Bedaquiline (BDQ) for the Treatment of Multi-Drug Resistant Tuberculosis: a Protocol for an Individual Patient Data Meta-Analysis

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Bedaquiline (BDQ) for the treatment of multi-drug resistant tuberculosis: a protocol for an individual patient data meta-analysis

Version 2

Date: 2016-02-04

Lawrence Mbuagbaw

Joseph Beyene

Mark Loeb

Christian Lienhardt

Licé González-Angulo

Lehana Thabane

BACKGROUND: The emergence of drug-resistant tuberculosis (TB) is a major threat to global TB care and control. In 2014, the World Health Organization (WHO) estimated that 480 000 people developed multidrug-resistant TB (MDR-TB), of which 190 000 died (1). Current treatment regimens for MDR-TB patients are far from satisfactory. These usually require at least 20 months of treatment with a combination of second-line drugs, that are more toxic and less effective than the drugs used to treat drug-susceptible TB (2, 3). In the 2012 global cohort of detected MDR-TB cases, only 50% were successfully treated, as a result of high frequency of death (16%), treatment failure (10%) and loss to follow-up (16%) commonly associated with adverse drug reactions, among other factors. One hundred and five countries have reported at least one case of extensively drug-resistant TB (XDR-TB), a form of MDRTB with additional resistance to fluoroquinolones and second-line injectable drugs (amikacin, kanamycin or capreomycin). On average, an estimated 9.7% of MDR-TB cases have XDR-TB. Treatment options for XDR-TB patients are even more limited with lower cure rates compared to that of MDR-TB. In a subset of 200 XDR-TB patients in 14 countries, treatment success was achieved in only 33% of the cases while 26% of the patients died (4).

The landscape of drug development for treatment of TB has evolved dramatically over the last ten years, and 6 new compounds are in the final stages of clinical development (1). One of those, bedaquiline, was provided marketing authorisation by the US-FDA under a procedure of “accelerated approval” for the treatment of MDR-TB, in December 2012 (5). Although limited data were available, and the drug had not been tested in a full Phase III randomized controlled trial in humans – but only in a Phase II b trial – in view of the importance of this progress, the likelihood of this drug to contribute effectively to the treatment of a life-threatening disease, and the request by member states to get guidance on the way to use the drug, and following the recommendations of the WHO Guidelines Review Committee (GRC), WHO organised in January 2013 an expert group meeting to review all available data. Based on available knowledge about the safety and efficacy of the product, the evaluation of the balance of potential harms and expected benefit, the target population(s) and the likely conditions of use, in association with the MDR-TB treatment currently recommended by WHO, the expert group advised WHO that the drug may be used under five (5) strict conditions (see Box below). This led to the issuance of an Interim Guidance for the use of bedaquiline in the treatment of MDR- TB in June 2013 (6). Since then, the drug has been registered in a number of countries (including the EU, South Africa, Korea, Russia). WHO estimates that, up to now, the drug has

been introduced and used at least once in 46 countries worldwide, under various mechanisms of compassionate use, expanded access programme, donation programmes, import waiver and registered market access (1).

Box — Brief summary of the main recommendations of the Interim Policy Guidance on the use of bedaquiline for treatment of MDR-TB

WHO recommends that ‘bedaquiline may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB (conditional recommendation, very low confidence in estimates of effects)’ (6).

The WHO recommendation for the inclusion of bedaquiline in the adult treatment regimen of MDR-TB is subject to the following five conditions being met:

1. Proper patient inclusion (special caution in persons above 65 years of age or adults living with HIV; use not advised in pregnant women and children).

2. Signed patient informed consent obtained after detailed explanations on the novel nature of the drug, the reasons why it is added to the regimen, and its risks and benefits have all been provided to the patient.

3. Adherence to principles of designing a WHO-recommended MDR-TB regimen typically composed of at least pyrazinamide and four second-line drugs that are considered to be effective based on drug susceptibility test and/or previous use and/or drug resistance surveillance data: a fluoroquinolone (preferably later generation), a second-line injectable agent and two bacteriostatic drugs, preferably prothionamide or ethionamide plus cycloserine or para-aminosalicylic acid. Bedaquiline may be indicated if such a regimen is not feasible because of: (i) in vitro resistance to fluoroquinolones and/or second-line injectable drugs; (ii) known adverse reaction, poor tolerance or contraindication to any component of the combination regimen; or (iii) unavailability or lack of a guaranteed supply of a drug(s).

4. Treatment administered under closely monitored conditions to enable optimal drug effectiveness and safety (sound treatment and management protocols must be in place, preferably submitted and approved by the relevant national ethics authority; review of treatment and management programmes by an independent group of experts in clinical

management and public health, such as the national MDR-TB advisory group is recommended).

5. Active pharmacovigilance and proper management of adverse drug reactions and prevention of complications from drug–drug interactions.

OBJECTIVES:

Overall aim: To re-evaluate the added benefit of bedaquiline to the treatment of MDR-TB, a life-threatening form of tuberculosis, and revise the WHO interim guidance issued in June 2013 in view of updated evidence on its use in conjunction with WHO-recommended MDR-TB treatment regimens.

Specific objectives: 1. To use individual level patient data to evaluate the harms/benefits ratio of bedaquiline in combination with currently recommended MDR-TB treatment regimen according to the following criteria:

(i) for safety, through the evaluation of the type, frequency, severity and seriousness of adverse events related to the use of bedaquiline;

(ii) for effectiveness, through the evaluation of treatment outcomes in cohorts of patients treated with bedaquiline in addition to (optimised) background regimen, in comparison with similar cohorts or programmatically available data;

(iii) for survival, through evaluation of the mortality rates when receiving bedaquiline (and related causes of death).

2. Based on this evaluation, to update the interim guidance on the use of bedaquiline as part of WHO-recommended MDR-TB treatment regimens, as appropriate.

METHODS:

Overview:

The overall approach for this update is to conduct a systematic review of cohorts of MDR-TB patients treated with bedaquiline, obtain individual patient data, and compare key safety, effectiveness and survival data with cohorts of patients treated for MDR-TB in the absence of bedaquiline, to complete relevant GRADE evidence tables and inform policy revision.

Literature search strategy: Bibliographic searches for this systematic review included MEDLINE®, Embase® and the Cochrane Central Register of Controlled Trials. Furthermore, the drug manufacturer was contacted for unpublished data on file. Conference proceedings and reference lists were also searched as an additional technique to identify published studies that were not retrieved in the initial search (See Annex 1: Search strategies for studies retrieval).

Limits such as age and language were not used in this search. Concepts or “facets” (topic specific terms) included in the PICO (Participants, Intervention, Comparison, Outcome) question were combined with Boolean operators to develop an optimal search strategy.

Inclusion criteria:  Humans, no age limit  Diagnosis of multi-drug resistant tuberculosis (pulmonary and extrapulmonary)  Bedaquiline added to background MDR-TB regimen for at least 6 months  Studies implementing drug-monitoring, at least at baseline and at end of treatment  Individual patient data available Exclusion criteria:  Studies not relevant to the main subject (title-screened)  Studies conducted in animals  PK-PD studies  Studies of only-bedaquiline therapy  Studies not providing information on background therapy (WHO recommended or any other)  Studies not providing outcome information  Samples size: Case reports or other observational studies with samples less than 10 participants

 Outcome different to safety and effectiveness  Quantitative data reports  Full texts were not available  Repetitive publications (Duplicates)  Language limitation (no translation possible by the time of data extraction)

Preliminary search synthesis: Through the preliminary search, a total of 687 studies have been identified (CENTRAL, 10 records; PubMed/MEDLINE®, 92 records; and Embase®, 572 records). Additionally, 13 studies have been identified through supplementary sources, namely conference proceedings and data from drug manufacturer.

Two (2) reviewers have been assigned to independently screen and assess the methodological quality of all identified studies (CL and LGA). Currently, one reviewer (LGA) has examined the records identified through searching CENTRAL and PubMed/MEDLINE®. Embase® search was also conducted, but studies are pending to be screened. In case of disagreement in the selection and inclusion of studies, agreement will be sought through a third reviewer (NG). The authors of eligible studies were contacted to retrieve individual patient data.

Included studies/data sources: To date, we have identified four studies of patients who received bedaquiline for whom individual patient data is available. They include an industry funded phase II multisite trial conducted in 11 countries, a retrospective cohort in France, a prospective cohort in Armenia and an interim cohort analysis conducted in South Africa. The key features of these studies are summarised in table 1.

Table 1: Intervention group: Studies of Bedaquiline use in MDR-TB patients

Janssen Guglielmetti MSF 2015(9) Ndjeka 2015(10) 2013(7) 2015(8) Design A phase II, Retrospective Prospective cohort Interim cohort single arm cohort analysis open label trial Location 31 sites, 11 France Armenia South Africa countries Inclusion Sputum smear MDR-TB MDR-TB patients with Pulmonary XDR- criteria positive receiving BDQ additional resistance to or pre-XDR-TB pulmonary for either a infection with compassionate fluoroquinolone or both MDR-TB use XDR-TB and failures of MDR-TB treatment Sample size 233 35 62 91+ Intervention Weeks 1-2: BDQ* 400mg BDQ* for 24 weeks as BDQ* 400mg BDQ* 400mg once daily for part of a regimen once daily for 2 once daily 2 weeks, then constructed according weeks, then Weeks 3-24: 200mg thrice a to WHO 200mg thrice a BDQ 200mg week Recommendations& week for 22 thrice a week weeks Co- Baseline BDQ* given as At least four other Optimised intervention Regimen part of an effective drugs Baseline Regimen individualised anti-TB regimen Duration of 96 weeks 30 months 24 weeks. 18 months follow-up Ethics An Institutional The NTP (National TB Universities of approval Independent review board control Programme) Witwatersrand Ethics of formed an Ethic and Cape Town Committee to review Committee the Bligny and Pharma- bedaquiline use for Hospital patients with TB (2012) Ethics Ethic Committee and MOH approved Bedaquiline importation for humanitarian reasons (2013)

*Bedaquiline; & At least 4 effective drugs including a FQ and injectable if possible; +Data from more than 91 patients may be available at time of retrieval

Given the limitations of using only observational cohorts for this update, we sought for and identified two suitable comparator cohorts of patients treated for MDR-TB without Bedaquiline (11) (12). See Table 2.

Table 2: Comparator group: Studies using conventional MDR-TB treatment (or other regimens) Ahuja 2012 (11) Cegielski 2015 (PETTS) (12) Design Systematic review and individual Prospective cohort study patient data meta-analysis Location Canada, USA, Taiwan, Uzbekistan, Estonia, Latvia, Philippines, Mexico, Spain, The Netherlands, Peru, Russia, South Africa, South South Africa, South Korea, Latvia, Korea, Taiwan, and Thailand Estonia, Iran, Italy, Peru, UK, Argentina, South Korea, Vietnam, South Africa, Russian Federation, Japan, Philippines, France, Bangladesh, Hong Kong Inclusion criteria Studies published after 1970 that Patients with microbiologically reported original data of treatment confirmed MDR tuberculosis of patients with microbiologically starting second-line drug treatment confirmed pulmonary MDR-TB. * Sample size 32 cohorts, 9898 patients 1244 patients Intervention WHO groups 1-5 drugs Treatment according to national standards of care with 5 drugs, including an SLI, for a 6–8- month intensive phase, followed by a continuation phase of 3–4 drugs for a total of 20–24 months Duration of follow- ? Till end of treatment or end of study up

Ethics approval Research Ethics Board of the Centers for Disease Control and Montreal Chest Institute, McGill Prevention University Health Centre and local (CDC) ethics boards *Patients within these datasets were excluded if they had only extra-pulmonary TB, had extensive drug resistance (XDR-TB, as defined elsewhere

Collaboration: The principal investigators of all the included studies will be invited to be co-authors of any published manuscripts, along with three members of their respective teams. They will be provided with monthly updates on progress with the analysis. All research teams and data sources will be fully acknowledged in the final report.

Data management: For each study, we will collect baseline data, and outcome variables. We will store all retrieved data on a controlled-access computer at the Biostatistics Unit of the Father Sean O’Sullivan Research Centre/McMaster University. Our computers are equipped with cloud drives with local and remote servers to prevent any accidental data losses. All data files will be stored in their original form but converted to suit our choice of analytical software. Prior to analysis, files will be checked for missing data and compared to published (or unpublished) reports when available. Any discrepancies will be resolved by contacting the corresponding authors or custodian of the data. In order to merge the files, common variables will be converted to a pre-specified format and given new names. Each data source will have a unique identifier in the merged data set, and another identifier indicating the presence or absence Bedaquiline. Data retrieved for this analysis will be used only for this purpose, and will be completely deleted as soon as the final reports have been completed.

Data merging procedures: We will provide a list of variables of interest to all investigator teams (See Table 3). Variables that may be categorised or measured differently will be recoded to standard WHO definitions. To make studies more comparable, primary analyses will be restricted to variables available in all cohorts. Further analyses with subsets of the data will be conducted if pertinent questions cannot be answered by the whole data set.

Table 3: Variables of interest

Variables Measure Type Study level data Country Country name Nominal Duration of follow-up Months Continuous Individual level data Baseline Age Years Continuous Sex Male/Female Binary HIV status Yes/No Binary Ethnicity (if available) Ethnic group Nominal Type of TB Pulmonary/extra pulmonary Binary Date of diagnosis of TB Date Continuous Severity of TB (cavities) Yes/No Binary Susceptibility to drugs in OBR/resistance profile (or other MDR List Nominal treatment) Associated medical conditions (and other risk factors, if available) List Nominal Composition (type of drugs) of OBR (and doses) List Nominal Date treatment started Date Continuous Date treatment ended Date Continuous Treatment with bedaquiline Yes/No Binary Date BDQ started Date Continuous BDQ dose Numerical Continuous Date BDQ ended Date Continuous Changes to treatment Yes/No Binary Drugs added List Nominal Drugs stopped List Nominal Outcome data Safety* Number of adverse events per patient Numerical Continuous Severity Mild/moderate/severe Ordinal Seriousness Yes/No Binary Number with at least one adverse event Numerical Continuous Number with at least one severe adverse event Numerical Continuous Number with at least one serious adverse event Numerical Continuous All events Yes/No Binary Gastrointestinal symptoms Yes/No Binary Nausea Yes/No Binary Diarrhea Yes/No Binary

Vomiting Yes/No Binary Infections and infestations Yes/No Binary Investigations Yes/No Binary Metabolisms and nutrition disorders Yes/No Binary Hyperuriceamia Yes/No Binary Musculoskeletal and connective tissue disorders Yes/No Binary Arthralgia Yes/No Binary Nervous system disorders (dizziness, headache) Yes/No Binary Headache Yes/No Binary Skin and subcutaneous tissue disorders Yes/No Binary Rash Yes/No Binary Pruritus Yes/No Binary General disorders and administration site conditions Yes/No Binary Respiratory, thoracic and mediastinal disorders Yes/No Binary Ear and labyrinth disorders Yes/No Binary Eye disorders Yes/No Binary Psychiatric disorders Yes/No Binary Blood and lymphatic system disorders Yes/No Binary Cardiac disorders Yes/No Binary Reproductive system and breast disorders Yes/No Binary ECG changes (QTc prolongation) Yes/No Binary QTc measurement Numerical Continuous Major laboratory disorders (> grade II modifications) Yes/No Binary Laboratory signs of hepatitis Numerical Continuous ALAT Numerical Continuous ASAT Numerical Continuous Bilirubin Numerical Continuous Laboratory signs of pancreatitis Numerical Continuous Amylase Numerical Continuous Lipase Numerical Continuous Effectiveness Culture conversion at 6 months Yes/No Binary Time to culture conversion Time-to-event Continuous Cure (sustained microbiological conversion at end of treatment) Yes/No Binary Treatment success Yes/No Binary Death Yes/No Binary Cause of death Cause reported Nominal *Counts and severity will also be collected.

Statistical methods: Descriptive statistics: Baseline covariates will be summarised as counts (percentage) for categorical variables, mean (standard deviation) or median (first quartile, third quartile) for continuous or discrete variables as appropriate depending on the distribution. Baseline covariates and outcomes will be analysed individually for each cohort, and then according to the presence or absence of bedaquiline.

Primary analysis: We will use random-effects logistic regression to determine the effects on safety outcomes among participants who received bedaquiline versus those that did not receive bedaquiline, adjusting for baseline characteristics—in particular, age, sex, HIV status, ethnicity, components of baseline regimen, type of TB, susceptibility to drugs in baseline regimen, associated medical conditions, changes to treatment. In this analysis, study will be used as a random-effect. For this analysis we will use the PETTS study as the comparator group (12) because it is a more homogenous cohort in terms of participants, interventions, outcomes and follow-up time. These analyses will be replicated for the effectiveness and survival outcomes—with the latter based on random-effects Cox-regression approach.

Sensitivity analysis: In order to test the robustness of our analyses, we will repeat the analysis using the Ahuja et al study as a comparator group. It is a more heterogeneous data set including 32 cohorts (9898 patients) from different countries. (11)

Subgroup analyses: We will investigate subgroup effects by introducing interaction terms into our models for age, sex, HIV status, type and severity of TB. These analyses will be based on adding interactions between each subgroup variable and the treatment group in the primary analysis models.

All statistical analyses will be two-sided with α levels set at 0.05. The results for all analyses will be reported as odds ratio (OR), corresponding 95% confidence interval (CI) and associated p- values. All p-values will be reported to three decimal places with those less 0.001 reported as p<0.001. We will also examine the model assumptions including collinearity and goodness-of- fits as appropriate for all the analyses. Data will be analysed using SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). An overview of out statistical approach can be seen in Figure 1.

Figure 1: Overview of analytical plan

Investigation of heterogeneity: The included studies will be examined carefully for any clinical differences related to the participants, interventions and outcomes that might affect treatment outcomes. Possible differences include the population studied and the duration of follow-up. Between study heterogeneity will be assessed using intraclass correlation coefficients.

Assessment of study quality: The quality of reporting for published studies will be assessed using the New Castle Ottawa Scale (NOS).(13) The NOS can be used to assess the quality of cohort studies by allocating stars based on the selection of participants for the cohort, the comparability of the cohorts on the basis of design or analysis and how outcome data was collected. A maximum of 13 stars can be allocated to a cohort study with no relevant issues.

Assessment of the quality of evidence across studies: The quality of the body of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach via the GRADEpro Guideline Development Tool (GDT).(14) Using this tool, the extent to which one can be confident that the estimate of effect is close to the truth can be rated as high, moderate, low and very low. With this approach, observational studies are typically categorised as low quality but can be upgraded if there is a large effect size, if plausible confounding would reduce the demonstrated effect and if there is a dose-response gradient.

Reporting: Our findings will be reported according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. (15) Moose is a checklist of 35 items that include recommended elements of background information, search strategy, methodological details, results, discussion and conclusion. (15) GRADE tables will be constructed for each outcome of interest. (14)

Potential Limitations: Potential limitations include considerable differences in the studies that used Bedaquiline and the use of an external control group for the analysis which comes from a different analysis. We will address these limitations by incorporating the heterogeneity between studies by using random effects models and also adjusting for study level characteristics.

Ethics and dissemination: The Hamilton Integrated Research Ethics Board (HIREB) has been consulted for ethics approval. Given that we will be working with anonymized pre-collected data, from studies that already have ethics approval, a formal application for ethical clearance is not required. The results will be disseminated as WHO reports and as peer reviewed publications.

References:

1. World Health Organization. Global tuberculosis report 2015 Geneva: 2015 (WHO/HTM/TB/2015.22 http://www.who.int/tb/publications/global_report/en/, accessed 12 November 2015). 2015. 2. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis - 2008 emergency update (http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf, accessed 30 July 2015): World Health Organization; 2008. 3. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update (http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf, accessed 15 March 2015). 2011. 4. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta- analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. PubMed PMID: 22952439. Pubmed Central PMCID: PMC3429397. 5. United States Food and Drug Administration. FDA news release. 31 December 2012 (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm accessed on 15 March 2015). 2012. 6. World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance: World Health Organization; 2013 (http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf, accessed 10 September 2015). 7. Janssen Infectious Diseases-Diagnostics B. A Phase II, open-label trial with TMC207 as part of a multi-drug resistant tuberculosis (MDR-TB) treatment regimen in subjects with sputum smear-positive pulmonary infection with MDR-TB. 2013. 8. Guglielmetti L, Le Du D, Jachym M, Henry B, Martin D, Caumes E, et al. Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Infect Dis. 2015 Jan 15;60(2):188-94. PubMed PMID: 25320286. Epub 2014/10/17. eng. 9. MSF. Compassionate use of bedaquiline: Interim outcomes from the Armenian National Tuberculosis Control Office. 10. Ndjeka N, Conradie F, Schnippel K, Hughes J, Bantubani N, Ferreira H, et al. Treatment of drug- resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis. Int J Tuberc Lung Dis. 2015 Aug;19(8):979-85. PubMed PMID: 26162365. Epub 2015/07/15. eng. 11. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta- analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. PubMed PMID: 22952439. Pubmed Central PMCID: PMC3429397. Epub 2012/09/07. eng. 12. Cegielski JP, Kurbatova E, van der Walt M, Brand J, Ershova J, Tupasi T, et al. Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance. Clin Infect Dis. 2016 Feb 15;62(4):418-30. PubMed PMID: 26508515. Pubmed Central PMCID: PMC4725381. Epub 2015/10/29. eng. 13. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses 2014 [13 January 2014]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

14. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction- GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011 Apr;64(4):383-94. PubMed PMID: 21195583. Epub 2011/01/05. eng. 15. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008-12. PubMed PMID: 10789670. Epub 2000/05/02. eng.

Annex 1: Search strategies for studies retrieval

PubMed Search ("Tuberculosis"[Mesh] AND "Tuberculosis, Multidrug-Resistant"[Mesh]) AND "Drug Resistance, Bacterial"[Mesh] AND ("bedaquiline"[Supplementary Concept] OR "bedaquiline"[All Fields]) OR diarylquinoline[All Fields] OR sirturo[All Fields] OR ("bedaquiline"[Supplementary Concept] OR "bedaquiline"[All Fields] OR "tmc207"[All Fields]) OR ("bedaquiline"[Supplementary Concept] OR "bedaquiline"[All Fields] OR "r207910"[All Fields]) AND ("safety"[MeSH Terms] OR "safety"[All Fields]) AND ("2011/01/05"[PDat] : "2016/01/03"[PDat] AND "humans"[MeSH Terms])

New PubMed Search "Tuberculosis"[Mesh] OR tuberculosis [TW] OR “ Lupus Vulgaris ”[TIAB] OR “ koch s disease ” [TW] OR tubercul*[TW] OR tuberculoma [TW] OR Silicotuberculosis [TW] OR "Tuberculosis Vaccines"[Mesh] OR "BCG Vaccine"[Mesh] OR ( calmette*[TW] AND vaccin*[TW]) OR "Tuberculin Test"[Mesh] OR Tuberculin [TW] OR "Mycobacterium tuberculosis"[Mesh] OR TB [Ti]

EMBASE Search (http://www.embase.com) bedaquiline'/exp OR '1 (6 bromo 2 methoxy 3 quinolinyl) 4 dimethylamino 2 (1 naphthyl) 1 phenyl 2 butanol':de,ab,ti OR '1 (6 bromo 2 methoxyquinolin 3 yl) 4 (dimethylamino) 2 (naphthalen 1 yl) 1 phenylbutan 2 ol':de,ab,ti OR '6 bromo alpha [2 (dimethylamino) ethyl] 2 methoxy alpha (1 naphthalenyl) beta phenyl 3 quinolineethanol':de,ab,ti OR '6 bromo alpha [2 (dimethylamino) ethyl] 2 methoxy alpha (1 naphthyl) beta phenyl 3 quinolineethanol':de,ab,ti OR 'bedaquiline fumarate':de,ab,ti OR 'r 207910':de,ab,ti OR 'r 403323':de,ab,ti OR 'r207910':de,ab,ti OR 'r403323':de,ab,ti OR 'sirturo':de,ab,ti OR 'tmc 207':de,ab,ti OR 'tmc207':de,ab,ti OR bedaquiline

Cochrane Central Register of Controlled Trials multidrug resistant OR drug-resistant AND tuberculosis OR TB AND bedaquiline OR sirturo OR TMC207 AND treatment in Title, Abstract, Keywords Publication Year from 2000 to 2016, in Cochrane Reviews (Reviews only) and Trials (Word variations have been searched)