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The n e w e ng l a n d j o u r na l of m e dic i n e

original article

Multidrug-Resistant Tuberculosis
and Culture Conversion with Bedaquiline
Andreas H. Diacon, M.D., Ph.D., Alexander Pym, M.D., Ph.D.,
Martin P. Grobusch, M.D., Ph.D., Jorge M. de los Rios, M.D.,
Eduardo Gotuzzo, M.D., Irina Vasilyeva, M.D., Ph.D., Vaira Leimane, M.D.,
Koen Andries, D.V.M., Ph.D., Nyasha Bakare, M.D., M.P.H., Tine De Marez, Ph.D.,
Myriam Haxaire-Theeuwes, D.D.S., Nacer Lounis, Ph.D., Paul Meyvisch, M.Sc.,
Els De Paepe, M.Sc., Rolf P.G. van Heeswijk, Pharm.D., Ph.D.,
and Brian Dannemann, M.D., for the TMC207-C208 Study Group*

A bs t r ac t

Background
Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP The authors’ affiliations are provided in
synthase, has been associated with accelerated sputum-culture conversion in pa- the Appendix. Address reprint requests
to Dr. Dannemann at Janssen Research
tients with multidrug-resistant tuberculosis, when added to a preferred background and Development, 1125 Trenton Har-
regimen for 8 weeks. bourton Rd., Titusville, NJ 08560, or at
bdannema@its.jnj.com.
Methods * A complete list of investigators in the
In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, TMC207-C208 Study Group is provided
smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of beda- in the Supplementary Appendix, avail-
able at NEJM.org.
quiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks,
or placebo, both in combination with a preferred background regimen. The pri- N Engl J Med 2014;371:723-32.
DOI: 10.1056/NEJMoa1313865
mary efficacy end point was the time to sputum-culture conversion in liquid broth. Copyright © 2014 Massachusetts Medical Society.
Patients were followed for 120 weeks from baseline.

Results
Bedaquiline reduced the median time to culture conversion, as compared with pla-
cebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95%
confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased
the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks
(62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome defini-
tions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the
bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence
of adverse events was similar in the two groups. There were 10 deaths in the beda-
quiline group and 2 in the placebo group, with no causal pattern evident.

Conclusions
The addition of bedaquiline to a preferred background regimen for 24 weeks re-
sulted in faster culture conversion and significantly more culture conversions at 120
weeks, as compared with placebo. There were more deaths in the bedaquiline group
than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208
ClinicalTrials.gov number, NCT00449644.)

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T
he World Health Organization positive, pulmonary, multidrug-resistant tubercu-
(WHO) estimates that the global incidence losis on the basis of proportion-method results,11,12
of tuberculosis in 2012 was 8.6 million positive rapid-screening tests (FASTPlaque-­
cases, with 1.3 million deaths, predominantly Response assay [Biotec] and GenoType MTBDR
occurring in developing countries.1 Although there plus line-probe tests [Hain Lifescience]). Patients
has been some progress in reducing tuberculosis who had received previous treatment for multi-
cases and deaths in the past 20 years, multidrug- drug-resistant tuberculosis were excluded. Addi-
resistant tuberculosis (i.e., with resistance to at tional exclusion criteria were a positive test for the
least isoniazid and rifampin) remains a major human immunodeficiency virus (HIV) with a CD4+
challenge. The 2012 global incidence of multi- count of less than 300 cells per cubic millimeter,
drug-resistant tuberculosis was 450,000 cases.1 complicated or severe extrapulmonary or neuro-
Therapy for multidrug-resistant tuberculosis is a logic manifestations of tuberculosis, severe cardi-
long, arduous regimen of antiquated drugs that ac arrhythmia requiring medication, a corrected
are mainly bacteriostatic and have an unfavorable QT interval with the use of Fridericia’s formula
side-effect profile.2 The WHO reports that major (QTcF)13 of more than 450 msec, a history of risk
efforts are needed to improve the current average factors for torsades de pointes, concomitant seri-
rate of 48% for successful treatment of patients ous illness, alcohol or drug abuse, pregnancy or
with multidrug-resistant tuberculosis.1 By 2012, breast-feeding, and previous treatment with beda-
extensively drug-resistant tuberculosis (i.e., with quiline. According to the protocol, moxifloxacin,
additional resistance to injectable second-line gatifloxacin, and systemic use of cytochrome
drugs and fluoroquinolones) was reported in 92 P-450 3A4 inhibitors or inducers were prohibited
countries worldwide, with the presence of exten- during and for 1 month after completion of the
sively drug-resistant isolates reported in 9.6% of study treatment.
patients with multidrug-resistant tuberculosis.1
Bedaquiline (Sirturo, TMC207), a diarylquino- Study Design
line that inhibits mycobacterial ATP synthase,3 is
In this randomized, double-blind, placebo-con-
the first antituberculosis drug with a new mecha-trolled study, patients were stratified according
nism of action to be approved for use in multi- to study site and radiographic assessment of lung
drug-resistant tuberculosis in 40 years.4 Beda- cavitation (≥2 cm bilaterally, ≥2 cm unilaterally,
quiline has shown bactericidal activity in vitro,or <2 cm). Trial sites were located in Brazil, India,
in murine models of tuberculosis,3,5-7 and in a Latvia, Peru, the Philippines, Russia, South Africa,
7-day proof-of-concept study involving patients and Thailand. Patients received either bedaqui-
with drug-sensitive tuberculosis.8 In stage 1 of an
line (400 mg once daily for 2 weeks, followed by
exploratory phase 2b randomized trial, called 200 mg three times a week for 22 weeks, admin-
TMC207-C208, involving patients with newly diag- istered as 100-mg tablets) or placebo, plus a pre-
nosed, smear-positive, multidrug-resistant tuber-ferred five-drug, second-line antituberculosis
culosis, 8 weeks of bedaquiline treatment had background regimen (Fig. 1). Patients were in-
better antibacterial activity than placebo when structed to take bedaquiline or placebo with wa-
added to a preferred five-drug, second-line back-ter after breakfast. National treatment-program
ground regimen.9,10 In stage 2 of the TMC207- regimens were respected, although the preferred
C208 study, a phase 2b study in which bedaqui- five-drug background regimen was ethionamide,
line was administered for 24 weeks to a larger pyrazinamide, ofloxacin, kanamycin, and cyclo-
number of patients, we evaluated the time to serine. Changes in the background regimen were
sputum-culture conversion, the rates of culture permitted on the basis of the results of drug-
conversion and drug resistance, pharmacokinetics,susceptibility testing, side effects, or unavailabil-
and safety over a 120-week period in patients re-ity of drugs on site.
ceiving a preferred five-drug background regimen. After the 24-week treatment period, there was
a 96-week period during which patients were
Me thods instructed to complete their background regi-
men (Fig. 1). Patients who prematurely discon-
Patients tinued the trial were followed for collection of
We recruited patients between the ages of 18 and survival data until trial completion unless they
65 years with newly diagnosed, sputum smear– withdrew consent.

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Tuberculosis Culture Conversion with Bedaquiline

Overall Treatment Phase Last Study Visit


120 Wk

Investigational Treatment Phase Postinvestigational Treatment Phase

24 Wk 96 Wk

Bedaquiline plus background regimen Background regimen only

24-Wk 120-Wk analysis


evaluation

24 Wk 96 Wk

Placebo plus background regimen Background regimen only

Figure 1. Study Design and Drug Regimens.


Patients with multidrug-resistant tuberculosis were assigned in a 1:1 ratio to receive either bedaquiline (400 mg
once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks) or placebo, plus a preferred five-drug,
second-line antituberculosis background regimen. The total treatment period was 18 to 24 months, during which
bedaquiline was administered for 6 months. The total trial duration was 120 weeks (30 months), which included an
anticipated 6-month period after the completion of treatment.

Each site obtained approval of the study pro- isolates. Isolates for which the MIC was increased
tocol from at least one (or more, if required by by a factor of 4 or more, as compared with the
local regulations) independent ethics committee baseline value, were considered to have decreased
or institutional review board. The trial was con- susceptibility to bedaquiline.
ducted in accordance with the principles of
Good Clinical Practice and the Declaration of Safety Assessments
Helsinki. All patients provided written informed Safety assessments included monitoring for ad-
consent before trial entry. Details regarding the verse events, clinical laboratory testing, and elec-
study design are provided in the protocol, avail- trocardiography at predefined intervals through-
able with the full text of this article at NEJM.org. out the study. Toxicity was graded on the basis of
the Division of Microbiology and Infectious Dis-
Microbiologic Assessments eases (DMID) adult toxicity tables.14
Triplicate spot sputum samples were collected at
every visit (except on the day of the first adminis- Study End Points
tration of the study drug) and at the time of with- The primary end point was the time to sputum-
drawal, for patients who did not complete the culture conversion, which was defined as two
study, for culture of Mycobacterium tuberculosis in consecutive negative liquid cultures from sputum
liquid medium (Mycobacteria Growth Indicator samples that were collected at least 25 days apart
Tube, Becton Dickinson). Drug-susceptibility test- and were not followed by confirmed positive cul-
ing was performed at a central laboratory (Insti- tures. The primary analysis was performed on
tute of Tropical Medicine, Antwerp, Belgium) at the basis of data at 24 weeks. Secondary efficacy
baseline and at 8, 24, and 72 weeks in all patients measurements were the rates of culture conver-
and in those with reversion to a positive culture sion after 24 weeks and after 120 weeks. We also
after initial culture conversion. The minimal in- performed 11 subgroup efficacy analyses of the
hibitory concentration (MIC) of bedaquiline on rate of culture conversion, including in patients
7H11 agar was defined as the lowest concentra- with M. tuberculosis isolates that were resistant
tion (measured in micrograms per milliliter) that only to isoniazid and rifampin and in those with
prevented the growth of 99% of M. tuberculosis isolates that also were resistant to any second-

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The n e w e ng l a n d j o u r na l of m e dic i n e

line injectable drug or any fluoroquinolone patients were considered to have had no response.
(which were categorized as having pre-extensive We used a Cox proportional-hazards model with
drug resistance) and in patients with isolates that adjustment for stratification variables to com-
were susceptible or resistant to pyrazinamide. pare the time to culture conversion in the two
(For details regarding all 11 subgroups, see the study groups.
Methods section in the Supplementary Appendix, For the 11 prespecified subgroup analyses, no
available at NEJM.org.) formal adjustments for multiple comparisons
were made. With this number of subgroups, there
Study Oversight is a probability of 43% that at least one test would
The study was funded by Janssen Pharmaceuti- be significant (P<0.05) on the basis of chance
cals. Medical-writing support (funded by Janssen) alone. A post hoc analysis was performed to as-
was provided by an employee of Gardiner- sess treatment outcomes on the basis of WHO
Caldwell Communications, who wrote the initial definitions for multidrug-resistant tuberculosis.15
draft of the manuscript and incorporated com-
ments from the authors. The data were collected R e sult s
by the investigators and analyzed by the sponsor.
All the authors made the decision to submit the Study Population
manuscript for publication and vouch for the Of 282 patients who were screened, 160 under-
accuracy and completeness of the data reported went randomization and received at least one
and the fidelity of the study to the protocol. dose of the assigned study drug (the intention-to-
treat population, comprising 79 patients in the
Statistical Analysis bedaquiline group and 81 in the placebo group).
We determined that enrollment of 75 patients in The modified intention-to-treat population con-
each study group would provide a power of 80% sisted of 132 patients (Fig. 2). In the intention-to-
to detect a difference of 22 percentage points in treat population, 60 patients (38%) discontinued
the 6-month rate of culture conversion between the trial prematurely, with no relevant differences
the placebo group (estimated at 50%) and the between the two study groups in the reasons for
bedaquiline group (estimated at 72%) at a two- discontinuation (Fig. 2, and Fig. S1 in the Supple-
sided significance level of 0.05. The safety analy- mentary Appendix). The most common reasons
sis was conducted in the intention-to-treat pop- for discontinuation were withdrawal of consent
ulation and included all patients who had and adverse events.
undergone randomization and received at least In the modified intention-to-treat population
one dose of the assigned study drug. Safety data (protocol-defined efficacy population), there were
are presented for the 120-week treatment period. more men (64%) than women, and more black
The efficacy analyses were performed in the patients (37%) than any other racial or ethnic
modified intention-to-treat population, which group (Table 1, and Table S3 in the Supplemen-
excluded patients who had no positive mycobac- tary Appendix). Baseline demographic and dis-
terial cultures from sputum samples obtained ease characteristics were similar in the two study
before administration of the first dose of the groups except that the proportion of patients
study drug or a positive culture up to week 8 in who had isolates with resistance to pyrazin-
cases in which baseline cultures were negative, amide and the proportion classified as having
those for whom susceptibility to rifampin and isolates with pre-extensive drug resistance were
isoniazid was shown or resistance could not be nonsignificantly larger in the bedaquiline group,
confirmed, those with extensively drug-resistant and the proportions of HIV-positive patients and
tuberculosis, and those who had not undergone patients with abnormally low albumin levels
assessment after baseline. were significantly larger in the placebo group
The primary end point was analyzed in the (Table 1). The median overall treatment phase
modified intention-to-treat population. In this was longer in the placebo group than in the
analysis, data for patients who discontinued treat- bedaquiline group (Table 2). A higher proportion
ment, died, or did not have sputum-culture con- of patients in the placebo group than in the
version before 24 weeks were censored at the last bedaquiline group (58% vs. 47%) had at least
assessment, regardless of the culture status at one new antituberculosis drug added to their
the time of study dropout or death, and these background regimen.

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Tuberculosis Culture Conversion with Bedaquiline

282 Patients were assessed for eligibility

122 Were ineligible


103 Did not fulfill all inclusion criteria
or met exclusion criteria
7 Withdrew consent
12 Had other reasons

Intention-to-Treat Group Modified Intention-to-Treat Group


160 Underwent randomization 132 Underwent randomization
and were treated and were treated

28 Were excluded from


modified intention-to-
treat group

79 Were assigned 81 Were assigned 66 Were assigned 66 Were assigned


to bedaquiline to placebo to bedaquiline to placebo

1 Crossed over to open-


label bedaquiline 1 Crossed over to open-
29 Discontinued study
label bedaquiline
9 Had adverse event
23 Discontinued study
6 Withdrew consent
31 Discontinued study 8 Had adverse event
5 Were lost to 24 Discontinued study
6 Had adverse event 5 Withdrew consent
follow-up 5 Had adverse event
7 Withdrew consent 5 Were lost to
3 Did not adhere to 7 Withdrew consent
3 Were lost to follow-up
study regimen 3 Were lost to
follow-up 2 Did not adhere to
3 Were pregnant follow-up
7 Did not adhere to study regimen
2 Were determined 7 Did not adhere to
study regimen 3 Were pregnant
to be ineligible study regimen
2 Were pregnant
1 Acquired extensive 2 Were pregnant
6 Were determined
drug resistance
to be ineligible

50 Completed study 49 Completed study 43 Completed study 41 Completed study

Figure 2. Enrollment and Outcomes.


The modified intention-to-treat population was a subgroup of the intention-to-treat population, with a total of 28 patients excluded:
9 patients (6 in the bedaquiline group and 3 in the placebo group) who had sputum-culture results that did not allow for primary efficacy
evaluation (either no evidence of culture positivity before the first dose of the study drug was administered or no results during the first
8 weeks after the first dose was administered), 7 patients (3 patients and 4 patients, respectively) who were infected with extensively
drug-resistant tuberculosis, 8 patients (4 in each group) who had drug-sensitive tuberculosis, and 4 patients (all in the placebo group)
for whom status with respect to multidrug-resistant tuberculosis could not be confirmed.

Antimycobacterial Activity with respect to pyrazinamide susceptibility, HIV


In the modified intention-to-treat population, status, and baseline albumin grade) was still sig-
the median time to sputum-culture conversion nificant and was similar to the estimate obtained
was faster in the bedaquiline group than in the from the unadjusted model. (Pre-extensive drug
placebo group (83 days vs. 125 days), for a hazard resistance was not included in the model because
ratio for conversion in the bedaquiline group of the between-group difference was small [7%].)
2.44 (95% confidence interval [CI], 1.57 to 3.80; More patients in the bedaquiline group than
P<0.001) (Fig. 3). The same analysis in the full in the placebo group had confirmed culture
intention-to-treat population had similar results conversion at both 24 and 120 weeks: 52 of 66
(Fig. S2 in the Supplementary Appendix). The patients (79%) and 38 of 66 patients (58%) in the
treatment difference in a model with adjustment two groups, respectively, at 24 weeks (P = 0.008)
for unequally distributed baseline factors (status and 41 of 66 patients (62%) and 29 of 66 patients

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Table 1. Demographic and Clinical Characteristics in the Modified Intention-to-Treat Population at Baseline.*

Bedaquiline Placebo All Patients


Characteristic (N = 66) (N = 66) (N = 132)
Demographic characteristics
Median age (range) — yr 32 (18–63) 34 (18–57) 34 (18–63)
Male sex — no. (%) 45 (68) 40 (61)   85 (64)
Black race — no. (%)† 24 (36) 25 (38)   49 (37)
Clinical characteristics
HIV positivity — no. (%) 5 (8) 14 (21)   19 (14)
Cavitary disease of ≥2 cm — no. (%) 54 (82) 56 (85) 110 (83)
Baseline albumin grade of 1 to 3 — no. (%)‡ 28 (42) 42 (64)   70 (53)
Drug resistance — no./total no. (%)§
Limited to isoniazid and rifampin 39/54 (72) 46/58 (79) 85/112 (76)
Pre-extensive drug resistance¶ 15/54 (28) 12/58 (21) 27/112 (24)
Fluoroquinolone resistance 6/54 (11) 4/58 (7) 10/112 (9)
Amikacin, kanamycin, or capreomycin resistance 9/54 (17) 8/58 (14) 17/112 (15)
Sensitivity to ≥3 drugs in the background regimen 40/53 (75) 44/55 (80) 84/108 (78)
Pyrazinamide resistance‖ 38/56 (68) 33/59 (56) 71/115 (62)
Background regimen — no. (%)
Aminoglycosides 64 (97) 63 (95) 127 (96)
Fluoroquinolones   66 (100) 65 (98) 131 (99)
Ethionamide or protionamide 65 (98) 64 (97) 129 (98)
Pyrazinamide 65 (98) 61 (92) 126 (95)
Ethambutol 46 (70) 46 (70)   92 (70)
Cycloserine or terizidone 25 (38) 26 (39)   51 (39)
Other agent** 4 (6) 6 (9) 10 (8)

* There were no significant differences between the two study groups except for the proportion of patients who were
HIV-positive (P = 0.04) and those who had a baseline albumin grade of 1 to 3 (P = 0.02). Fisher’s exact test was used
for the categorical measures, and an asymptotic Wilcoxon test for the continuous measures.
† Race was reported by the investigators.
‡ Albumin was graded according to the Division of Microbiology and Infectious Diseases criteria14 as follows: grade 1,
less than the lower limit of the normal range to 3 g per deciliter; grade 2, less than 3 g per deciliter to 2 g per decili-
ter; and grade 3, less than 2 g per deciliter.
§ For 12 patients in the bedaquiline group and 8 patients in the placebo group, no confirmation of isoniazid and ri-
fampin resistance was available from the central laboratory.
¶ Pre-extensively drug-resistant tuberculosis is defined as multidrug-resistant tuberculosis with resistance to either any
second-line injectable drug (amikacin, kanamycin, or capreomycin) or any fluoroquinolone.
‖ Some isolates did not grow for resistance testing.
** Other agents included aminosalicylic acid, capreomycin, amoxicillin plus clavulanic acid, and streptomycin.

(44%), respectively, at 120 weeks (P = 0.04) (Fig. 4). conversion or conversion status (Fig. S3 in the
At 120 weeks, of the 25 patients in the bedaqui- Supplementary Appendix).
line group who did not have a response, 8 did
not have culture conversion, 6 had subsequent Subgroup Analyses
reversion, and 11 discontinued the study after In subgroup analyses at 120 weeks, sputum-cul-
culture conversion. Of the 37 patients in the ture conversion occurred in more patients in the
placebo group who did not have a response, 15 bedaquiline group than in the placebo group
did not have culture conversion, 10 had subse- among those who had isolates with resistance
quent reversion, and 12 discontinued the study only to isoniazid and rifampin (27 of 39 patients
after culture conversion. In the bedaquiline [69%] and 20 of 46 patients [43%], respectively)
group, there was no relationship between the and among those who had isolates with pre-
area under the plasma concentration–time curve extensive drug resistance (9 of 15 patients [60%]
over a 24-hour period at week 2 and the time to and 5 of 12 patients [42%], respectively). In addi-

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Tuberculosis Culture Conversion with Bedaquiline

Table 2. Adverse Events during 120 Weeks in the Intention-to-Treat Population.*

Bedaquiline Placebo
Variable (N = 79) (N = 81)
Median duration of overall treatment phase (range) — wk 91.7 (2.0–120.0) 94.1 (2.0–137.3)
Adverse event — no. (%)
Any 78 (99) 79 (98)
Related to treatment 55 (70) 56 (69)
Grade 3 or 4† 34 (43) 29 (36)
Leading to discontinuation of treatment 4 (5) 5 (6)
Serious adverse events — no. (%)‡ 18 (23) 15 (19)
Adverse event occurring in ≥20% of patients — no. (%)
Nausea 32 (41) 30 (37)
Arthralgia 29 (37) 22 (27)
Vomiting 23 (29) 22 (27)
Headache 23 (29) 18 (22)
Hyperuricemia 20 (25) 27 (33)
Hemoptysis 16 (20) 14 (17)

* There were no significant differences between the two groups in any category as calculated by means of Fisher’s exact
test in a post hoc analysis.
† Events were graded according to the Division of Microbiology and Infectious Diseases criteria.14
‡ Two serious adverse events were considered by the investigator to be possibly related to a study drug, including 2 events
of acute pancreatitis in 1 patient in the bedaquiline group and spontaneous abortion in 1 patient in the placebo group.

tion, there were more culture conversions in the (extensive drug resistance, observed in 1 patient);
bedaquiline group than in the placebo group the 1 patient in the bedaquiline group did not
among patients with isolates that were suscepti- have either pre-extensive or extensive drug resis-
ble to pyrazinamide (13 of 18 patients [72%] and tance. Though the number of paired isolates (10)
14 of 26 patients [54%], respectively) and among is limited, the isolate from 1 patient in the beda-
those with isolates that were resistant to pyrazin- quiline group who had pre-extensive drug resis-
amide (23 of 38 patients [61%] and 11 of 33 pa- tance at baseline had an increase by a factor of
tients [33%], respectively). 4 in the bedaquiline MIC at the end of the study,
On the basis of the WHO definition of cure,15 as compared with baseline. No mutations were
in the modified intention-to-treat population at observed in the ATP synthase operon.
120 weeks, more patients in the bedaquiline
group than in the placebo group were cured (38 Safety
of 66 patients [58%] and 21 of 66 patients [32%], During 120 weeks in the intention-to-treat popu-
respectively; P = 0.003) (Fig. 4). lation, there were similar rates of adverse events,
treatment-related adverse events, and adverse
Drug Resistance events leading to study discontinuation in the
New resistance to at least one antituberculosis two study groups (Table 2). The most frequent
drug developed in isolates from 2 patients in the adverse events were nausea, arthralgia, and vom-
bedaquiline group and in 16 patients in the pla- iting. The severity of most adverse events was
cebo group; 1 of the 2 patients in the bedaquiline grade 1 or 2.14
group (50%) and 9 of the 16 in the placebo group Overall, 10 of 79 patients (13%) in the beda-
(56%) did not have a response to treatment. Of quiline group and 2 of 81 patients (2%) in the
the latter patients, 6 of the 9 patients (67%) in the placebo group died (P = 0.02). (Detailed case re-
placebo group were found to have isolates with ports on all deaths are provided in Table S5 in
resistance either to injectable second-line drugs the Supplementary Appendix.) In the bedaqui-
or fluoroquinolones (pre-extensive drug resis- line group, deaths occurred during study-drug
tance, observed in 5 patients) or to both inject- treatment in 1 patient and after study week 24 in
able second-line drugs and fluoroquinolones 9 patients (median time after receipt of the last

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QTcF prolongation of more than 500 msec (sin-


Time to Culture Conversion
gle time point), as compared with no patients in
100
the placebo group. No direct relationship was
90
seen between bedaquiline or the bedaquiline
80
metabolite (M2) plasma level and corresponding
Positive Culture (%)

70
60
Placebo plus absolute QTcF values or changes in the QTcF.
background
50 regimen
There were no reports of clinically significant
40 dysrhythmia during the trial.
30 Bedaquiline plus
background
20 regimen Discussion
10
0 In this study, we found that 24 weeks of treat-
0 4 8 12 16 20 24
ment with bedaquiline in combination with a
Weeks
five-drug, second-line background regimen (con-
No. at Risk sistent with WHO recommendations for the
Bedaquiline 58 37 25 12 7 3
Placebo 61 53 40 30 22 5 treatment of multidrug-resistant tuberculosis at
that time15) significantly shortened the time to
Figure 3. Time to Sputum-Culture Conversion in the Modified Intention-to- culture conversion and increased the rate of cul-
Treat Population.
ture conversion at 24 weeks, as compared with
Shown is the proportion of patients in each study group who had positive
results on Mycobacterium tuberculosis culture during the 24-week investiga-
placebo plus the background regimen. These re-
tional treatment phase of the study. Patients who withdrew from the study, sults confirm the faster culture conversion re-
who died, or who did not have sputum-culture conversion by week 24 were ported in a previous phase 2b trial of 8 weeks of
considered to have had treatment failure in the primary analysis, regardless bedaquiline.9 The treatment benefit of adding
of their culture status at the time of dropout or death. For these patients, bedaquiline to the background regimen that was
data were censored at their last assessment, so the proportion of patients
who had culture conversion cannot be derived from the data in the figure.
seen at 24 weeks in terms of the proportion of
Analysis based on a Cox proportional-hazards model with adjustment for patients with a response was durable and of sim-
study center and degree of radiographic lung cavitation showed significant- ilar magnitude at the end of the 120-week trial.
ly faster conversion in the bedaquiline group than in the placebo group at Evaluation of the study outcome on the basis
24 weeks (P<0.001). The number of patients at risk at each time point is of the modified WHO definitions for multidrug-
the number of patients who did not have culture conversion and who were
still participating in the study.
resistant tuberculosis supported our results at 24
weeks and 120 weeks. On the basis of the WHO
definition of cure, nearly twice as many patients
dose of study drug, 49.1 weeks; range 12.3 to in the bedaquiline group as in the placebo group
130.1), with 1 of these deaths occurring after were cured, a finding that addresses the unmet
study week 120. In 6 patients, the deaths were need for improved long-term treatment outcomes
attributed to tuberculosis (in 5 patients in the in patients with multidrug-resistant tuberculo-
bedaquiline group and 1 in the placebo group). sis. The treatment-success rate among patients
There was no difference in the duration of fol- in the placebo group in our trial was lower than
low-up between the two study groups. No deaths that reported in a recent meta-analysis (32% vs.
were considered to be related to the study drug 54%).16 This finding might be explained by the
by an investigator who was unaware of the higher proportions of patients in our study, as
group assignments, nor was there any associa- compared with the meta-analysis, who had iso-
tion between the deaths and bedaquiline plasma lates that were positive for acid-fast bacilli (100%
concentrations or a QTcF interval of 500 msec or vs. 66%), cavitary disease (83% vs. 52%), and
more during the trial. pyrazinamide resistance (62% vs. 26%). In addi-
At study week 24, the mean change from tion, we collected triplicate sputum samples and
baseline in the QTcF was an increase of 15.4 msec used liquid culture, which is more sensitive than
in the bedaquiline group and an increase of the solid medium used in the studies cited in the
3.3 msec in the placebo group (P<0.001). After meta-analysis.17
bedaquiline treatment ended, the QTcF gradu- The inclusion of bedaquiline in the regimen
ally decreased, and the mean value was similar was associated with a reduced risk of pre-exten-
to that in the placebo group by study week 60. sive drug resistance or extensive drug resistance
Only one patient in the bedaquiline group had a and a reduced risk of additional resistance to

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Tuberculosis Culture Conversion with Bedaquiline

other background drugs. Culture conversion was


A Protocol-Defined Analysis
higher in the bedaquiline group than in the
100
placebo group, despite a greater proportion of 12 23 No conversion
90 Reversion to positive test
isolates with pyrazinamide resistance and pre-­ 80
9

Treatment Outcome (%)


Withdrawal after
extensive drug resistance at baseline in the 70 17
15 conversion
bedaquiline group. Both patients with multi- 60 Conversion
62 18
drug-resistant isolates and those with pre-exten- 50
sive drug-resistant isolates had more frequent 40 44
and more rapid culture conversion with bedaqui- 30
line than with placebo. 20
As in the 8-week study of bedaquiline,9,10 the 10
most frequent adverse events that we observed 0
Bedaquiline plus Placebo plus
were similar to those commonly seen in patients Background Background
with tuberculosis who are receiving second-line Regimen (N=66) Regimen (N=66)
treatment for multidrug-resistant tuberculosis.18,19
Adverse events leading to the discontinuation of B Analysis Based on WHO Definitions
100 3
bedaquiline were uncommon. Increased hepatic 12 Death
90 35
aminotransferase levels, which had been ob- 23
Withdrawal
80
Treatment Outcome (%)
served in preclinical studies, were seen more Treatment failure
70 Cure
frequently in the bedaquiline group than in the 8
60
placebo group (Table S4 in the Supplementary 50 58 30
Appendix), but only three patients (two of whom 40
had hepatitis B virus infection) discontinued the 30
32
assigned study drug. The use of bedaquiline was 20
associated with moderate prolongation in the 10
QT interval (mean, 15.4 msec at study week 24). 0
Bedaquiline plus Placebo plus
There is a risk of increased QT-interval prolonga- Background Background
tion for bedaquiline in combination with other Regimen (N=66) Regimen (N=66)
QT-interval–prolonging drugs, such as fluoro-
quinolones and 4-aminoquinoline antimalarial Figure 4. Study Outcomes at 120 Weeks According to the Protocol-Defined
drugs.4 Analysis and an Analysis Based on World Health Organization Definitions.
The reason for higher mortality in the beda- Shown are study outcomes in the modified intention-to-treat population
on the basis of the protocol-defined analysis method (Panel A) and World
quiline group than in the placebo group is un- Health Organization (WHO) definitions15 (Panel B) with respect to study
clear. All 6 patients whose deaths were attrib- data at 120 weeks. In the two analyses, patients in the bedaquiline group
uted to tuberculosis either did not have culture had higher rates of sputum-culture conversion than did those in the placebo
conversion or had conversion with subsequent group on the basis of a logistic model with treatment as the only covariate
reversion during the trial and had one or more (P = 0.04 for the study analysis and P = 0.003 for the WHO definitions). Per-
centages may not total 100 because of rounding.
risk factors for a poor outcome. In addition,
mortality in the placebo group was surprisingly
low, as compared with mortality in a meta- small size. Only 79 patients received bedaquiline
analysis involving 9153 patients with multidrug- in this study, which was initiated at a time when
resistant tuberculosis (15%)16 and in an open- information about the safety of bedaquiline was
label, phase 2 trial of bedaquiline involving 233 limited. Our conservative selection criteria lim-
patients with newly diagnosed or previously ited the inclusion of patients with HIV coinfec-
treated multidrug-resistant tuberculosis (7%).20 tion who were receiving antiretroviral therapy. A
The development of bedaquiline for indications planned phase 3 study will enroll a larger num-
for which a reasonably efficacious and safe alter- ber of patients, including HIV-positive patients
native exists (e.g., treatment of drug-sensitive receiving antiretroviral therapy. The enrollment
tuberculosis or preventive treatment) should be in our study was calculated to show significant
approached with caution until more data have differences in the surrogate end point of spu-
been collected to clarify the implication of the tum-culture conversion at 24 weeks rather than
excess deaths. clinical cure. However, the significant difference
One limitation of our trial is its relatively in cure rates was maintained at 120 weeks,

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Tuberculosis Culture Conversion with Bedaquiline

which provides evidence of the potential useful- 120-week period, with more negative sputum
ness of this surrogate end point. The study did cultures, fewer culture reversions, and a reduced
not assess whether the use of bedaquiline can risk of evolution to a more resistant subtype.
simplify or shorten treatment. Supported by Janssen Pharmaceuticals.
In conclusion, the addition of bedaquiline to Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
a five-drug regimen for patients with multidrug- We thank the patients and their families, along with study-
resistant tuberculosis resulted in faster sputum- center staff and public health authorities, for their support; Jans-
culture conversion and a higher rate of culture sen study personnel, in particular Chrispin Kambili and Ross
Underwood for their critical review; David McNeeley, who previ-
conversion at 24 weeks, as compared with pla- ously worked for Janssen Pharmaceuticals; and Ian Woolveridge of
cebo. This effect remained significant during a Gardiner-Caldwell Communications for medical-writing support.

Appendix
The authors’ affiliations are as follows: the Division of Medical Physiology and the Department of Science and Technology/National
Research Foundation Centre of Excellence for Biomedical Tuberculosis Research and Medical Research Council Centre for Tuberculosis
Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (A.H.D.), and the Medical Research Council
and Kwazulu Research Institute for Tuberculosis and HIV, Durban (A.P.) — both in South Africa; the Center for Tropical Medicine and
Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam,
Amsterdam (M.P.G.); Centro de Excelencia para el Control de la Tuberculosis Niño Jesús, Servicio de Neumología, Hospital María
Auxiliadora (J.M.R.), and Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia (E.G.) —
both in Lima, Peru; Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow (I.V.); Riga East University
Hospital–Center for Tuberculosis and Lung Diseases, Riga, Latvia (V.L.); Janssen Infectious Diseases, Beerse, Belgium (K.A., N.B.,
M.H.-T., N.L., P.M., E.D.P., R.P.G.H.); and Janssen Research and Development, Titusville, NJ (T.D.M., B.D.).

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