1

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

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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

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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

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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.

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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

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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.

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

Janssen

2013(7)

Guglielmetti

2015(8)

MSF 2015(9) Ndjeka 2015(10)

Design A phase II,

single arm

open label trial

Retrospective

cohort

Prospective cohort Interim cohort

analysis

Location 31 sites, 11

countries

France Armenia South Africa

Inclusion

criteria

Sputum smear

positive

pulmonary

infection with

MDR-TB

MDR-TB

receiving BDQ

for

compassionate

use

MDR-TB patients with

additional resistance to

either a

fluoroquinolone or both

XDR-TB and failures of

MDR-TB treatment

Pulmonary XDR-

or pre-XDR-TB

Sample size 233 35 62 91+

Intervention Weeks 1-2:

BDQ* 400mg

once daily

Weeks 3-24:

BDQ 200mg

thrice a week

BDQ* 400mg

once daily for

2 weeks, then

200mg thrice a

week

BDQ* for 24 weeks as

part of a regimen

constructed according

to WHO

Recommendations&

BDQ* 400mg

once daily for 2

weeks, then

200mg thrice a

week for 22

weeks

Co-

intervention

Baseline

Regimen

BDQ* given as

part of an

individualised

anti-TB

regimen

At least four other

effective drugs

Optimised

Baseline Regimen

Duration of

follow-up

96 weeks 30 months 24 weeks. 18 months

Ethics

approval

An

Independent

Ethics

Committee

Institutional

review board

of

the Bligny

Hospital

The NTP (National TB control Programme) formed an Ethic Committee to review bedaquiline use for patients with TB (2012) Ethic Committee and MOH approved Bedaquiline importation for humanitarian reasons (2013)

Universities of

Witwatersrand

and Cape Town

and Pharma-

Ethics

*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

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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

patient data meta-analysis

Prospective cohort study

Location Canada, USA, Taiwan, Uzbekistan,

Mexico, Spain, The Netherlands,

South Africa, South Korea, Latvia,

Estonia, Iran, Italy, Peru, UK,

Argentina, South Korea, Vietnam,

South Africa, Russian Federation,

Japan, Philippines, France,

Bangladesh, Hong Kong

Estonia, Latvia, Philippines,

Peru, Russia, South Africa, South

Korea, Taiwan, and Thailand

Inclusion criteria Studies published after 1970 that

reported original data of treatment

of patients with microbiologically

confirmed pulmonary MDR-TB. *

Patients with microbiologically

confirmed MDR tuberculosis

starting second-line drug treatment

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-

up

? Till end of treatment or end of study

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Ethics approval Research Ethics Board of the

Montreal Chest Institute, McGill

University Health Centre and local

ethics boards

Centers for Disease Control and

Prevention

(CDC)

*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.

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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

treatment)

List Nominal

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

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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.

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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.

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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.

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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.

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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.

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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.

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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)