Treatment Effect Measures for Culture Conversion Endpoints in Phase IIb Tuberculosis Treatment Trials.
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ABSTRACT:
SUBMITTER: Weir IR
PROVIDER: S-EPMC8664460 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To investigate risk factors for delayed sputum culture conversion to negative during anti-tuberculosis treatment, with an emphasis on smoking.Nested case-control study of adults with non-cavitary, culture-confirmed pulmonary tuberculosis (TB) participating in an anti-tuberculosis treatment trial in Brazil. A case of delayed culture conversion was a patient who remained culture-positive after 2 months of treatment. Odds ratios with 95% confidence intervals were calculated.Fifty-three cases and 240 control patients were analyzed. Smokers had three-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.007) than non-smokers, while smokers and ex-smokers who smoked >20 cigarettes a day had two-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.045).Cigarette smoking adversely affects culture conversion during anti-tuberculosis treatment. Support for smoking cessation should be considered to improve outcomes in TB control programs.
| S-EPMC4497564 | biostudies-literature
Project description:BackgroundTuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.MethodsIn TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.ResultsAfrican TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.ConclusionsCompared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.Trial registrationClinicalTrials.gov NCT00144417.
| S-EPMC3073969 | biostudies-literature
Project description:It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial.
| S-EPMC3648512 | biostudies-literature
Project description:RationaleCavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.ObjectivesTo assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.MethodsThis study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.Measurements and main resultsEnrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).ConclusionShortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.
| S-EPMC2742745 | biostudies-literature
Project description:BACKGROUND/AIMS:Patients with diabetes mellitus (DM) and tuberculosis (TB) have increased morbidity and a high risk of treatment failure or recurrence. It is important to manage both diseases simultaneously. Among anti-diabetic drugs, metformin inhibits intracellular growth of mycobacteria. Therefore, we examined the effects of metformin on TB treatment, especially in patients with DM. METHODS:This retrospective cohort study included patients with culture-positive pulmonary TB diagnosed between 2011 and 2012. The primary study outcome was sputum culture conversion after 2 months of treatment. RESULTS:Of 499 patients diagnosed with culture-positive pulmonary TB, 105 (21%) had DM at diagnosis. Among them, 62 (59.5%) were treated with metformin. Baseline characteristics, except for the presence of chronic renal disease, were not significantly different between the metformin and non-metformin groups. Metformin treatment had no significant effect on sputum culture conversion (p = 0.60) and recurrence within 1 year after TB treatment completion (p = 0.39). However, metformin improved the sputum culture conversion rate in patients with cavitary pulmonary TB, who have higher bacterial loads (odds ratio, 10.8; 95% confidence interval, 1.22 to 95.63). CONCLUSION:Among cavitary pulmonary TB patients with DM, metformin can be an effective adjunctive anti-TB agent to improve sputum culture conversion after 2 months of treatment.
| S-EPMC6129638 | biostudies-literature
Project description:Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31-92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs.
| S-EPMC4169600 | biostudies-other
Project description:BackgroundA systematic review of early clinical outcomes in tuberculosis was undertaken to determine ranking of efficacy of drugs and combinations, define variability of these measures on different endpoints, and to establish the relationships between them.MethodsStudies were identified by searching PubMed, Medline, Embase, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists of included studies. Outcomes were early bactericidal activity results over 2, 7, and 14 days, and the proportion of patients with negative culture at 8 weeks.ResultsOne hundred thirty-three trials reporting phase 2A (early bactericidal activity) and phase 2B (culture conversion at 2 months) outcomes were identified. Only 9 drug combinations were assessed on >1 phase 2A endpoint and only 3 were assessed in both phase 2A and 2B trials.ConclusionsThe existing evidence base supporting phase 2 methodology in tuberculosis is highly incomplete. In future, a broader range of drugs and combinations should be more consistently studied across a greater range of phase 2 endpoints.
| S-EPMC5850317 | biostudies-literature
Project description:BackgroundRandomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials. The estimand framework outlined in the recent ICH E9(R1) addendum offers a timely opportunity for randomized trials of TB treatment to adopt broadly standardized outcome definitions and analytic approaches. We previously proposed and defined four estimands for use in this context. Our objective was to evaluate how the use of these estimands and choice of estimation method impacts results and interpretation of a large phase III TB trial.MethodsWe reanalyzed participant-level data from the REMoxTB trial. We applied four estimands and various methods of estimation to assess non-inferiority of both novel 4-month treatment regimens against standard of care.ResultsWith each of the four estimands, we reached the same conclusion as the original trial analysis that the novel regimens were not non-inferior to standard of care. Each estimand and method of estimation gave similar estimates of the treatment effect with fluctuations in variance and differences driven by the methods applied for handling intercurrent events.ConclusionsOur application of estimands defined by the ICH E9 (R1) addendum offers a formalized framework for addressing the primary TB treatment trial objective and can promote uniformity in future trials by limiting heterogeneity in trial outcome definitions. We demonstrated the utility of our proposal using data from the REMoxTB randomized trial. We outlined methods for estimating each estimand and found consistent conclusions across estimands. We recommend future late-phase TB treatment trials to implement some or all of our estimands to promote rigorous outcome definitions and reduce variability between trials.Trial registrationClinicalTrials.gov NCT00864383. Registered on March 2009.
| S-EPMC10929173 | biostudies-literature
Project description:BackgroundRandomized trials for the treatment of tuberculosis (TB) rely on a composite primary outcome to capture unfavorable treatment responses. However, variability between trials in the outcome definition and estimation methods complicates across-trial comparisons and hinders the advancement of treatment guidelines. The International Council for Harmonization (ICH) provides international regulatory standards for clinical trials. The estimand framework outlined in the recent ICH E9(R1) addendum offers a timely opportunity for randomized trials of TB treatment to adopt broadly standardized outcome definitions and analytic approaches. We previously proposed and defined four estimands for use in this context. Our objective was to evaluate how the use of these estimands and choice of estimation method impacts results and interpretation of a large phase III TB trial.MethodsWe reanalyzed participant level data from the REMoxTB trial. We applied four estimands and various methods of estimation to assess non-inferiority of both novel 4-month treatment regimens against standard of care.ResultsWith each of the four estimands we reached the same conclusion as the original trial analysis; that the novel regimens were not non-inferior to standard of care. Each estimand and method of estimation gave similar estimates of the treatment effect with fluctuations in variance and differences driven by the methods applied for handling intercurrent events.ConclusionsOur application of estimands defined by the ICH E9(R1) addendum offers a formalized framework for addressing the primary TB treatment trial objective and can promote uniformity in future trials by limiting heterogeneity in trial outcome definitions. We demonstrated the utility of our proposal using data from the REMoxTB randomized trial. We outlined methods for estimating each estimand and found consistent conclusions across estimands. We recommend future late-phase TB treatment trials to implement some or all of our estimands to promote rigorous outcome definitions and reduce variability between trials.Trial registration: NCT00864383.
| S-EPMC10659528 | biostudies-literature
Project description:A number of potential therapeutic approaches for neurological disorders have failed to provide convincing evidence of efficacy, prompting pharmaceutical and health companies to discontinue their involvement in drug development. Limitations in the statistical analysis of complex endpoints have very likely had a negative impact on the translational process.We propose a transitional ordinal model with an autoregressive component to overcome previous limitations in the analysis of Upper Extremity Motor Scores, a relevant endpoint in the field of Spinal Cord Injury. Statistical power and clinical interpretation of estimated treatment effects of the proposed model were compared to routinely employed approaches in a large simulation study of two-arm randomized clinical trials. A revisitation of a key historical trial provides further comparison between the different analysis approaches.The proposed model outperformed all other approaches in virtually all simulation settings, achieving on average 14 % higher statistical power than the respective second-best performing approach (range: -1 %, +34 %). Only the transitional model allows treatment effect estimates to be interpreted as conditional odds ratios, providing clear interpretation and visualization.The proposed model takes into account the complex ordinal nature of the endpoint under investigation and explicitly accounts for relevant prognostic factors such as lesion level and baseline information. Superior statistical power, combined with clear clinical interpretation of estimated treatment effects and widespread availability in commercial software, are strong arguments for clinicians and trial scientists to adopt, and further extend, the proposed approach.
| S-EPMC5100172 | biostudies-literature