On 2013 Nov 27, R Aldridge commented:

At a time when there is considerable interest in the potential for the fluoroquinolones to shorten treatment for drug-sensitive tuberculosis, the trial conducted by the National Institute for Research in Tuberculosis (NIRT) in Chennai[1] could represent an important contribution to our understanding of whether this is achievable. Unfortunately, we have serious concerns about the conduct and analysis of this study which makes the interpretation of the results challenging.

Because moxifloxacin was not available at the start of the study, patients were only enrolled into the gatifloxacin and control regimens during the first 12 months. Thereafter, an attempt was made to equalise the numbers in each treatment arm by changing the allocation ratio to 2:1:1 in favour of the moxifloxacin arm. However, this meant that probably only around half of the 170 patients on the control arm were enrolled concurrently with patients allocated to the moxifloxacin arm. In addition the gatifloxacin arm was terminated 10 months before the moxifloxacin and control arms. No attempt appears to have been made to compare regimens during concurrent enrolment periods of the study in what would be a properly randomised comparison, in order to examine whether the conclusions would have been altered. Known or unknown differences in patient management or between patients enrolled in the different periods of enrolment could have an impact on the differences between regimens in the analyses presented.

The Data Safety and Monitoring Board (DSMB), whose members and independence are not noted in the report or the study protocol, made a recommendation in February 2006 to terminate the gatifloxacin arm of the study and in October 2006 to terminate the moxifloxacin arm. No information is given either on the guidelines under which the DSMB made this decision, or the results that were available to the DSMB in each case; only that that the decision was due to ‘high TB recurrence rates in these two arms compared to the control arm’[1]. However, most of the data on recurrence (from 24 months follow-up) would have accrued after the study had terminated. The final reported results comparing moxifloxacin with the control arm would suggest there was minimal difference between the outcomes of these two regimens, and that there was no evidence for a difference in the recurrence rate between these two arms (P=0.38). These results suggest the termination of the study is very likely to have been premature. Early termination introduces bias and, as noted in Pocock and White in relation to another trial: ‘the premature pulling out of the trial on insufficiently convincing evidence inhibits the ability of clinical science to resolve an important therapeutic issue’[2].

The culture results at two months are of particular interest since they suggest that 10% more patients receiving moxifloxacin converted at that time compared to the control arm. The authors fail to comment on what this means for the predictive ability of two month culture conversion for successful treatment shortening, a subject recently addressed by other publications in this journal.[3,4]

The results of this study might appear to support those of the OFLOTUB randomised controlled trial, presented at the recent conference of the IUATLD in Paris, which failed to show a shortened daily gatifloxacin based arm was non-inferior to the standard six month daily regimen. However, as we have pointed out, there are several serious limitations in the NIRT trial report, in particular the premature closure of enrolment, which need to be recognised when assessing the conclusions of the study and any future meta-analyses which includes these data.

Rob Aldridge on behalf of the North London TB Journal Club (http://northlondontb.org/). North London TB Journal Club meets monthly; it is organised by the London School of Hygiene and Tropical Medicine, University College London and MRC Clinical Trials Unit. The points above represent concerns raised during a discussion of this paper at a meeting of the Journal Club on 12th November 2013.

1. Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, et al. (2013) Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One 8: e67030.
2. Pocock S, White I (1999) Trials stopped early: too good to be true? Lancet 353: 943-944.
3. Phillips PP, Fielding K, Nunn AJ (2013) An Evaluation of Culture Results during Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse. PLoS One 8: e63840.
4. Wallis RS, Wang C, Meyer D, Thomas N (2013) Month 2 Culture Status and Treatment Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model. PLoS One 8: e71116.

On 2013 Nov 27, R Aldridge commented:

At a time when there is considerable interest in the potential for the fluoroquinolones to shorten treatment for drug-sensitive tuberculosis, the trial conducted by the National Institute for Research in Tuberculosis (NIRT) in Chennai[1] could represent an important contribution to our understanding of whether this is achievable. Unfortunately, we have serious concerns about the conduct and analysis of this study which makes the interpretation of the results challenging.

Because moxifloxacin was not available at the start of the study, patients were only enrolled into the gatifloxacin and control regimens during the first 12 months. Thereafter, an attempt was made to equalise the numbers in each treatment arm by changing the allocation ratio to 2:1:1 in favour of the moxifloxacin arm. However, this meant that probably only around half of the 170 patients on the control arm were enrolled concurrently with patients allocated to the moxifloxacin arm. In addition the gatifloxacin arm was terminated 10 months before the moxifloxacin and control arms. No attempt appears to have been made to compare regimens during concurrent enrolment periods of the study in what would be a properly randomised comparison, in order to examine whether the conclusions would have been altered. Known or unknown differences in patient management or between patients enrolled in the different periods of enrolment could have an impact on the differences between regimens in the analyses presented.

The Data Safety and Monitoring Board (DSMB), whose members and independence are not noted in the report or the study protocol, made a recommendation in February 2006 to terminate the gatifloxacin arm of the study and in October 2006 to terminate the moxifloxacin arm. No information is given either on the guidelines under which the DSMB made this decision, or the results that were available to the DSMB in each case; only that that the decision was due to ‘high TB recurrence rates in these two arms compared to the control arm’[1]. However, most of the data on recurrence (from 24 months follow-up) would have accrued after the study had terminated. The final reported results comparing moxifloxacin with the control arm would suggest there was minimal difference between the outcomes of these two regimens, and that there was no evidence for a difference in the recurrence rate between these two arms (P=0.38). These results suggest the termination of the study is very likely to have been premature. Early termination introduces bias and, as noted in Pocock and White in relation to another trial: ‘the premature pulling out of the trial on insufficiently convincing evidence inhibits the ability of clinical science to resolve an important therapeutic issue’[2].

The culture results at two months are of particular interest since they suggest that 10% more patients receiving moxifloxacin converted at that time compared to the control arm. The authors fail to comment on what this means for the predictive ability of two month culture conversion for successful treatment shortening, a subject recently addressed by other publications in this journal.[3,4]

The results of this study might appear to support those of the OFLOTUB randomised controlled trial, presented at the recent conference of the IUATLD in Paris, which failed to show a shortened daily gatifloxacin based arm was non-inferior to the standard six month daily regimen. However, as we have pointed out, there are several serious limitations in the NIRT trial report, in particular the premature closure of enrolment, which need to be recognised when assessing the conclusions of the study and any future meta-analyses which includes these data.

Rob Aldridge on behalf of the North London TB Journal Club (http://northlondontb.org/). North London TB Journal Club meets monthly; it is organised by the London School of Hygiene and Tropical Medicine, University College London and MRC Clinical Trials Unit. The points above represent concerns raised during a discussion of this paper at a meeting of the Journal Club on 12th November 2013.

1. Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, et al. (2013) Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One 8: e67030.
2. Pocock S, White I (1999) Trials stopped early: too good to be true? Lancet 353: 943-944.
3. Phillips PP, Fielding K, Nunn AJ (2013) An Evaluation of Culture Results during Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse. PLoS One 8: e63840.
4. Wallis RS, Wang C, Meyer D, Thomas N (2013) Month 2 Culture Status and Treatment Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model. PLoS One 8: e71116.