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Meta-Analysis
. 2017 Jul 1;65(1):46-54.
doi: 10.1093/cid/cix247.

Comparing the Efficacy of Drug Regimens for Pulmonary Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials

Laura J Bonnett  1 , Gie Ken-Dror  1 , Gavin C K W Koh  2 , Geraint R Davies  3
Affiliations
Meta-Analysis

Comparing the Efficacy of Drug Regimens for Pulmonary Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials

Laura J Bonnett et al. Clin Infect Dis. .

Abstract

Background: A 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.

Methods: Studies 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.

Results: One 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.

Conclusions: The 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.

Keywords: efficacy; meta-analysis; tuberculosis.

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Figures

Figure 1.
Figure 1.
Literature review process.
Figure 2.
Figure 2.
Drug combinations of included studies. Abbreviations: E, ethambutol; G, gatifloxacin; H, isoniazid; J, bedaquiline; L, levofloxacin; M, moxifloxacin; O, ofloxacin; P, para-aminosalicylic acid; Pa, PA-824/pretomanid; R, rifampicin; Rb, rifabutin; Rp, rifapentine; S, streptomycin; T, thiacetazone; Z, pyrazinamide.
Figure 3.
Figure 3.
Results of early bactericidal activity over 2 days (fixed effects, generalized inverse variance method). Abbreviations: CFU, colony-forming units; E, ethambutol; EBA, early bactericidal activity; G, gatifloxacin; H, isoniazid; J, bedaquiline; L, levofloxacin; M, moxifloxacin; O, ofloxacin; P, para-aminosalicylic acid; Pa, PA-824/pretomanid; R, rifampicin; Rb, rifabutin; Rp, rifapentine; S, streptomycin; T, thiacetazone; Z, pyrazinamide.
Figure 4.
Figure 4.
Results of early bactericidal activity over 7 days (fixed effects, generalized inverse variance method). Abbreviations: CFU, colony-forming units; E, ethambutol; EBA, early bactericidal activity; H, isoniazid; J, bedaquiline; M, moxifloxacin; Pa, PA-824/pretomanid; R, rifampicin; Z, pyrazinamide.
Figure 5.
Figure 5.
Results of early bactericidal activity over 14 days (fixed effects, generalized inverse variance method). Abbreviations: CFU, colony-forming units; E, ethambutol; EBA, early bactericidal activity; G, gatifloxacin; H, isoniazid; J, bedaquiline; M, moxifloxacin; Pa, PA-824/pretomanid; R, rifampicin; Z, pyrazinamide.
Figure 6.
Figure 6.
Culture negativity at 8 weeks: solid culture (random effects, DerSimonian and Laird method). Abbreviations: -ve, negative; E, ethambutol; G, gatifloxacin; H, isoniazid; J, bedaquiline; L, levofloxacin; M, moxifloxacin; O, ofloxacin; P, para-aminosalicylic acid; Pa, PA-824/pretomanid; R, rifampicin; Rb, rifabutin; Rp, rifapentine; S, streptomycin; T, thiacetazone; Z, pyrazinamide.
Figure 7.
Figure 7.
Culture negativity at 8 weeks: liquid culture (random effects, DerSimonian and Laird method). Abbreviations: -ve, negative; E, ethambutol; G, gatifloxacin; H, isoniazid; M, moxifloxacin; O, ofloxacin; R, rifampicin; Rp, rifapentine; Z, pyrazinamide.
Figure 8.
Figure 8.
Culture negativity at 8 weeks: solid and liquid culture (random effects, DerSimonian and Laird method). Abbreviations: -ve, negative; E, ethambutol; H, isoniazid; M, moxifloxacin; P, para-aminosalicylic acid; R, rifampicin; Rb, rifabutin; Z, pyrazinamide.
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References

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