Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase ii trial
Articles Moxiﬂ oxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial 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 ChaissonSummary 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 treatment. 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 ClinicalTrials.gov, 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. Introduction
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-vitroactivity 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
www.thelancet.comVol 373 April 4, 2009 Articles
Ethics Committee of the Ministry of Health (CONEP),
Brasilia, and the Agencia Nacional de Vigilancia Sanitaria (ANVISA), Brazil. Procedures
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
www.thelancet.comVol 373 April 4, 2009 Articles
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)
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 ClinicalTrials.gov,
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).
www.thelancet.comVol 373 April 4, 2009 Articles
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
www.thelancet.comVol 373 April 4, 2009 Articles
and rifampicin. DNA ﬁ ngerprinting data on these
Days from Primary diagnosis
isolates to distinguish relapse from re-infection are not
enrolment to event Ethambutol Discussion
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
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
www.thelancet.comVol 373 April 4, 2009 Articles
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
would reduce workloads for overburdened tuberculosis 1
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