A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project

Trials

Katherine Fielding^1,12  Christian Lienhardt⁸  Roxana Rustomjee⁶  Piero Olliaro^1,10  Joseph Odhiambo¹  Francoise Portaels⁹  Christian Perronne^1,11  Denis A Mitchinson²  Mame Bocar Lo⁷  Olivier Lapujade^1,10  John Horton⁵  Martin Gninafon³  Oumou Bah Sow⁴  Charalambos Sismanidis^1,12  Corinne SC Merle^1,12 

[1] Kenya Medical Research Institute, Off Mbaghathi Road, P.O. Box 47855, Nairobi, Kenya;Centre for Infections, St George’s, University of London, SW17 0RE, London, UK;Centre National Hospitalier de Pneumo-Phtisiologie, Cotonou, Benin;Service de pneumo phtisiologie, Hopital Ignace Deen, Conakry, Guinea;Tropical Projects, Hitchin, UK;Medical Research Council, Unit for Clinical and Biomedical TB Research, 491 Ridge Road, P.O. Box 70380, Overport, 4067, South Africa;Programme National de Lutte contre la Tuberculose, BP 5899, Dakar, Fann, Sénégal;WHO Stop TB partnership 213, rue La Fayette, Geneva, Switzerland;Françoise Portaels, Department of Microbiology, Tropical Institute of Medicine of Antwerp, Antwerp, Belgium;WHO/TDR, 20 av Appia, CH-1211, Geneva 27, Switzerland;Infectious Diseases Department, Raymond Poincaré Hospital, Assistance Publique – Hôpitaux de Paris, Université de Versailles, Saint Quentin, France;Faculty of Epidemiology and Population Health, Tropical Epidemiological Group, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

关键词: Gatifloxacin;    Phase III;    Design issues;    Multicenter;    Non-inferiority design;    Tuberculosis treatment;    Randomized controlled trial;   

Others  :  1095585
DOI  :  10.1186/1745-6215-13-61

 received in 2011-11-02, accepted in 2012-04-02,  发布年份 2012

【 摘 要 】

Background

There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation?

Methods

Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385).

Results

In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements.

Conclusion

When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.

【 授权许可】

   
2012 Merle et al.; licensee BioMed Central Ltd.

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