Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline

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1 The new england journal of medicine 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* Abstract Background Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. Methods In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline 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 primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. The authors affiliations are provided in the Appendix. Address reprint requests to Dr. Dannemann at Janssen Research and Development, 1125 Trenton Harbourton Rd., Titusville, NJ 08560, or at bdannema@its.jnj.com. * A complete list of investigators in the TMC207-C208 Study Group is provided in the Supplementary Appendix, available at NEJM.org. N Engl J Med 2014;371: DOI: /NEJMoa Copyright 2014 Massachusetts Medical Society. Results Bedaquiline reduced the median time to culture conversion, as compared with placebo, 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 definitions 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 bedaquiline 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 resulted 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, NCT ) n engl j med 371;8 nejm.org august 21,

2 The new england journal of medicine The World Health Organization (WHO) estimates that the global incidence of tuberculosis in 2012 was 8.6 million cases, with 1.3 million deaths, predominantly occurring in developing countries. 1 Although there has been some progress in reducing tuberculosis cases and deaths in the past 20 years, multidrugresistant tuberculosis (i.e., with resistance to at least isoniazid and rifampin) remains a major challenge. The 2012 global incidence of multidrug-resistant tuberculosis was 450,000 cases. 1 Therapy for multidrug-resistant tuberculosis is a long, arduous regimen of antiquated drugs that are mainly bacteriostatic and have an unfavorable side-effect profile. 2 The WHO reports that major efforts are needed to improve the current average rate of 48% for successful treatment of patients with multidrug-resistant tuberculosis. 1 By 2012, extensively drug-resistant tuberculosis (i.e., with additional resistance to injectable second-line drugs and fluoroquinolones) was reported in 92 countries worldwide, with the presence of extensively drug-resistant isolates reported in 9.6% of patients with multidrug-resistant tuberculosis. 1 Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, 3 is the first antituberculosis drug with a new mechanism of action to be approved for use in multidrug-resistant tuberculosis in 40 years. 4 Bedaquiline has shown bactericidal activity in vitro, in murine models of tuberculosis, 3,5-7 and in a 7-day proof-of-concept study involving patients with drug-sensitive tuberculosis. 8 In stage 1 of an exploratory phase 2b randomized trial, called TMC207-C208, involving patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis, 8 weeks of bedaquiline treatment had better antibacterial activity than placebo when added to a preferred five-drug, second-line background regimen. 9,10 In stage 2 of the TMC207- C208 study, a phase 2b study in which bedaquiline was administered for 24 weeks to a larger number of patients, we evaluated the time to sputum-culture conversion, the rates of culture conversion and drug resistance, pharmacokinetics, and safety over a 120-week period in patients receiving a preferred five-drug background regimen. Methods Patients We recruited patients between the ages of 18 and 65 years with newly diagnosed, sputum smear positive, pulmonary, multidrug-resistant tuberculosis on the basis of proportion-method results, 11,12 positive rapid-screening tests (FASTPlaque- Response assay [Biotec] and GenoType MTBDR plus line-probe tests [Hain Lifescience]). Patients who had received previous treatment for multidrug-resistant tuberculosis were excluded. Additional exclusion criteria were a positive test for the human immunodeficiency virus (HIV) with a CD4+ count of less than 300 cells per cubic millimeter, complicated or severe extrapulmonary or neurologic manifestations of tuberculosis, severe cardiac arrhythmia requiring medication, a corrected QT interval with the use of Fridericia s formula (QTcF) 13 of more than 450 msec, a history of risk factors for torsades de pointes, concomitant serious illness, alcohol or drug abuse, pregnancy or breast-feeding, and previous treatment with bedaquiline. According to the protocol, moxifloxacin, gatifloxacin, and systemic use of cytochrome P-450 3A4 inhibitors or inducers were prohibited during and for 1 month after completion of the study treatment. Study Design In this randomized, double-blind, placebo-controlled study, patients were stratified according to study site and radiographic assessment of lung cavitation ( 2 cm bilaterally, 2 cm unilaterally, or <2 cm). Trial sites were located in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa, and Thailand. Patients received either bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, administered as 100-mg tablets) or placebo, plus a preferred five-drug, second-line antituberculosis background regimen (Fig. 1). Patients were instructed to take bedaquiline or placebo with water after breakfast. National treatment-program regimens were respected, although the preferred five-drug background regimen was ethionamide, pyrazinamide, ofloxacin, kanamycin, and cycloserine. Changes in the background regimen were permitted on the basis of the results of drugsusceptibility testing, side effects, or unavailability of drugs on site. After the 24-week treatment period, there was a 96-week period during which patients were instructed to complete their background regimen (Fig. 1). Patients who prematurely discontinued the trial were followed for collection of survival data until trial completion unless they withdrew consent. 724 n engl j med 371;8 nejm.org august 21, 2014

3 Tuberculosis Culture Conversion with Bedaquiline Overall Treatment Phase Last Study Visit 120 Wk Investigational Treatment Phase Postinvestigational Treatment Phase 24 Wk Bedaquiline plus background regimen 96 Wk Background regimen only 24-Wk evaluation 120-Wk analysis 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 protocol from at least one (or more, if required by local regulations) independent ethics committee or institutional review board. The trial was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent before trial entry. Details regarding the study design are provided in the protocol, available with the full text of this article at NEJM.org. Microbiologic Assessments Triplicate spot sputum samples were collected at every visit (except on the day of the first administration of the study drug) and at the time of withdrawal, for patients who did not complete the study, for culture of Mycobacterium tuberculosis in liquid medium (Mycobacteria Growth Indicator Tube, Becton Dickinson). Drug-susceptibility testing was performed at a central laboratory (Institute of Tropical Medicine, Antwerp, Belgium) at baseline and at 8, 24, and 72 weeks in all patients and in those with reversion to a positive culture after initial culture conversion. The minimal inhibitory concentration (MIC) of bedaquiline on 7H11 agar was defined as the lowest concentration (measured in micrograms per milliliter) that prevented the growth of 99% of M. tuberculosis isolates. Isolates for which the MIC was increased by a factor of 4 or more, as compared with the baseline value, were considered to have decreased susceptibility to bedaquiline. Safety Assessments Safety assessments included monitoring for adverse events, clinical laboratory testing, and electrocardiography at predefined intervals throughout the study. Toxicity was graded on the basis of the Division of Microbiology and Infectious Diseases (DMID) adult toxicity tables. 14 Study End Points The primary end point was the time to sputumculture conversion, which was defined as two consecutive negative liquid cultures from sputum samples that were collected at least 25 days apart and were not followed by confirmed positive cultures. The primary analysis was performed on the basis of data at 24 weeks. Secondary efficacy measurements were the rates of culture conversion after 24 weeks and after 120 weeks. We also performed 11 subgroup efficacy analyses of the rate of culture conversion, including in patients with M. tuberculosis isolates that were resistant only to isoniazid and rifampin and in those with isolates that also were resistant to any second- n engl j med 371;8 nejm.org august 21,

4 The new england journal of medicine line injectable drug or any fluoroquinolone (which were categorized as having pre-extensive drug resistance) and in patients with isolates that were susceptible or resistant to pyrazinamide. (For details regarding all 11 subgroups, see the Methods section in the Supplementary Appendix, available at NEJM.org.) Study Oversight The study was funded by Janssen Pharmaceuticals. Medical-writing support (funded by Janssen) was provided by an employee of Gardiner- Caldwell Communications, who wrote the initial draft of the manuscript and incorporated comments from the authors. The data were collected by the investigators and analyzed by the sponsor. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data reported and the fidelity of the study to the protocol. Statistical Analysis We determined that enrollment of 75 patients in each study group would provide a power of 80% to detect a difference of 22 percentage points in the 6-month rate of culture conversion between the placebo group (estimated at 50%) and the bedaquiline group (estimated at 72%) at a twosided significance level of The safety analysis was conducted in the intention-to-treat population and included all patients who had undergone randomization and received at least one dose of the assigned study drug. Safety data are presented for the 120-week treatment period. The efficacy analyses were performed in the modified intention-to-treat population, which excluded patients who had no positive mycobacterial cultures from sputum samples obtained before administration of the first dose of the study drug or a positive culture up to week 8 in cases in which baseline cultures were negative, those for whom susceptibility to rifampin and isoniazid was shown or resistance could not be confirmed, those with extensively drug-resistant tuberculosis, and those who had not undergone assessment after baseline. The primary end point was analyzed in the modified intention-to-treat population. In this analysis, data for patients who discontinued treatment, died, or did not have sputum-culture conversion before 24 weeks were censored at the last assessment, regardless of the culture status at the time of study dropout or death, and these patients were considered to have had no response. We used a Cox proportional-hazards model with adjustment for stratification variables to compare the time to culture conversion in the two study groups. For the 11 prespecified subgroup analyses, no formal adjustments for multiple comparisons were made. With this number of subgroups, there is a probability of 43% that at least one test would be significant (P<0.05) on the basis of chance alone. A post hoc analysis was performed to assess treatment outcomes on the basis of WHO definitions for multidrug-resistant tuberculosis. 15 Results Study Population Of 282 patients who were screened, 160 underwent randomization and received at least one dose of the assigned study drug (the intention-totreat population, comprising 79 patients in the bedaquiline group and 81 in the placebo group). The modified intention-to-treat population consisted of 132 patients (Fig. 2). In the intention-totreat population, 60 patients (38%) discontinued the trial prematurely, with no relevant differences between the two study groups in the reasons for discontinuation (Fig. 2, and Fig. S1 in the Supplementary Appendix). The most common reasons for discontinuation were withdrawal of consent and adverse events. In the modified intention-to-treat population (protocol-defined efficacy population), there were more men (64%) than women, and more black patients (37%) than any other racial or ethnic group (Table 1, and Table S3 in the Supplementary Appendix). Baseline demographic and disease characteristics were similar in the two study groups except that the proportion of patients who had isolates with resistance to pyrazinamide and the proportion classified as having isolates with pre-extensive drug resistance were nonsignificantly larger in the bedaquiline group, and the proportions of HIV-positive patients and patients with abnormally low albumin levels were significantly larger in the placebo group (Table 1). The median overall treatment phase was longer in the placebo group than in the bedaquiline group (Table 2). A higher proportion of patients in the placebo group than in the bedaquiline group (58% vs. 47%) had at least one new antituberculosis drug added to their background regimen. 726 n engl j med 371;8 nejm.org august 21, 2014

5 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 160 Underwent randomization and were treated Modified Intention-to-Treat Group 132 Underwent randomization and were treated 28 Were excluded from modified intention-totreat group 79 Were assigned to bedaquiline 81 Were assigned to placebo 66 Were assigned to bedaquiline 66 Were assigned to placebo 29 Discontinued study 9 Had adverse event 6 Withdrew consent 5 Were lost to follow-up 3 Did not adhere to study regimen 3 Were pregnant 2 Were determined to be ineligible 1 Acquired extensive drug resistance 1 Crossed over to openlabel bedaquiline 31 Discontinued study 6 Had adverse event 7 Withdrew consent 3 Were lost to follow-up 7 Did not adhere to study regimen 2 Were pregnant 6 Were determined to be ineligible 23 Discontinued study 8 Had adverse event 5 Withdrew consent 5 Were lost to follow-up 2 Did not adhere to study regimen 3 Were pregnant 1 Crossed over to openlabel bedaquiline 24 Discontinued study 5 Had adverse event 7 Withdrew consent 3 Were lost to follow-up 7 Did not adhere to study regimen 2 Were pregnant 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 In the modified intention-to-treat population, the median time to sputum-culture conversion was faster in the bedaquiline group than in the placebo group (83 days vs. 125 days), for a hazard ratio for conversion in the bedaquiline group of 2.44 (95% confidence interval [CI], 1.57 to 3.80; P<0.001) (Fig. 3). The same analysis in the full intention-to-treat population had similar results (Fig. S2 in the Supplementary Appendix). The treatment difference in a model with adjustment for unequally distributed baseline factors (status with respect to pyrazinamide susceptibility, HIV status, and baseline albumin grade) was still significant and was similar to the estimate obtained from the unadjusted model. (Pre-extensive drug resistance was not included in the model because the between-group difference was small [7%].) More patients in the bedaquiline group than in the placebo group had confirmed culture conversion at both 24 and 120 weeks: 52 of 66 patients (79%) and 38 of 66 patients (58%) in the two groups, respectively, at 24 weeks (P = 0.008) and 41 of 66 patients (62%) and 29 of 66 patients n engl j med 371;8 nejm.org august 21,

6 The new england journal of medicine Table 1. Demographic and Clinical Characteristics in the Modified Intention-to-Treat Population at Baseline.* Characteristic Bedaquiline (N = 66) Placebo (N = 66) All Patients (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 criteria 14 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 deciliter; 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 rifampin 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). At 120 weeks, of the 25 patients in the bedaquiline group who did not have a response, 8 did not have culture conversion, 6 had subsequent reversion, and 11 discontinued the study after culture conversion. Of the 37 patients in the placebo group who did not have a response, 15 did not have culture conversion, 10 had subsequent reversion, and 12 discontinued the study after culture conversion. In the bedaquiline group, there was no relationship between the area under the plasma concentration time curve over a 24-hour period at week 2 and the time to conversion or conversion status (Fig. S3 in the Supplementary Appendix). Subgroup Analyses In subgroup analyses at 120 weeks, sputum-culture conversion occurred in more patients in the bedaquiline group than in the placebo group among those who had isolates with resistance only to isoniazid and rifampin (27 of 39 patients [69%] and 20 of 46 patients [43%], respectively) and among those who had isolates with preextensive drug resistance (9 of 15 patients [60%] and 5 of 12 patients [42%], respectively). In addi- 728 n engl j med 371;8 nejm.org august 21, 2014

7 Tuberculosis Culture Conversion with Bedaquiline Table 2. Adverse Events during 120 Weeks in the Intention-to-Treat Population.* Variable Bedaquiline (N = 79) Placebo (N = 81) Median duration of overall treatment phase (range) wk 91.7 ( ) 94.1 ( ) 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 bedaquiline group than in the placebo group among patients with isolates that were susceptible to pyrazinamide (13 of 18 patients [72%] and 14 of 26 patients [54%], respectively) and among those with isolates that were resistant to pyrazinamide (23 of 38 patients [61%] and 11 of 33 patients [33%], respectively). On the basis of the WHO definition of cure, 15 in the modified intention-to-treat population at 120 weeks, more patients in the bedaquiline group than in the placebo group were cured (38 of 66 patients [58%] and 21 of 66 patients [32%], respectively; P = 0.003) (Fig. 4). Drug Resistance New resistance to at least one antituberculosis drug developed in isolates from 2 patients in the bedaquiline group and in 16 patients in the placebo group; 1 of the 2 patients in the bedaquiline group (50%) and 9 of the 16 in the placebo group (56%) did not have a response to treatment. Of the latter patients, 6 of the 9 patients (67%) in the placebo group were found to have isolates with resistance either to injectable second-line drugs or fluoroquinolones (pre-extensive drug resistance, observed in 5 patients) or to both injectable second-line drugs and fluoroquinolones (extensive drug resistance, observed in 1 patient); the 1 patient in the bedaquiline group did not have either pre-extensive or extensive drug resistance. Though the number of paired isolates (10) is limited, the isolate from 1 patient in the bedaquiline group who had pre-extensive drug resistance at baseline had an increase by a factor of 4 in the bedaquiline MIC at the end of the study, as compared with baseline. No mutations were observed in the ATP synthase operon. Safety During 120 weeks in the intention-to-treat population, there were similar rates of adverse events, treatment-related adverse events, and adverse events leading to study discontinuation in the two study groups (Table 2). The most frequent adverse events were nausea, arthralgia, and vomiting. The severity of most adverse events was grade 1 or Overall, 10 of 79 patients (13%) in the bedaquiline group and 2 of 81 patients (2%) in the placebo group died (P = 0.02). (Detailed case reports on all deaths are provided in Table S5 in the Supplementary Appendix.) In the bedaquiline group, deaths occurred during study-drug treatment in 1 patient and after study week 24 in 9 patients (median time after receipt of the last n engl j med 371;8 nejm.org august 21,

8 The new england journal of medicine Time to Culture Conversion Positive Culture (%) No. at Risk Bedaquiline Placebo Weeks Bedaquiline plus background regimen Placebo plus background regimen Figure 3. Time to Sputum-Culture Conversion in the Modified Intention-to- Treat Population. Shown is the proportion of patients in each study group who had positive results on Mycobacterium tuberculosis culture during the 24-week investigational treatment phase of the study. Patients who withdrew from the study, who died, or who did not have sputum-culture conversion by week 24 were considered to have had treatment failure in the primary analysis, regardless of their culture status at the time of dropout or death. For these patients, 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. Analysis based on a Cox proportional-hazards model with adjustment for study center and degree of radiographic lung cavitation showed significantly faster conversion in the bedaquiline group than in the placebo group at 24 weeks (P<0.001). The number of patients at risk at each time point is the number of patients who did not have culture conversion and who were still participating in the study dose of study drug, 49.1 weeks; range 12.3 to 130.1), with 1 of these deaths occurring after study week 120. In 6 patients, the deaths were attributed to tuberculosis (in 5 patients in the bedaquiline group and 1 in the placebo group). There was no difference in the duration of follow-up between the two study groups. No deaths were considered to be related to the study drug by an investigator who was unaware of the group assignments, nor was there any association between the deaths and bedaquiline plasma concentrations or a QTcF interval of 500 msec or more during the trial. At study week 24, the mean change from baseline in the QTcF was an increase of 15.4 msec in the bedaquiline group and an increase of 3.3 msec in the placebo group (P<0.001). After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that in the placebo group by study week 60. Only one patient in the bedaquiline group had a 3 5 QTcF prolongation of more than 500 msec (single time point), as compared with no patients in the placebo group. No direct relationship was seen between bedaquiline or the bedaquiline metabolite (M2) plasma level and corresponding absolute QTcF values or changes in the QTcF. There were no reports of clinically significant dysrhythmia during the trial. Discussion In this study, we found that 24 weeks of treatment with bedaquiline in combination with a five-drug, second-line background regimen (consistent with WHO recommendations for the treatment of multidrug-resistant tuberculosis at that time 15 ) significantly shortened the time to culture conversion and increased the rate of culture conversion at 24 weeks, as compared with placebo plus the background regimen. These results confirm the faster culture conversion reported in a previous phase 2b trial of 8 weeks of bedaquiline. 9 The treatment benefit of adding bedaquiline to the background regimen that was seen at 24 weeks in terms of the proportion of patients with a response was durable and of similar magnitude at the end of the 120-week trial. Evaluation of the study outcome on the basis of the modified WHO definitions for multidrugresistant tuberculosis supported our results at 24 weeks and 120 weeks. On the basis of the WHO definition of cure, nearly twice as many patients in the bedaquiline group as in the placebo group were cured, a finding that addresses the unmet need for improved long-term treatment outcomes in patients with multidrug-resistant tuberculosis. The treatment-success rate among patients in the placebo group in our trial was lower than that reported in a recent meta-analysis (32% vs. 54%). 16 This finding might be explained by the higher proportions of patients in our study, as compared with the meta-analysis, who had isolates that were positive for acid-fast bacilli (100% vs. 66%), cavitary disease (83% vs. 52%), and pyrazinamide resistance (62% vs. 26%). In addition, we collected triplicate sputum samples and used liquid culture, which is more sensitive than the solid medium used in the studies cited in the meta-analysis. 17 The inclusion of bedaquiline in the regimen was associated with a reduced risk of pre-extensive drug resistance or extensive drug resistance and a reduced risk of additional resistance to 730 n engl j med 371;8 nejm.org august 21, 2014

9 Tuberculosis Culture Conversion with Bedaquiline other background drugs. Culture conversion was higher in the bedaquiline group than in the placebo group, despite a greater proportion of isolates with pyrazinamide resistance and preextensive drug resistance at baseline in the bedaquiline group. Both patients with multidrug-resistant isolates and those with pre-extensive drug-resistant isolates had more frequent and more rapid culture conversion with bedaquiline than with placebo. As in the 8-week study of bedaquiline, 9,10 the most frequent adverse events that we observed were similar to those commonly seen in patients with tuberculosis who are receiving second-line treatment for multidrug-resistant tuberculosis. 18,19 Adverse events leading to the discontinuation of bedaquiline were uncommon. Increased hepatic aminotransferase levels, which had been observed in preclinical studies, were seen more frequently in the bedaquiline group than in the placebo group (Table S4 in the Supplementary Appendix), but only three patients (two of whom had hepatitis B virus infection) discontinued the assigned study drug. The use of bedaquiline was associated with moderate prolongation in the QT interval (mean, 15.4 msec at study week 24). There is a risk of increased QT-interval prolongation for bedaquiline in combination with other QT-interval prolonging drugs, such as fluoroquinolones and 4-aminoquinoline antimalarial drugs. 4 The reason for higher mortality in the bedaquiline group than in the placebo group is unclear. All 6 patients whose deaths were attributed to tuberculosis either did not have culture conversion or had conversion with subsequent reversion during the trial and had one or more risk factors for a poor outcome. In addition, mortality in the placebo group was surprisingly low, as compared with mortality in a metaanalysis involving 9153 patients with multidrugresistant tuberculosis (15%) 16 and in an openlabel, phase 2 trial of bedaquiline involving 233 patients with newly diagnosed or previously treated multidrug-resistant tuberculosis (7%). 20 The development of bedaquiline for indications for which a reasonably efficacious and safe alternative exists (e.g., treatment of drug-sensitive tuberculosis or preventive treatment) should be approached with caution until more data have been collected to clarify the implication of the excess deaths. One limitation of our trial is its relatively A Protocol-Defined Analysis Treatment Outcome (%) Bedaquiline plus Background Regimen (N=66) B Analysis Based on WHO Definitions Treatment Outcome (%) Bedaquiline plus Background Regimen (N=66) small size. Only 79 patients received bedaquiline in this study, which was initiated at a time when information about the safety of bedaquiline was limited. Our conservative selection criteria limited the inclusion of patients with HIV coinfection who were receiving antiretroviral therapy. A planned phase 3 study will enroll a larger number of patients, including HIV-positive patients receiving antiretroviral therapy. The enrollment in our study was calculated to show significant differences in the surrogate end point of sputum-culture conversion at 24 weeks rather than clinical cure. However, the significant difference in cure rates was maintained at 120 weeks, Placebo plus Background Regimen (N=66) Placebo plus Background Regimen (N=66) No conversion Reversion to positive test Withdrawal after conversion Conversion Death Withdrawal Treatment failure Cure Figure 4. Study Outcomes at 120 Weeks According to the Protocol-Defined Analysis and an Analysis Based on World Health Organization Definitions. Shown are study outcomes in the modified intention-to-treat population on the basis of the protocol-defined analysis method (Panel A) and World Health Organization (WHO) definitions 15 (Panel B) with respect to study data at 120 weeks. In the two analyses, patients in the bedaquiline group had higher rates of sputum-culture conversion than did those in the placebo group on the basis of a logistic model with treatment as the only covariate (P = 0.04 for the study analysis and P = for the WHO definitions). Percentages may not total 100 because of rounding. n engl j med 371;8 nejm.org august 21,

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