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

<p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Merle Corinne SC [verfasserIn] Sismanidis Charalambos [verfasserIn] Sow Oumou [verfasserIn] Gninafon Martin [verfasserIn] Horton John [verfasserIn] Lapujade Olivier [verfasserIn] Lo Mame [verfasserIn] Mitchinson Denis A [verfasserIn] Perronne Christian [verfasserIn] Portaels Francoise [verfasserIn] Odhiambo Joseph [verfasserIn] Olliaro Piero [verfasserIn] Rustomjee Roxana [verfasserIn] Lienhardt Christian [verfasserIn] Fielding Katherine [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2012

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

Übergeordnetes Werk:	In: Trials - BMC, 2006, 13(2012), 1, p 61
Übergeordnetes Werk:	volume:13 ; year:2012 ; number:1, p 61

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/1745-6215-13-61

Katalog-ID:	DOAJ05884497X

Internformat


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allfields	10.1186/1745-6215-13-61 doi (DE-627)DOAJ05884497X (DE-599)DOAJ246b21082f80454b942c909e3dcdaadf DE-627 ger DE-627 rakwb eng R5-920 Merle Corinne SC verfasserin aut A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General) Sismanidis Charalambos verfasserin aut Sow Oumou verfasserin aut Gninafon Martin verfasserin aut Horton John verfasserin aut Lapujade Olivier verfasserin aut Lo Mame verfasserin aut Mitchinson Denis A verfasserin aut Perronne Christian verfasserin aut Portaels Francoise verfasserin aut Odhiambo Joseph verfasserin aut Olliaro Piero verfasserin aut Rustomjee Roxana verfasserin aut Lienhardt Christian verfasserin aut Fielding Katherine verfasserin aut In Trials BMC, 2006 13(2012), 1, p 61 (DE-627)326173552 (DE-600)2040523-6 17456215 nnns volume:13 year:2012 number:1, p 61 https://doi.org/10.1186/1745-6215-13-61 kostenfrei https://doaj.org/article/246b21082f80454b942c909e3dcdaadf kostenfrei http://www.trialsjournal.com/content/13/1/61 kostenfrei https://doaj.org/toc/1745-6215 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2012 1, p 61
spelling	10.1186/1745-6215-13-61 doi (DE-627)DOAJ05884497X (DE-599)DOAJ246b21082f80454b942c909e3dcdaadf DE-627 ger DE-627 rakwb eng R5-920 Merle Corinne SC verfasserin aut A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General) Sismanidis Charalambos verfasserin aut Sow Oumou verfasserin aut Gninafon Martin verfasserin aut Horton John verfasserin aut Lapujade Olivier verfasserin aut Lo Mame verfasserin aut Mitchinson Denis A verfasserin aut Perronne Christian verfasserin aut Portaels Francoise verfasserin aut Odhiambo Joseph verfasserin aut Olliaro Piero verfasserin aut Rustomjee Roxana verfasserin aut Lienhardt Christian verfasserin aut Fielding Katherine verfasserin aut In Trials BMC, 2006 13(2012), 1, p 61 (DE-627)326173552 (DE-600)2040523-6 17456215 nnns volume:13 year:2012 number:1, p 61 https://doi.org/10.1186/1745-6215-13-61 kostenfrei https://doaj.org/article/246b21082f80454b942c909e3dcdaadf kostenfrei http://www.trialsjournal.com/content/13/1/61 kostenfrei https://doaj.org/toc/1745-6215 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2012 1, p 61
allfields_unstemmed	10.1186/1745-6215-13-61 doi (DE-627)DOAJ05884497X (DE-599)DOAJ246b21082f80454b942c909e3dcdaadf DE-627 ger DE-627 rakwb eng R5-920 Merle Corinne SC verfasserin aut A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General) Sismanidis Charalambos verfasserin aut Sow Oumou verfasserin aut Gninafon Martin verfasserin aut Horton John verfasserin aut Lapujade Olivier verfasserin aut Lo Mame verfasserin aut Mitchinson Denis A verfasserin aut Perronne Christian verfasserin aut Portaels Francoise verfasserin aut Odhiambo Joseph verfasserin aut Olliaro Piero verfasserin aut Rustomjee Roxana verfasserin aut Lienhardt Christian verfasserin aut Fielding Katherine verfasserin aut In Trials BMC, 2006 13(2012), 1, p 61 (DE-627)326173552 (DE-600)2040523-6 17456215 nnns volume:13 year:2012 number:1, p 61 https://doi.org/10.1186/1745-6215-13-61 kostenfrei https://doaj.org/article/246b21082f80454b942c909e3dcdaadf kostenfrei http://www.trialsjournal.com/content/13/1/61 kostenfrei https://doaj.org/toc/1745-6215 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2012 1, p 61
allfieldsGer	10.1186/1745-6215-13-61 doi (DE-627)DOAJ05884497X (DE-599)DOAJ246b21082f80454b942c909e3dcdaadf DE-627 ger DE-627 rakwb eng R5-920 Merle Corinne SC verfasserin aut A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General) Sismanidis Charalambos verfasserin aut Sow Oumou verfasserin aut Gninafon Martin verfasserin aut Horton John verfasserin aut Lapujade Olivier verfasserin aut Lo Mame verfasserin aut Mitchinson Denis A verfasserin aut Perronne Christian verfasserin aut Portaels Francoise verfasserin aut Odhiambo Joseph verfasserin aut Olliaro Piero verfasserin aut Rustomjee Roxana verfasserin aut Lienhardt Christian verfasserin aut Fielding Katherine verfasserin aut In Trials BMC, 2006 13(2012), 1, p 61 (DE-627)326173552 (DE-600)2040523-6 17456215 nnns volume:13 year:2012 number:1, p 61 https://doi.org/10.1186/1745-6215-13-61 kostenfrei https://doaj.org/article/246b21082f80454b942c909e3dcdaadf kostenfrei http://www.trialsjournal.com/content/13/1/61 kostenfrei https://doaj.org/toc/1745-6215 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2012 1, p 61
allfieldsSound	10.1186/1745-6215-13-61 doi (DE-627)DOAJ05884497X (DE-599)DOAJ246b21082f80454b942c909e3dcdaadf DE-627 ger DE-627 rakwb eng R5-920 Merle Corinne SC verfasserin aut A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General) Sismanidis Charalambos verfasserin aut Sow Oumou verfasserin aut Gninafon Martin verfasserin aut Horton John verfasserin aut Lapujade Olivier verfasserin aut Lo Mame verfasserin aut Mitchinson Denis A verfasserin aut Perronne Christian verfasserin aut Portaels Francoise verfasserin aut Odhiambo Joseph verfasserin aut Olliaro Piero verfasserin aut Rustomjee Roxana verfasserin aut Lienhardt Christian verfasserin aut Fielding Katherine verfasserin aut In Trials BMC, 2006 13(2012), 1, p 61 (DE-627)326173552 (DE-600)2040523-6 17456215 nnns volume:13 year:2012 number:1, p 61 https://doi.org/10.1186/1745-6215-13-61 kostenfrei https://doaj.org/article/246b21082f80454b942c909e3dcdaadf kostenfrei http://www.trialsjournal.com/content/13/1/61 kostenfrei https://doaj.org/toc/1745-6215 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2012 1, p 61
language	English
source	In Trials 13(2012), 1, p 61 volume:13 year:2012 number:1, p 61
sourceStr	In Trials 13(2012), 1, p 61 volume:13 year:2012 number:1, p 61
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin Medicine (General)
isfreeaccess_bool	true
container_title	Trials
authorswithroles_txt_mv	Merle Corinne SC @@aut@@ Sismanidis Charalambos @@aut@@ Sow Oumou @@aut@@ Gninafon Martin @@aut@@ Horton John @@aut@@ Lapujade Olivier @@aut@@ Lo Mame @@aut@@ Mitchinson Denis A @@aut@@ Perronne Christian @@aut@@ Portaels Francoise @@aut@@ Odhiambo Joseph @@aut@@ Olliaro Piero @@aut@@ Rustomjee Roxana @@aut@@ Lienhardt Christian @@aut@@ Fielding Katherine @@aut@@
publishDateDaySort_date	2012-01-01T00:00:00Z
hierarchy_top_id	326173552
id	DOAJ05884497X
language_de	englisch
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author	Merle Corinne SC
spellingShingle	Merle Corinne SC misc R5-920 misc Randomized controlled trial misc Tuberculosis treatment misc Non-inferiority design misc Multicenter misc Design issues misc Phase III misc Gatifloxacin misc Medicine (General) A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project
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topic_title	R5-920 A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project Randomized controlled trial Tuberculosis treatment Non-inferiority design Multicenter Design issues Phase III Gatifloxacin
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title_auth	A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project
abstract	<p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
abstractGer	<p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
abstract_unstemmed	<p<Abstract</p< <p<Background</p< <p<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?</p< <p<Methods</p< <p<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).</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
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A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project

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