Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase ii trial

Moxifl oxacin versus ethambutol in the initial treatment of
tuberculosis: a double-blind, randomised, controlled phase II

Marcus B Conde, Anne Efron, Carla Loredo, Gilvan R Muzy De Souza, Nadja P Graça, Michelle C Cezar, Malathi Ram, Mohammad A Chaudhary, William R Bishai, Afranio L Kritski, Richard E Chaisson Summary
Background New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant Lancet
2009; 373: 1183–89
strains. The fl uoroquinolone moxifl oxacin is a promising new agent that might have additive activity to existing
See Editorial page 1145
antituberculosis agents. We assessed the activity and safety of moxifl oxacin in the initial stage of tuberculosis See Comment page 1148
Instituto de Doencas do Torax/
Hospital Clementino Fraga

Methods We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifl oxacin Filho, Federal University of Rio
in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received de Janeiro, Rio de Janeiro, Brazil

isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to G R Muzy De Souza MD,
receive either moxifl oxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15–20 mg/kg) plus N P Graça MD, M C Cezar MD,
moxifl oxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose A L Kritski MD); Center for
sputum culture had converted to negative by week 8. Analysis was by modifi ed intention to treat (ITT); patients whose Tuberculosis Research, Johns

Hopkins University School of
baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded Medicine, Baltimore, MD, USA
from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered
(A Efron MSN,
with, number NCT00082173.
Prof W R Bishai MD,
Prof R E Chaisson MD); and
Johns Hopkins Bloomberg

Findings 74 patients assigned to the moxifl oxacin group and 72 in the ethambutol group were included in the School of Public Health,
modifi ed ITT population. 125 patients had 8-week data (moxifl oxacin n=64, ethambutol n=61); the main reason for Baltimore, MD, USA
absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of
(M Ram PhD,
74 patients in the moxifl oxacin group compared with 45 (63%) of 72 in the ethambutol group (diff erence 17·2%,
95% CI 2·8–31·7; p=0·03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was
Correspondence to:
judged related to study drug (grade 3 cutaneous reaction in the ethambutol group).
for TB Research, 1550 Orleans Street, 1M.08 Baltimore, Interpretation Moxifl oxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to MD 21231, USA
[email protected]
assess whether moxifl oxacin can be used to shorten the duration of tuberculosis treatment are justifi ed.
Funding US Food and Drug Administration Offi
ce of Orphan Product Development, with additional support from the
US National Institutes of Health.
additive to isoniazid.6,7 On the basis of these studies, we The development of new drug regimens for tuberculosis designed a phase II clinical trial to test the hypothesis is an urgent global health priority.1 Although so-called that the substitution of ethambutol, an agent used short-course treatment can eff primarily to prevent the emergence of drug resistance, susceptible tuberculosis in 6 months, a large proportion with moxifl oxacin would signifi cantly increase the of patients in whom tuberculosis is diagnosed do not proportion of patients with negative sputum cultures complete a course of treatment.2 New drugs that shorten after 8 weeks of treatment. 8-week sputum conversion the duration of tuberculosis treatment would has proved a useful surrogate marker of the sterilising substantially reduce the likelihood of disease recurrence activity of tuberculosis regimens,8 and a substantial and death caused by inadequate therapy. Additionally, improvement in this endpoint after moxifl oxacin since every year there are 500 000 reported cases of treatment would support progression to a phase III trial tuberculosis caused by strains of Mycobacterium to assess whether a regimen including this drug could tuberculosis that are resistant to the key fi rst-line drugs shorten the duration of tuberculosis treatment.
isoniazid and rifampicin, agents that are active in multidrug-resistant tuberculosis are also needed.3 Moxifl oxacin is a fl uoroquinolone that has potent Patients
in-vitro activity against M tuberculosis.4,5 Early studies of We undertook a single-centre, randomised, double-blind, moxifl oxacin in murine models of tuberculosis showed double-dummy trial of moxifl oxacin versus ethambutol that the drug had good bactericidal activity that was in patients with sputum smear-positive tuberculosis Vol 373 April 4, 2009
Ethics Committee of the Ministry of Health (CONEP), Brasilia, and the Agencia Nacional de Vigilancia Sanitaria (ANVISA), Brazil.
Patients were stratifi ed by HIV serostatus and assigned by permuted block randomisation with blocks of four to receive treatment with either moxifl oxacin 400 mg with an ethambutol placebo or ethambutol 15–20 mg/kg plus moxifl oxacin placebo (control). Treatment allocation was concealed and allocation slips sealed in opaque envelopes that were opened after enrolment. The study statistician, who generated the randomisation sequence, had no involvement in the conduct of the study. The study was designed to ensure that all patients received an eff ective regimen for tuberculosis irrespective of the contribution of the two experimental agents; therefore, all patients received isoniazid 300 mg, rifampicin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), and pyrazinamide 20–25 mg/kg by directly observed treatment. Patients, study clinicians, and study staff were unaware of the treatment allocation, with the exception of the pharmacist who dispensed medication packets. All treatment was Figure 1: Trial profi le
given by direct supervision either in the hospital clinic or in the community by study personnel, 5 days per week. with no previous history of treatment in Hospital At the end of 8 weeks, all patients were placed on Clementino Fraga Filho, Rio de Janeiro, Brazil. Patients open-label treatment with isoniazid and rifampicin two aged 18 years or older were eligible for enrolment if they times per week to complete another 4 months of had clinical signs and symptoms of pulmonary treatment. Moxifl oxacin and matching placebo were tuberculosis, including an abnormal chest radiograph provided by Bayer Healthcare (West Haven, CT, USA) and at least one sputum smear with acid-fast bacilli and ethambutol, ethambutol placebo, isoniazid, rifampi-visible by Ziehl-Neelsen staining. Potential participants cin, and pyrazinamide were provided by Farman guinhos underwent baseline screening that included blood cell (Rio de Janeiro, Brazil). All study agents were produced counts, liver-function testing, kidney-function testing, under good manufacturing processes.
HIV serology, chest radiography, and culture and drug Patients visited the clinic once a week to assess clinical susceptibility testing for mycobacteria. Exclusion criteria status and to monitor for adverse reactions. Amino trans- were: haemoglobin concentration less than 70 g/L; ferase concentration, serum creatinine con aspartate aminotransferase or alanine aminotransferase and complete blood counts were measured every month, concentration more than three times the upper limit of and an electrocardiogram was obtained at weeks 2, 4, 6, normal; serum creatinine concentration more than and 8. A sputum specimen (spontaneous or induced) twice the upper limit of normal; an electrocardiogram was obtained every week for smear and culture. Sputum with a QTc interval more than 450 ms; pregnancy or specimens were digested and decontaminated by the breastfeeding; silico losis; a history of severe N-acetyl-L-cysteine-sodium hydroxide method.9,10 Pellets adverse reactions to fl uoroquinolone drugs or any other were resuspended in a fi nal volume of 2 mL and used study agent; and seropositivity for HIV with a CD4-cell immediately for inoculation of Löwenstein-Jensen count less than 200 cells per μL, since this fi nding would culture medium. Löwenstein-Jensen slants were be an indication for antiretroviral therapy, which could prepared from a commercial powder medium base be aff ected by interactions with antituberculosis drugs. (BD, Sparks, MD, USA), according to the manufacturer’s Randomised patients were excluded if their baseline instructions. 200 μL of each decontaminated respiratory culture did not grow M tuberculosis or grew a strain of specimen was inoculated onto each of two slants. M tuberculosis that was resistant to isoniazid, rifampicin, Slants were incubated at 37°C in ambient carbon dioxide and examined visually for growth twice a week Written informed consent was obtained from study for 8 weeks by laboratory personnel who were not participants before enrolment. Ethical review of the involved in the study and blinded to treatment status. protocol was obtained from the Johns Hopkins Medicine Growth on slants was quantifi ed by number of visible Institutional Review Board and the Ethics Committee of colonies, and then examined by acid-fast staining to the Federal University of Rio de Janeiro, the National confi rm the presence of mycobacteria; isolates were Vol 373 April 4, 2009
speciated by use of standard biochemical tests.10 Drug Moxifl oxacin (n=74)
Ethambutol (n=72)
susceptibility testing of all baseline cultures growing M tuberculosis was done by the proportions method.10 The primary endpoint of the study was the proportion of patients with negative sputum cultures after 8 weeks of treatment. Patients were followed up for at least 12 months after completion of their 6-month course of Duration of treatment before enrolment (days) Statistical analysis
We assumed that the conversion rate in the control group (ethambutol) would be 65%,8 and that moxifl oxacin would lead to an increase of 20% to a rate of 85%. To achieve a power of 0·8 with an alpha of 0·05, we needed 70 patients with 8-week data in each group of the trial. We aimed to enrol 85 patients per group to allow for exclusions based on negative initial culture, growth of non-tuberculous mycobacteria, or baseline drug resistance. The primary endpoint of the trial, culture conversion, was assessed by modifi ed intention-to-treat (ITT) analysis; patients whose baseline cultures were negative, contaminated, or contained drug-resistant M tuberculosis were excluded and all missing 8-week results were deemed treatment failures. We also analysed all patients with available 8-week cultures. p values were calculated by χ² test. Multivariate logistic regression was done with treatment allocation and selected baseline characteristics as covariates and culture conversion as the dependent variable. Time to conversion of sputum cultures to negative was estimated by the Kaplan-Meier method and the diff erence in median times compared by the log-rank test. All analyses were done with SAS version 9. This study is registered with, Role of the funding source
The funding agencies were not involved in the design,
conduct, or analysis of the study. The Investigational and made suggestions about the study design before initiation of the trial, but this was unrelated to any funding decisions. The decision to publish was made solely by the authors and the funding agencies did not Table 1: Baseline characteristics of study participants
review or approve the manuscript. Bayer Healthcare donated moxifl oxacin and matching placebo for the Baseline characteristics of the patients are shown in trial, but had no input into the study design, execution, table 1. A higher proportion of patients assigned to or analysis. The corresponding author had full access to moxifl oxacin had cavitation on chest radiograph than those assigned to ethambutol. The mean baseline weight was about 4 kg lower in the moxifl oxacin group From October, 2004, up to March, 2007, 197 patients 59 (80%) of 74 patients in the moxifl oxacin group and were screened for participation in the trial. Figure 1 45 (63%) of 72 in the ethambutol group had negative shows the trial profi le. 74 patients assigned to the sputum cultures at week 8 (diff erence 17·2%, 95% CI moxifl oxacin group and 72 assigned to the ethambutol 2·8–31·7; p=0·03). Of patients with sputum culture data group were assessed for the primary outcome. In the available at week 8, 59 (92%) of 64 had negative cultures modifi ed ITT analysis, all missing data were deemed in the moxifl oxacin group compared with 45 (74%) of treatment failures.
61 controls (diff erence 18·4%, 5·6–31·3; p=0·006). Vol 373 April 4, 2009
shown in table 2. Treatment with moxifl oxacin was associated with an increase in the odds of being culture negative at week 8 in the multivariate analysis (p=0·0009). Age was associated with culture conversion in the univariate analysis; patients with positive cultures were a mean of 2·5 years older than those who had conversion to negative culture, but this association was not signifi cant in the multivariate analysis. Weight, sex, and cavitation on chest radiograph were not signifi cantly associated with the likelihood of conversion. Patients who had positive sputum cultures at 8 weeks were more likely than those with negative cultures to have had baseline sputum smears with more than ten bacilli per Adverse events did not diff er by treatment group. There were 16 serious adverse events (eight in each group) in 12 patients (table 3); one grade 3 cutaneous reaction in the ethambutol group was judged to be related to study drugs by the treating physicians who were not aware of treatment assignment. All other serious adverse events were judged not related to study Figure 2: Proportion of patients with negative sputum cultures during 8 weeks of treatment
Data are for patients with 8-week culture data available at each timepoint.
drugs. Eight patients died during the study, including one in each group still receiving study phase treatment. Patients assigned to moxifl oxacin became culture No death was attributed to study treatment. Only fi ve negative more rapidly than those assigned to ethambutol. patients discontinued treatment because of toxic eff ects; After only 1 week, nine (13%) of 69 patients in the two patients in the moxifl oxacin group stopped because moxifl oxacin group had negative sputum cultures of grade 2 nausea and vomiting and one because of compared with two (3%) of 68 in the ethambutol group grade 2 paraesthesias and ataxia. Two patients in the (p=0·03). At every week after enrolment, patients ethambutol group stopped because of grade 2 rash and assigned to moxifl oxacin had a higher rate of culture pruritis and one because of grade 3 peripheral conversion than those assigned to ethambutol, and this neuropathy. No clinically or statistically signifi cant diff erence was signifi cant at all timepoints apart from changes in the QTc interval were recorded in patients in weeks 6 and 7 (fi gure 2). The median time to consistently negative cultures was 35·0 days (IQR 22·0–55·0) for Seven patients (5%) had recurrence of tuberculosis patients in the experimental group compared with confi rmed by positive culture and compatible clinical 48·5 days (41·0–56·0) for controls (log rank p=0·005).
symptoms: three patients in the moxifl oxacin group (at Univariate and multivariate logistic regression analysis 11, 16, and 27 months after completing treatment) and with the modifi ed ITT population or with those patients four in the ethambutol group (at 6, 7, 22, and 32 months with sputum culture data available at week 8 (as treated) after completion). Six of seven isolates were tested for showed similar results; the modifi ed ITT analysis is drug resistance, and all remained susceptible to isoniazid Univariate analysis
Multivariate analysis
Acid-fast bacilli per high-power fi eld on smear OR=odds ratio. *Data are mean (95% CI) or number (%). †Moxifl oxacin versus ethambutol. Table 2: Univariate and multivariate logistic regression analysis for culture conversion at week 8 in the modifi ed intention-to-treat population Vol 373 April 4, 2009
and rifampicin. DNA fi ngerprinting data on these Days from
Primary diagnosis
isolates to distinguish relapse from re-infection are not enrolment to event
In this phase II clinical trial, we found that compared with ethambutol, moxifl oxacin increased the proportion of sputum cultures that converted to negative in patients with pulmonary tuberculosis. More patients in the moxifl oxacin group were culture negative after 1 week of treatment than in the ethambutol group, and this intensive-phase treatment. Compared with the control Moxifl oxacin
group, patients assigned to moxifl oxacin had an absolute diff erence in culture conversion after 8 weeks of just The addition of rifampicin to tuberculosis regimens in the 1970s increased culture conversion rates at 2 months by 15–20% and allowed the duration of treatment to be reduced from 18 months to 6–9 months.11,12 In subsequent years, the addition of pyrazinamide to regimens containing isoniazid, rifampicin, and ethambutol or NA=not applicable. All adverse events were judged as not related to study drugs, apart from the event in patient 1, streptomycin increased the 8-week sputum conversion which was judged as probably related to study drugs.
rate by 13% and allowed treatment duration to be shortened from 9 months to 6 months.13 Our data suggest Table 3: Serious adverse events
that the improvement in sterilisation provided by moxifl oxacin could shorten tuberculosis treatment by The OFLOTUB study, undertaken at several sites in one or several months, on the basis of reductions in South Africa, found that patients treated with moxifl oxacin treatment duration achieved by similar improvements in or gatifl oxacin had higher culture conversion rates on 2-month culture conversion with pyrazinamide.13 solid media after 8 weeks than patients treated with Additionally, in studies published since this trial was ethambutol, whereas conversion rates for ofl oxacin initiated, moxifl oxacin has shortened treatment to 3 or treatment did not diff er from those for ethambutol.17 4 months in murine models of tuberculosis.14,15 Modelled data from quantitative cultures also suggested Two other trials done at the same time as this study that moxifl have shown potency of moxifl oxacin. The Tuberculosis conversion, although solid media data were not reported Trials Consortium Study 27 compared moxifl oxacin with for earlier timepoints.
ethambutol and found that culture conversion occurred In multivariate analysis, assignment to moxifl oxacin more rapidly in patients treated with moxifl oxacin; was associated with culture conversion. Age was however, the proportions of patients with negative associated with culture conversion in the univariate cultures were similar in both trial groups after 8 weeks.16 analysis only. Older age has been associated with poorer Study 27 was a multicentre trial and had a factorial treatment responses in several trials of tuberculosis design in which half of all patients were treated with a treatment.16,18 More patients assigned to moxifl oxacin thrice-weekly regimen and the other half with daily had cavities on chest radiograph at baseline, but this treatment. Additionally, the culture methods used were feature was not associated with lower effi not standardised in the participating laboratories, and contrast, several studies have reported lower culture more sensitive liquid culture media were used. We used conversion rates in patients with cavitary lesions on the well-validated Löwenstein-Jensen culture method in chest radiograph, although results from another large our study, and all cultures were done in one laboratory clinical trial did not support these fi ndings.16,18–20 If the with a standard protocol. Although a single-centre study presence of cavities is truly associated with slower time cient and ensures standardisation of to culture conversion, the results of this study might laboratory methods in a phase II trial, the results from underestimate the potency of moxifl oxacin. Notably, one population might not be generalisable to all baseline sputum-smear grade was signifi cantly populations. However, our study was done in a setting associated with culture conversion, and heavy smear with high tuberculosis burden, and previous studies of positivity (more than ten organisms per high-power tuberculosis treatment in similar settings have proved to fi eld) was equally distributed in the two study groups. be broadly relevant to the treatment of patients Both cavitation on radiograph and sputum-smear worldwide.11–13 positivity are semiquantitative measures that are subject Vol 373 April 4, 2009
to observer bias and inter-observer variability. The of isoniazid with moxifl oxacin shortens tuberculosis number of patients with HIV infection, which was treatment more than does replacement of ethambutol,14 found to be associated with poorer outcomes in the but human studies have not yet supported this fi nding.26 Tuberculosis Trials Consortium study,16 was too small The results of our study support the undertaking of for meaningful analysis in this study.
clinical trials to assess whether shorter courses of moxi- Moxifl oxacin was well tolerated and not associated fl oxacin-containing regimens can cure tuberculosis as with increased occurrence of adverse reactions or clinical well as or better than the current 6-month regimen. complications compared with ethambutol, a drug Such trials are under way and their results are eagerly
generally considered to be very safe. In particular, we awaited.
found no change in the QTc interval on serial Contributors
electrocardiograms taken during the trial (data not WRB, ALK, and REC designed the study. MBC, AE, CL, GRMDS, NPG,
shown). QTc prolongation is a reported toxic eff ect of MCC, ALK, and REC participated in the implementation of the trial.
other fl uoroquinolone drugs, but has not been noted MBC, AE, CL, GRMDS, and ALK participated in administration and
MBC and AE in regulatory support. AE, CL, MR, MAC, and REC with moxifl oxacin during short durations of treatment. participated in data management. CL, NPG, and MCC participated in Because tuberculosis treatment lasts longer than data collection. AE, MR, MAC, and REC contributed to data analysis. treatment of community-acquired pneumonia (the main REC wrote the report. All authors saw and approved the fi nal report.
clinical use for moxifl oxacin), the fi nding of few adverse Confl ict of interest statement
events is reassuring and suggests that moxifl oxacin We declare that we have no confl ict of interest.
could be safely used for longer periods; however, this Acknowledgments
suggestion needs to be confi rmed in additional studies The study was funded by the Offi ce of Orphan Product Development,
US Food and Drug Administration (grant number R01FD002135). that are large enough to detect small but important rates Additional support for training was provided by the Fogarty International Center of the US National Institutes of Health (grant The results of our trial have substantial implications TW006885 and NIH grant 01607). Moxifl oxacin and matching placebo for future trials. First, the improved culture conversion were supplied by Bayer Healthcare, which had no role in the design, conduct, or analysis of the study. A career development grant helped to rates found after 8 weeks in the experimental group support REC’s participation. We thank the members of our data safety suggest that moxifl oxacin, in combination with other and monitoring board, Reynaldo Dietze (Chair), Leda Jamal, and fi rst-line antituberculosis drugs, could shorten the time Ronir Raggio Luiz. We also thank Jacques Grosset, Eric Nuermberger, needed to cure tuberculosis by several months. Because Andrew Vernon, Fernanda Mello, Susan Dorman, and Richard O’Brien for encouragement and advice; Anna Grazia Marsico and treatment default is directly related to the duration of Gisele Betzler de Oliveira Vieira for managing laboratory specimens; and treatment, a reduction in the duration of tuberculosis Bonnie S King for assistance with data management. Finally, we thank therapy would substantially improve outcomes. all the patients who volunteered to participate in this trial.
Additionally, shorter regimens for tuberculosis treatment References
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