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Abstract
BackgroundNew drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.ObjectiveThe goal of the present study was to infer the required duration of these treatments.MethodA meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect.ResultsThe model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for ≥5 months.ConclusionsThis model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.
Highlights
Modern tuberculosis chemotherapy has evolved as a result of hundreds of randomized, controlled clinical trials conducted over decades
The upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was,10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for $5 months
The present analysis extends that report by examining the relationship between 3 parameters –month 2 culture status, treatment duration, and relapse risk – with the goal of informing the required duration of treatment of new TB regimens for phase 3 trials and accelerated regulatory approvals
Summary
Modern tuberculosis chemotherapy has evolved as a result of hundreds of randomized, controlled clinical trials conducted over decades. Through the introduction of rifampin and pyrazinamide, these trials shortened the required duration of treatment from 18 months to the present 6 months without increasing the rate of recurrence due to relapse. The finding supported the use of month 2 culture status in phase 2 trials to select drug doses and evaluate new drug combinations. It did not directly inform the required duration of these new treatments, potentially impeding their accelerated or conditional approval for patients at greatest medical need, such as those with multiple or extensive drug resistance [1]. New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials
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