Advances in clinical trial design: Weaving tomorrow’s TB treatments

Autoři: Christian Lienhardt aff001;  Andrew Nunn aff002;  Richard Chaisson aff003;  Andrew A. Vernon aff004;  Matteo Zignol aff005;  Payam Nahid aff006;  Eric Delaporte aff001;  Tereza Kasaeva aff005
Působiště autorů: Unité Mixte Internationale TransVIHMI, UMI 233 IRD–U1175 INSERM—Université de Montpellier, Institut de Recherche pour le Développement (IRD), Montpellier, France aff001;  MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom aff002;  Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, United States of America aff003;  Division of TB Elimination, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America aff004;  Global TB Programme, World Health Organization, Geneva, Switzerland aff005;  UCSF Center for Tuberculosis and Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California, United States of America aff006
Vyšlo v časopise: Advances in clinical trial design: Weaving tomorrow’s TB treatments. PLoS Med 17(2): e32767. doi:10.1371/journal.pmed.1003059
Kategorie: Collection Review
doi: 10.1371/journal.pmed.1003059


Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

Klíčová slova:

Clinical trials – Drug research and development – Drug therapy – Extensively drug-resistant tuberculosis – HIV infections – Phase II clinical investigation – Phase III clinical investigation – Tuberculosis


1. Fox W, Mitchison DA. State of the Art. Short-course chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis. 1975; 111: 325–353. doi: 10.1164/arrd.1975.111.3.325 47233

2. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999; 3(Suppl):S231–S279.

3. Tiberi S, du Plessis N, Walzl G, Vjecha MJ, Rao M, Ntoumi F, et al. Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis. 2018;18: e183–98

4. Working Group on New Drugs [Internet]. New York: The Working Group for New TB Drugs; c2016. [cited 2019 Sept 29] Available from:

5. Lienhardt C, Kraigsley AM, Sizemore CF. Driving the Way to Tuberculosis Elimination: The Essential Role of Fundamental Research. Clin Infect Dis. 2016;63(3):370–5. doi: 10.1093/cid/ciw250 27270671

6. Lienhardt C, Nahid P. Advances in clinical trial design for development of new TB treatments: A call for innovation. PLoS Med. 2019; 16(3):e1002769. doi: 10.1371/journal.pmed.1002769 30901322

7. World Health Organization. Global investments in Tuberculosis research and development: past, present, and future. Proceedings of the First WHO global ministerial conference on ending tuberculosis in the sustainable development era: a multisectoral response; 2017 Nov 16–17; Moscow, Russia. World Health Organization: Geneva; 2017. WHO/HTM/TB/2017.26

8. World Health Organization. Report of the Technical Consultation on Advances in Clinical Trial Design for Development of New TB Treatments, Glion-sur-Montreux, Switzerland, 2018 Mar 14–16. Geneva: World Health Organization; 2018 (WHO/CDS/TB/2018.17).

9. Mitchison DA, Dickinson J M. Bactericidal mechanisms in short–course chemotherapy. Bull Int Union Tuberc. 1978; 53:254–259.

10. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000; 4(9):796–806. 10985648

11. McDermott W. Microbial persistence. Yale J Biol Med. 1958, 30:257–291. 13531168

12. Zhang Y, Yew WW, Barer MR. Targeting persisters for tuberculosis control. Antimicrob Agents Chemoth. 2012; 5:2223–2230.

13. Nathan C, Barry CE. TB drug development: immunology at the table. Immunol Rev 2015; 264:308–18. doi: 10.1111/imr.12275 25703568

14. Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O'Brien RJ, et al. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. AJRCCM 2004; 170:10.

15. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, and the Gatifloxacin for TB (OFLOTUB) study team. A phase II study of the sterilizing activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008; 12(2):128–138. 18230244

16. Conde MB, Efron A, Loredo C, De Souza GRM, Graça NP, Cezar MC. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet. 2009; 373: 1183–1189. doi: 10.1016/S0140-6736(09)60333-0 19345831

17. Imperial MJ, Nahid P, Phillips PPJ, Davies GR, Fielding K, Hanna D, et al. A Patient-Level Pooled Analysis of Treatment Shortening Regimens for Drug-Susceptible Pulmonary Tuberculosis. Nature Med. 2018; 24(11): 1708–1715. doi: 10.1038/s41591-018-0224-2 30397355

18. Nielsen EI, Friberg LE. Pharmacokinetic–pharmacodynamic modeling of antibacterial drugs. Pharmacol Rev. 2013; 65:1053–1090. doi: 10.1124/pr.111.005769 23803529

19. Dartois V. The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nat Rev Microbiol. 2014 Mar;12(3):159–67 doi: 10.1038/nrmicro3200 24487820

20. Prideaux B, Via LE, Zimmerman MD, Eum S, Sarathy J, O'Brien P, et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. 2015;21(10):1223–7. doi: 10.1038/nm.3937 26343800

21. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000 Sep;4(9):796–806. 10985648

22. Strydom N, Gupta SV, Fox WS, Via LE, Bang H, Lee M, et al. Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization. PLoS Med. 2019 Apr 2;16(4). doi: 10.1371/journal.pmed.1002773 30939136

23. Clemens DL, Lee BY, Silva A, Dillon BJ, Masleša-Galić S, Nava S, et al. Artificial intelligence enabled parabolic response surface platform identifies ultra-rapid near-universal TB drug treatment regimens comprising approved drugs. PLoS ONE. 2019 May 10;14(5):e0215607. doi: 10.1371/journal.pone.0215607 Erratum in: PLoS ONE. 2019 May 30;14(5):e0217670. 31075149

24. Bartelink IH, Zhang N, Keizer RJ, Strydom N, Converse PJ, Dooley KE, et al. New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response. Clin Transl Sci. 2017 Sept 01;10(5):366–379. doi: 10.1111/cts.12472 28561946

25. Wallis RS, Johnson JL. The role of surrogate markers in the clinical evaluation of antituberculous chemotherapy. Curr Med Chem—Anti-Infective Agents. 2005;4(4):1–8.

26. Dooley KE, Hanna D, Mave V, Eisenach K, Savic RM. Advancing the development of new tuberculosis treatment regimens: The essential role of translational and clinical pharmacology and microbiology. PLoS Med 2019; 16(7):e1002842. doi: 10.1371/journal.pmed.1002842 31276490

27. Savic RM, Weiner M, MacKenzie WR, Engle M, Whitworth WC, Johnson JL, et al. Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials. Clin Pharmacol Ther. 2017 Aug 01;102(2):321–331. doi: 10.1002/cpt.634 28124478

28. Svensson EM, Svensson RJ, Te Brake L H M, Boeree MJ, Heinrich N, Konsten S, et al. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis. Clin Infect Dis. 2018 June 18;67(1):34–41. doi: 10.1093/cid/ciy026 29917079

29. Jindani A, Aber V, Edwards E, Mitchison D. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121:939–949. doi: 10.1164/arrd.1980.121.6.939 6774638

30. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months. Am Rev Respir Dis. 1993; 147: 1062–1063. doi: 10.1164/ajrccm/147.4.1062 8466107

31. Davies G, Hoelscher M, Boeree M, Hermann D. Accelerating the transition of new tuberculosis drug combinations from Phase II to Phase III trials: New technologies and innovative designs. PLoS Med. 2019; 16(7): e1002851. doi: 10.1371/journal.pmed.1002851 31287813

32. Dooley KE, Phillips PPJ, Nahid P, Hoelscher M. Challenges in the clinical assessment of novel tuberculosis drugs. Adv Drug Deliv Rev. 2016; 102:116–22. doi: 10.1016/j.addr.2016.01.014 26827911

33. Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomized trial. Lancet. 2012; 380(9846):986–93. doi: 10.1016/S0140-6736(12)61080-0 22828481

34. Davies GR, Brindle R, Khoo SH, Aarons LJ. Use of nonlinear mixed-effects analysis for improved precision of early pharmacodynamic measures in tuberculosis treatment. Antimicrob Agents Chemother. 2006;50(9):3154–6. doi: 10.1128/AAC.00774-05 16940116

35. Sloan DJ, Mwandumba HC, Garton NJ, Khoo SH, Butterworth AE, Allain TJ, et al. Pharmacodynamic modeling of bacillary elimination rates and detection of bacterial lipid bodies in sputum to predict and understand outcomes in treatment of pulmonary tuberculosis. Clin Infect Dis. 2015;61(1):1–8. doi: 10.1093/cid/civ195 25778753

36. Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017;17(1):39–49. doi: 10.1016/S1473-3099(16)30274-2 28100438

37. Phillips PPJ, Dooley KE, Gillespie SH, Heinrich N, Stout JE, Nahid P, et al. A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Posttreatment follow-up (STEP). BMC Med. 2016 Mar 23;14:51. doi: 10.1186/s12916-016-0597-3 27004726

38. Ginsberg AM, Spigelman M. Challenges in tuberculosis drug research and development. Nat Med. 2007;13(3):290–294. doi: 10.1038/nm0307-290 17342142

39. Phillips PPJ, Mitnick CD, Neaton JD, Nahid P, Lienhardt C, Nunn AJ. Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape. PLoS Med. 2019; 16(3):e1002767. doi: 10.1371/journal.pmed.1002767 30901331

40. Olliaro PL, Vaillant M. Designing noninferiority tuberculosis treatment trials: Identifying practical advantages for drug regimens with acceptable effectiveness. PLoS Med. 2019; 16(7):e1002850. doi: 10.1371/journal.pmed.1002850 31299047

41. Odem-Davis K, Fleming TR. A Simulation Study Evaluating Bio-Creep Risk in Serial Noninferiority Clinical Trials for Preservation of Effect. Stat Biopharm Res. 2015;7(1):12–24. doi: 10.1080/19466315.2014.1002627 26052374

42. Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Conradie F, Dalai D, et al. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis. N Engl J Med. 2019;380:1201–1213. doi: 10.1056/NEJMoa1811867 30865791

43. Phillips PPJ, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, et al. Innovative trial designs are practical solutions for improving the treatment of tuberculosis. J Infect Dis. 2012;205 Suppl 2:S250–7.

44. Cellamare M, Ventz S, Baudin E, Mitnick CD, Trippa L. A Bayesian response-adaptive trial in tuberculosis: The endTB trial. Clin Trials. 2017;14:17–28. doi: 10.1177/1740774516665090 27559021

45. Alipanah N, Jarlsberg L, Miller C, Linh NN, Falzon D, Jaramillo E, Nahid P. Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies. PLoS Med. 2018 Jul 3;15(7):e1002595 doi: 10.1371/journal.pmed.1002595 29969463

46. Vernon A, Fielding K, Savic R, Dodd L, Nahid P. The importance of adherence in tuberculosis treatment clinical trials and its relevance in explanatory and pragmatic trials. PLoS Med. 2019; 16(12): e1002884. doi: 10.1371/journal.pmed.1002884 31821323

47. Coronary Drug Project Research Group. Influence of Adherence to Treatment and Response of Cholesterol on Mortality in the Coronary Drug Project. N Engl J Med. 1980;303(18):1038–1041. doi: 10.1056/NEJM198010303031804 6999345

48. Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016;375:454–63. doi: 10.1056/NEJMra1510059 27518663

49. Walley JD, Khan AN, Newell JN & Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet. 2001; 357, 664–669. doi: 10.1016/S0140-6736(00)04129-5 11247549

50. Newell JN, Baral SC, Pande SB, Bam DS, Malla P. Family-member DOTS and community DOTS for tuberculosis control in Nepal: cluster-randomised controlled trial. Lancet 2006; 367, 903–909 doi: 10.1016/S0140-6736(06)68380-3 16546538

51. Thiam S, LeFevre AM, Hane F, Ndiaye A, Ba F, Fielding K, et al. Improving adherence to tuberculosis treatment in a resource-poor setting: A Cluster Randomised Controlled Trial. JAMA. 2007; 297(4):380–6. doi: 10.1001/jama.297.4.380 17244834

52. Gupta A, Hughes MD, Garcia-Prats AJ, McIntire K, Hesseling AC. Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons. PLoS Med. 2019;16(8): e1002882. doi: 10.1371/journal.pmed.1002882 31415563

53. McKenna L, Frick M, Lee C, Namutamba D, Smit L, Theunissen M, et al. A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials. Clin Infect Dis. 2017;65(8):1383–1387. doi: 10.1093/cid/cix533 29017245

54. Mathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect Dis. 2012;55(11):1532–1549. doi: 10.1093/cid/cis732 22942202

55. Gupta A, Mathad JS, Abdel-Rahman SM, Albano JD, Botgros R, Brown V, et al. Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus statements from an international expert panel. Clin Infect Dis. 2016; 62(6):761–769. doi: 10.1093/cid/civ991 26658057

56. Nachman S, Ahmed A, Amanullah F, Becerra MC, Botgros R, Brigden G et al. Towards early inclusion of children in tuberculosis drugs trials: a consensus statement. Lancet Infect Dis. 2015 Jun;15(6):711–720. doi: 10.1016/S1473-3099(15)00007-9 25957923

57. Weld ED, Dooley KE. State-of-the-Art Review of HIV-TB Coinfection in Special Populations. Clin Pharmacol Ther. 2018;104(6):1098–1109. doi: 10.1002/cpt.1221 30137652

58. Tornheim JA, Dooley KE. Challenges of TB and HIV co-treatment: updates and insights. Curr Opin HIV AIDS. 2018;13(6):486–491. doi: 10.1097/COH.0000000000000495 30080683

59. The Working Group for New TB Drugs [Internet]. New York: The Working Group for New TB Drugs; c2016. [cited 2019 July 12]. Available from:

60. US Food and Drug Administration [Internet]. [cited 2019 Sept 18] Available from:

61. Adebamowo C., Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy JF, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet. 2014; 18; 384(9952): 1423–1424. doi: 10.1016/S0140-6736(14)61734-7 25390318

62. Lienhardt C, Vernon AA, Cavaleri M, Nambiar S, Nahid P. Development of new TB regimens: Harmonizing trial design, product registration requirements, and public health guidance. PLoS Med. 2019; 16(9): e1002915. doi: 10.1371/journal.pmed.1002915 31490921

63. Brigden G, Nhung NV, Skrahina A, Ndjeka N, Falzon D, Zignol M. Advances in clinical trial design for development of new TB treatments—Translating international tuberculosis treatment guidelines into national strategic plans: Experiences from Belarus, South Africa, and Vietnam. PLoS Med. 2019;16(10): e1002896. doi: 10.1371/journal.pmed.1002896 31626628

64. World Health Organization. End TB Strategy: global strategy and targets for tuberculosis prevention, care, and control after 2015 [Internet]. Geneva: World Health Organization; 2014 May [cited 2019 Oct 4]. Available from:

65. World Health Organization. Global Investments in Tuberculosis Research and Development: Past, Present, and Future [Internet]. Geneva: World Health Organization, 2017. WHO/HTM/TB/2017.26 Available from:

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