3(7):1027–30 (In Russ.). EDN: QGPUGL

8. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 t o 2 016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017;390(10113):2627–42. https://doi.org/10.1016/S0140-6736(17)32129-3

9. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387(10026):1377–96. https://doi.org/10.1016/S0140-6736(16)30054-X

10. Kelly T, Yang W, Chen CS, Reynolds K, J He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond). 2008;32(9):1431–7. https://doi.org/10.1038/ijo.2008.102

11. Schutz DD, Busetto L, Dicker D, Farpour-Lambert N, Pryke R, Toplak H, et al. European practical and patient- centred guidelines for adult obesity management in Primary Care. Obes Facts. 2019;12(1):40–66. https://doi.org/10.1159/000496183

12. Dedov II, Shestakova MV, Galstyan GR. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Diabetes Mellitus. 2016;19(2):104–12 (In Russ.). https://doi.org/10.14341/DM2004116-17

13. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: a short history. Circulation. 2012;125(17):2156–64. https://doi.org/10.1161/CIRCULATIONAHA.111.028381

14. Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL. Indices of relative weight and obesity. J Chronic Dis. 1972;25:329–43. Reprinted Int J Epidemiol. 2014;43(3):655–65. https://doi.org/10.1093/ije/dyu058

15. Drapkina OM, Samorodskaya IV, Starinskaya MA, Kim OT, Neymark AE. Obesity: assessment and management tactics. Collective monograph. Moscow: National Research Institute of Cardiology and Therapy of the Ministry of Health of Russia; Silicea-Polygraph; 2021 (In Russ.).

16. Mathus-Vliegen L, Toouli J, Fried M, Khan AG, Garisch J, Hunt R et al. World Gastroenterology Organisation Global Guidelines on Obesity. J Clin Gastroenterol. 2012;46(7):555–61. https://doi.org/10.1097/MCG.0b013e318259bd04

17. Garvey WT, Garber AJ, Mechanick I, Bray A, Dagogo- Jack S, Einhorn D, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20(9):977–89. https://doi.org/10.4158/EP14280.PS

18. Dedov II, Shestakova MV, Melnichenko GA, Mazurina NV, Andreeva EN, Bondarenko IZ, et al. Interdisciplinary clinical practice guidelines “Management of obesity and its comorbidities”. Obesity and Metabolism. 2021;18(1):5–99 (In Russ.). https://doi.org/10.14341/omet12714

19. Wharton S, Lau DCW, Vallis M, Sharma AM, Biertho L, Campbell-Scherer D, et al. Obesity in adults: a clinical practice guideline. CMAJ. 2020;192(31):E875–91. https://doi.org/10.1503/cmaj.191707

20. Pasquali R, Casanueva F, Haluzik M, Hulsteijn L, Ledoux S, Monteiro MP, et al. European Society of Endocrinology Clinical Practice Guideline: endocrine workup in obesity, Eur J Endocrinol. 2020;182(1):G1–G32. https://doi.org/10.1530/eje-19-0893

21. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults. J Am Coll Cardiol. 2014;63(25):2985–3023. https://doi.org/10.1016/j.jacc.2013.11.004

22. Blundell JE, Dulloo AG, Salvador J, Frühbeck G. Beyond BMI — phenotyping the obesities. Obes Facts. 2014;7(5):322–8. https://doi.org/10.1159/000368783

23. Sampsel S, May J. Assessment and management of obesity and comorbid conditions. Dis Manag. 2007;10(5):252–65. https://doi.org/10.1089/dis.2007.105712

24. Hainer V, Toplak H, Mitrakou A. Treatment modalities of obesity: what fits whom? Diabetes Care. 2008;31(2):S269–S277. https://doi.org/10.2337/dc08-s265

25. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. https://doi.org/10.1056/NEJMoa012512

26. Biddle SJH, Bengoechea EG, Pedisic Z, Bennie J, Vergeer I, Wiesner G. Screen time, other sedentary behaviours, and obesity risk in adults: a review of reviews. Curr Obes Rep. 2017;6(2):134–47. https://doi.org/10.1007/s13679-017-0256-9

27. Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med. 2017;376(3):254–66. https://doi.org/10.1056/NEJMra1514009

28. Müller TD, Clemmensen C, Finan B, Di Marchi RD, Tschöp MH. Anti-obesity therapy: from rainbow pills to polyagonists. Pharmacol Rev. 2018;70(4):712–46. https://doi.org/10.1124/pr.117.014803

29. Dunlop DM. The use of 2:4-dinitrophenol as a metabolic stimulant. Br Med J. 1934;1(3820):524–7. https://doi.org/10.1136/bmj.1.3820.524

30. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–34. https://doi.org/10.1001/jama.2016.7602

31. Després JP, Golay A, Sjöström L, Rimonabant in Obesity- Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353(20):2121–34. https://doi.org/10.1056/NEJMoa044537

32. Hauner H, Hastreiter L, Werdier D, Chen-Stute A, Scholze J, Blüher M. Efficacy and safety of cathine (nor-pseudoephedrine) in the treatment of obesity: a randomized dose-finding study. Obes Facts. 2017;10(4):407–19. https://doi.org/10.1159/000478098

33. Müller TD, Blüher M, Tschöp MH. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201–23. https://doi.org/10.1038/s41573-021-00337-8

34. Alieva VA. Modern medicines for the treatment of obesity. Clinical pharmacology and therapy. 2020;29(4):61–6 (In Russ.). https://doi.org/10.32756/0869-5490-2020-4-61-66

35. Beverly GT, Mohini A, Rekha BK, Louis JA, Kenneth RF, Bradley A, et al. Pharmacologic treatment of overweight and obesity in adults. In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. PMID: 25905267

36. Greenway F, Aronne L, Raben A, Astrup A, Apovian C, Hill JO, et al. A randomized, double-blind, placebo-controlled study of Gelesis100: a novel nonsystemic oral hydrogel for weight loss. Obesity. 2018;27(2):205–16. https://doi.org/10.1002/oby.22347

37. Farooqi IS. Defining the neural basis of appetite and obesity: from genes to behaviour. Clin Med (Lond). 2014;14(3):286–9. https://doi.org/10.7861/clinmedicine.14-3-286

38. Heal D, Gosden J, Smith S. The 5-HT6 receptor as a target for developing novel antiobesity drugs. Int Rev Neurobiol. 2011;96:73–109. https://doi.org/10.1016/B978-0-12-385902-0.00004-8

39. Vickers SP, Jackson HC, Cheetham SC. The utility of animal models to evaluate novel anti-obesity agents. Br J Pharmacol. 2011;164(4):1248–62. https://doi.org/10.1111/j.1476-5381.2011.01245.x

40. Tschöp MH, Speakman JR, Arch JRS, Auwerx J, Brüning JC, Chan L, et al. A guide to analysis of mouse energy metabolism. Nat Methods. 2011;9(1):57–63. https://doi.org/10.1038/nmeth.1806

41. Farooqi IS, O’Rahilly S. Monogenic human obesity syndromes. Recent Prog Horm Res. 2004;59:409–24. https://doi.org/10.1210/rp.59.1.409

42. Farooqi IS, O’Rahilly S, Feingold KR, Anawalt B, Boyce A, Chrousos G. The genetics of obesity in humans. In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. PMID: 25905292

43. Xue A, Wu Y, Zhu Z, Zhang F, Kemper KF, Zheng Z, et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018;9(1):2941. https://doi.org/10.1038/s41467-018-04951-w

44. Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 2018;6(5):361–9. https://doi.org/10.1016/S2213-8587(18)30051-2

45. Fall T, Ingelsson E. Genome-wide association studies of obesity and metabolic syndrome. Mol Cell Endocrinol. 2014;382(1):740–57. https://doi.org/10.1016/j.mce.2012.08.018

46. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206. https://doi.org/10.1038/nature14177

47. Huypens P, Sass S, Wu M, Dyckhoff D, Theis F, et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat Genet. 2016;48(5):497–9. https://doi.org/10.1038/ng.3527

48. Melvin A, O’Rahilly S, Savage DB. Genetic syndromes of severe insulin resistance. Curr Opin Genet Dev. 2018;50:60–7. https://doi.org/10.1016/j.gde.2018.02.002

49. Tak YJ, Lee SY. Anti-obesity drugs: long-term efficacy and safety: an updated review. World J Mens Health. 2021;39(2):208–21. https://doi.org/10.5534/wjmh.200010

50. Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387(100031):1947–56. https://doi.org/10.1016/S0140-6736(16)00271-3

51. Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27. https://doi.org/10.1056/NEJMoa1614362

52. Taube AA, Romanov BK. Expert evaluation of prognostic criteria for non-clinical trials when registering medicinal products for medical use. Vestnik of the Smolensk State Medical Academy. 2021;20(1):18–25 (In Russ.). https://doi.org/10.37903/vsgma.2021.1.3

53. Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, et al. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol. 2018;14(3):140–62. https://doi.org/10.1038/nrendo.2017.161

54. Elangbam CS. Review paper: Current strategies in the development of anti-obesity drugs and their safety concerns. Vet Pathol. 2009;46(1):10–24. https://doi.org/10.1354/vp.46-1-10

55. Atkinson A, Colburn W, Degruttola V, Demets D, Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. https://doi.org/10.1067/mcp.2001.113989

56. Wharton S, Astrup A, Endahl L, Lean MEJ, Satylganova A, Skovgaard D, et al. Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data. Int J Obes (Lond). 2021;45(5):923–33. https://doi.org/10.1038/s41366-020-00733-x

57. Toplak H, Woodward E, Yumuk V, Oppert JM, Halford JCD, Frühbeck G. 2014 EASO Position statement on the use of anti-obesity drugs. Obes Facts. 2015;8(3):166–74. https://doi.org/10.1159/000430801

58. Rothman RB, Baumann JE, Savage JE, Rauser L, McBri-de A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102(23):2836–41. https://doi.org/10.1161/01.CIR.102.23.2836

59. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8(8):443–55. https://doi.org/10.1038/nrcardio.2011.87