Observed and predicted relapse rates in arms of three phase 3 trials of fluoroquinolone-containing regimens.

<p>Evaluable subjects are those who at end-of-treatment have not met other unsatisfactory endpoints. Observed relapse rates are from per-protocol analyses, calculated as the number of subjects meeting the primary definition of recurrence in each trial (REMox: “relapse” + “retreated”; OFLOTUB: unfavorable outcomes at 18 months; RIFAQUIN: “culture confirmed” + “other”) divided by the number of evaluable subjects. Relapse was predicted using a model developed without data from the 3 trials in question, whose variables included total treatment duration and month 2 culture status using solid media [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125403#pone.0125403.ref005" target="_blank">5</a>]. E = ethambutol; G = gatifloxacin; H = isoniazid; M = moxifloxacin; P = rifapentine; R = rifampin; Z = pyrazinamide. Leading numbers in regimens indicate duration in months. Drugs were administered 7 days per week except as indicated by subscripts.</p><p>Observed and predicted relapse rates in arms of three phase 3 trials of fluoroquinolone-containing regimens.</p

Month 2 Culture Status and Treatment Duration as Predictors of Recurrence in Pulmonary Tuberculosis: Model Validation and Update

<div><p>Background</p><p>New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.</p><p>Methods</p><p>Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.</p><p>Findings</p><p>The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.</p><p>Interpretation</p><p>Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.</p></div

Observed and predicted relapse rates in the treatment shortening study of Johnson et al [9].

<p>Predictions were based on updated model parameters, a month 2 culture positive proportion of 0.005 (0.5%), and a sample size of N = 185 per arm. H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol.</p><p>Observed and predicted relapse rates in the treatment shortening study of Johnson et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125403#pone.0125403.ref009" target="_blank">9</a>].</p

Observed and predicted proportions of subjects with tuberculosis recurrence in the 8 arms of the 3 trials comprising the validation dataset, based on all recurrences (left panel) and only those with full culture confirmation (right panel).

<p>Recurrences were predicted using the original mathematical model as reported in reference [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125403#pone.0125403.ref005" target="_blank">5</a>]. Axes indicate logit-transformed recurrence risk; inset scales indicate corresponding percentages. Red symbols indicate 4 month regimens; green symbols indicate 6 month regimens. Error bars indicate 80% confidence intervals (10%-90%). Vertical and horizontal dotted lines indicate recurrence rates of 10% (-2.2 after logit transformation).</p

Parameter estimates of original and revised meta-regression models.

<p>SE = standard error; CV = coefficient of variation.</p><p>Parameter estimates of original and revised meta-regression models.</p

Characteristics of regimens included in the original (training), validation, and full dataset.

<p>Values indicate median (IQR) except as indicated. Regimens were scored as 1 if a criterion was fully met, 0.5 if partially met, and 0 if absent. Asterisks indicate differences between training and validation datasets at P≤.01 by Mann-Whitney rank test.</p><p>Characteristics of regimens included in the original (training), validation, and full dataset.</p

Predicted proportion of patients with recurrence based on the proportion positive after 2 months of treatment, for regimens of 4 and 6 months duration.

<p>Axes indicate logit-transformed proportions; inset scales indicate corresponding percentages. Solid and dotted lines indicate updated and original model predictions, respectively. Shading indicates 80% confidence intervals for the updated estimates.</p

Predicted relapse rates for hypothetical regimens of 4, 6, and 8 months duration.

<p>The prediction interval (PI) indicates uncertainty regarding the predicted relapse rate in a hypothetical study with 680 subjects per arm. Parameters yielding a risk of approximately 10% of a relapse rate >10% are indicated in bold.</p><p>Predicted relapse rates for hypothetical regimens of 4, 6, and 8 months duration.</p

Month 2 Culture Status and Treatment Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model

<div><p>Background</p><p>New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.</p><p>Objective</p><p>The goal of the present study was to infer the required duration of these treatments.</p><p>Method</p><p>A 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.</p><p>Results</p><p>The 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.</p><p>Conclusions</p><p>This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.</p></div

Observed rates of culture positivity at month 2 (center columns) and predicted rates of relapse (right columns) based on data from five 2-month trials of experimental moxifloxacin-containing regimens.

<p>Relapse rates were predicted using the equation parameters in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071116#pone-0071116-t002" target="_blank">table 2</a>. Treatment durations of 4 and 5 months were considered for the moxifloxacin regimens; a duration of 6 months was assumed for standard (HRZE) treatment. Parentheses indicate 80% prediction intervals for a trial with 680 subjects per arm. Findings from 4 of the 5 studies could be considered as supporting a role for moxifloxacin in 5 month regimens; however, none supported a role as a 4 month regimen, due to increased relapse risk.</p