Phase 4 Operational Study to Assess the Effectiveness, Feasibility, Acceptability, and Cost-effectiveness of the GeneXpert MTB/XDR (Xpert XDR; Cepheid) Assay for Rapid Triage-and-treatment of DR-TB
Conditions: Drug Resistant Tuberculosis, MDR-TB, XDR-TB, Tuberculosis
Sponsor: Centre for the AIDS Programme of Research in South Africa

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PROTOCOL 
CAPRISA 094 
Triage Test for All Oral DR-TB Regimen 
(TRiAD Study) 
 
A Phase 4 operational study to assess the effectiveness, feasibility, 
acceptability, and cost effectiveness of the GeneXpert MTB/XDR 
(Xpert XDR; Cepheid) assay for rapid triage-and-treatment of DR-TB 
 
A multi-centre, multi-country prospective cohort study 
 
 
Funded by: 
The European and Developing Countries Clinical Trials Partnership 
(EDCTP) – Grant #RIA2019IR-2888 
 
 
Principal Investigator 
Prof Kogieleum Naidoo, 
CAPRISA 2nd Floor 
Doris Duke Medical Research Institute 
Nelson R. Mandela School of Medicine 
University of KwaZulu Natal 
719 Umbilo Road 
Congella, 4013, Durban 
South Africa

 
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PARTICIPATING ORGANISATIONS IN THE STUDY 
 
Study Clinical Research Sites 
Centre for the Aids Programme of Research in South Africa 
(CAPRISA)  
Springfield Research Site, King DinuZulu Hospital (KDH) 
Complex Durban, South Africa 
CAPRISA Study Team 
Kogieleum Naidoo, MBChB, PhD  
 
Principal Investigator 
CAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
E-mail: kogie.naidoo@caprisa.org 
Tel: +27 31 260 4969 
Anushka Naidoo, PhD 
Project Director/ Co-investigator 
CAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
E-mail: anushka.naidoo@caprisa.org  
Tel: +27 655 0573   
Rubeshan Perumal, MBChB  
Co-investigator  
CAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
E-mail: rubeshan.perumal@caprisa.org Tel: 
+27 655 0610  
Nonhlanhla Yende Zuma, PhD 
Statistician 
CAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
E-mail: 
nonhlanhla.yende@caprisa.org 
Tel: +27 31 655 0520 
Khodhani Ramakulukhusha 
Data Manager 
CAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
Email:Khodani.Ramakulukusha@caprisa.org 
Tel: +27 31 655 0527 
Letitia Shunmugam, PhD Post-doctoral 
FellowCAPRISA  
Nelson R Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Congella 4013, Durban, 
South Africa 
E-mail: letitia.shunmugam@caprisa.org  
Tel: +27 655 0568    
Sunitha Chotoo, MBChB  
Co-Investigator  
King DinuZulu Hospital MDR TB Complex 
Corner of Dr R D Naidoo Drive and Viola Road 
Sydenham Durban, South Africa 
E-mail: sunitha.chotoo@kznhealth.gov.za 
Tel: +27 (0) 31 242 6000 
Khine Swe Swe-Han, MBBS, FCPath, 
PhD 
Co-investigator 
Inkosi Albert Luthuli Central Hospital, 
800 Vusi Mzimela Rd, Cato Manor, 
4091, Durban, South Africa. 
Email: khine.han@nhls.ac.za 
Tel: +27 312402793 
Nomonde Dlamini, MBChB, FCPath 
Keeren Lutchminarain, MBChB, FCPath 

 
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Co-investigator 
Inkosi Albert Luthuli Central Hospital, 800 Vusi 
Mzimela Rd, Cato Manor, 4091, Durban, South 
Africa. 
Email: nomonde.dlamini@nhls.ac.za 
Tel: +27 312402793 
Co-investigator 
Inkosi Albert Luthuli Central Hospital, 
800 Vusi Mzimela Rd, Cato Manor, 
4091, Durban, South Africa. 
Email: 
keeren.lutchminarain@nhls.ac.za 
Tel: +27 312402793 
Clinical HIV Research Unit (CHRU), WITS Health Consortium 
Jose Pearson TB Hospital, Bethelsdorp, Port  Elizabeth, South 
Africa 
WITS CHRU Study Team  
Francesca Miranda Conradie, MD, DTM&H, 
Diploma in HIV Management, Diploma in 
Epidemiology, Principle and Practice  
Co- Investigator 
 
University of the Witwatersrand 
Clinical HIV Research Unit (CHRU) 
Department of Medicine, University of 
Witwatersrand 
Helen Joseph Hospital 
Perth Road, Westdene 
Johannesburg,2092  
Email: fconradie@witshealth.co.za 
Tel: +27 11 276 8800 
Zoleka Nini 
Data Manager 
Isango Lethemba TB Research Unit 
Jose Pearson TB Hospital 
Mission Road, Bethledorp, 
Port Elizabeth, 6200 
South Africa 
Email: znini@witshealth.co.za 
Tel: +27 41 492 2490 
 
 
 
Tasnim Badat (MMedSci, MBChB) 
Co- Principal Investigator 
Clinical HIV Research Unit (CHRU) 
Jose Pearson TB Hospital 
Mission Road, Bethledorp, 
Port Elizabeth, 6200 
South Africa 
Email: tbadat@witshealth.co.za 
Tel: +27 41 492 2490 
Hannelise Feyt 
Internal Monitor 
Clinical HIV Research Unit (CHRU) 
Jose Pearson TB Hospital 
Mission Road, Bethledorp, 
Port Elizabeth, 6200 
South Africa 
Email: hfeyt@witshealth.co.za 
Tel: +27 41 492 2490    
Institute of Human Virology Nigeria LTDGTE (IHVN), Nigeria 
IHVN Study Sites: 
ERCC Hospital Alushi, Akwanga, Nasawara State, Nigeria 
Mainland Hospital Yaba, Mainland hospital Road, Yaba, Lagos 
State, Nigeria 
IHVN Study Team  
Alash'le Abimiku, BSc, MSc and PhD 
 
Co-Principal Investigator 
 
Institute of Human Virology Nigeria LTDGTE 
(IHVN) 
Plot 252, Herbert Macaulay Way, Central 
Business District, Abuja, Nigeria  
Email : aabimiku@ihv.umaryland.edu 
Tel: +234 813 944 4759 
Co-investigators 
Dr. Evaezi Okpokoro 
Study Manager (Nigerian site) 
Institute of Human Virology Nigeria 
Plot 252, Herbert Macaulay Way, 
Central Business District, Abuja, Nigeria  
Email: eokpokoro@ihvnigeria.org 
Tel: +234 813 944 4759 

 
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Dr. Aderonke Agbaje  
Institute of Human Virology, Nigeria  
2a Herbert Macaulay Crescent 
GRA, Ikeja, Lagos 
email: aagbaje@ihvnigeria.org  
Office line: 09-4610342  | Fax: 09-4610343 | 
Mobile: 08057928400 | 07062042044 | 
 
Ethiopian Public Health Institute (EPHI), Ethiopia 
EPHI Study Sites: 
Alert Hospital, Addis Ababa, Ethiopia 
St. Peter Hospital, Addis Ababa, Ethiopia 
Geda Health Center, Adama Hospital, Adama, Ethiopia 
Tulu Bolo Hospital, Oromia, Ethiopia 
Kuyera Treatment Initiation Center, Shashemene Town, Oromia, Ethiopia  
EPHI Study Team 
Getachew Tollera, MD, MPH 
Ethiopian Public Health Institute (EPHI) 
Gulelle Arbegnoch Street  
Gulele Sub City 
Addis Ababa 
Ethiopia 
Email: getachewtollera@gmail.com 
Shewki Moga  
Ethiopian Public Health Institute (EPHI) 
Gulelle Arbegnoch Street  
Gulele Sub City 
Addis Ababa 
Ethiopia 
Email: shewki2002@gmail.com 
 
COLLABORATING PARTNER ORGANISATIONS 
 
Koninklljke Nederlandse Centrale Vereniging tot Bestrijding 
der Tuberculose (KNCV), Netherlands 
KNCV Study Team 
Edine Tiemersma, MSc, PhD  
Co- Investigator 
 
Koninklijke Nederlandse Centrale Vereniging 
tot Bestrijding der Tuberculose (KNCV) 
Maanweg 174 
2516 AB Den Haag  
Netherlands 
Email : edine.tiemersma@kncvtbc.org 
Dr Agnes Gebhard 
Co- Investigator 
 
Koninklijke Nederlandse Centrale 
Vereniging tot Bestrijding der 
Tuberculose (KNCV) 
Maanweg 174 
2516 AB Den Haag  
Netherlands 
Email : agnes.gebhard@kncvtbc.org 
 
Katja Lumelova 
Project manager 
Koninklijke Nederlandse Centrale 
Vereniging tot Bestrijding der 
Tuberculose (KNCV) 
Maanweg 174 
2516 AB Den Haag  
Netherlands 
email: katja.lumelova@kncvtbc.org 
 
Dr Ahmed Bedru 

 
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Study Manager (Ethiopian site) 
Co- Investigator 
 
KNCV Tuberculosis foundation  
Gulelle Arbegnoch Street  
Gulele Sub City 
Addis Ababa 
Ethiopia 
Email : ahmed.bedru@kncvtbc.org 
Kalkidan Yae (MD) 
Project coordinator  
KNCV Tuberculosis foundation  
Gulelle Arbegnoch Street  
Gulele Sub City 
Addis Ababa 
Ethiopia 
Email: Kalkidan.yae@kncvtbc.org 
Mobile: +251 91 365 5594 
 
Amsterdam Institute for Global Health and Development 
(AIGHD), Netherlands 
AIGHD Study Team 
Sabine Hermans, MD, Internal Medicine 
specialization, Infectious Diseases Fellowship, 
PhD and MSc  
Co- Investigator and study statistician 
 
Stichting Amsterdam Institute for Global Health 
and Development (AIGHD) 
Paasheuvelweg 25, 1105 BP Amsterdam,  
the Netherlands  
Email : s.hermans@aighd.org 
Logan Stuck 
Stichting Amsterdam Institute for 
Global Health and Development 
(AIGHD) 
Paasheuvelweg 25, 1105 BP 
Amsterdam,  
the Netherlands  
Email : l.stuck@aighd.org 
 
Mark van Knegsel 
Project manager 
Stichting Amsterdam Institute for Global Health 
and Development (AIGHD) 
Paasheuvelweg 25, 1105 BP Amsterdam,  
the Netherlands  
Email: m.vanknegsel@aighd.org 
 
Ospedale San Raffaele SRL (OSR), Italy 
OSR Study Team 
Daniela Maria Cirillo, MD, Specialty In Medical 
Microbiology and PhD 
Co- Investigator and Microbiologist  
Emerging Bacterial Pathogens Unit 
WHO Collaborating Centre in Tuberculosis 
Laboratory Strengthening 
Andrea Maurizio Cabibbe, PhD 
Emerging Bacterial Pathogens Unit 
WHO Collaborating Centre in 
Tuberculosis Laboratory 
Strengthening 
Tuberculosis Supranational Reference 
Laboratory  

 
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Tuberculosis Supranational Reference 
Laboratory  
Div. of Immunology, Transplantation and 
Infectious Diseases 
Ospedale San Raffaele 
San Gabriele Building 1 
Via Olgettina, 60 
20132 Milano, ITALY 
Telephone +39 02 2643 5685  
Fax +39 02 2643 5183 
Email: cirillo.daniela@hsr.it 
 
Div. of Immunology, Transplantation 
and Infectious Diseases 
Ospedale San Raffaele 
San Gabriele Building 1 
Via Olgettina, 60 
20132 Milano, ITALY 
Telephone +39 02 2643 5548  
Fax +39 02 2643 5183 
Email: 
cabibbe.andreamaurizio@hsr.it 
Foundation for Innovative New Diagnostics, Switzerland (FIND), 
Switzerland  
FIND Study Team  
Morten Ruhwald, MD, PhD 
 
Co- Investigator 
Campus Biotech 
9 Chemin des Mines 
1202 Geneva 
Switzerland 
Email: morten.ruhwald@finddx.org 
Sophia Georghiou, PhD 
Campus Biotech 
9 Chemin des Mines 
1202 Geneva 
Switzerland 
Email: 
sophia.georghiou@finddx.org 
National Institute for Medical Research (NIMR), Tanzania  
NIMR Study Team 
Nyanda Elias Ntinginya, MD, MSc, PhD 
Co- Investigator 
 
NIMR-Mbeya Medical Research Centre, 
Hospital Hill Rd, 
P.BOX 2410, 
Mbeya, Tanzania 
Email: nelias@nimr-mmrc.org  
Dr Bariki Mtafya, MSc, PhD 
TB-MBLA Implementation Support 
NIMR-Mbeya Medical Research Centre, 
Hospital Hill Rd, 
P.BOX 2410, 
Mbeya, Tanzania 
Email: bmtafya@nimr-mmrc.org 
The University Court of the University of St Andrews (USTAN), 
United Kingdom  
USTAN Study Team 
Stephen Gillespie, FRSE 
 
Co- Investigator and Medical Monitoring 
The University Court of the University of St 
Andrews 
College Gate, North Street 
St Andrews KY16 9AJ 
St Andrews 
United Kingdom  
Tel: +44 (0)1334 461871 
Derek Sloan MBChB PhD 
Medical Monitoring 
The University Court of the University of 
St Andrews 
College Gate, North Street 
St Andrews KY16 9AJ 
St Andrews 
United Kingdom  
Tel: +44 (0)1334 461871 

 
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Email : shg3@st-andrews.ac.uk 
Email : djs26@st-andrews.ac.uk 
Global Alliance for TB Drug Development (TB Alliance), 
United States of America  
TB Alliance Study Team 
Eugene Sun, BA and MD 
 
Co- Investigator 
 
TB Alliance 
40 Wall Street  
24th Floor  
New York, NY  10005   
United States of America 
Email: Eugene.Sun@tballiance.org 
Morounfulo Olugbosi, MD 
TB Alliance 
Boardwalk Office Park, Block 1/Suite 5, 
107 Haymeadow Street, Faerie Glen 
Pretoria 0043, South Africa  
Email: 
Morounfolu.Olugbosi@tballiance.org 
Salah Foraida, MD, MS 
TB Alliance 
40 Wall Street  
24th Floor  
New York, NY  10005   
United States of America 
Email: salah.foraida@tballiance.org 
Zvia Shwirtz MA, BA 
TB Alliance 
40 Wall Street  
24th Floor  
New York, NY  10005   
United States of America 
Email: Zvia.Shwirtz@tballiance.org 

 
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INVESTIGATOR SIGNATURE FORM 
Version 5.0 
04 November 2022  
INVESTIGATOR APPROVAL STATEMENT 
 
I have read the protocol and agree that it contains all necessary details for carrying out the 
Study as described.  I will conduct this protocol as outlined therein and will make a reasonable 
effort to complete the study within the time designated. All individuals responsible for the 
design and conduct of this study have completed Human Subjects Protection Training. 
 
The signature below constitutes the approval of this protocol and the attachments and 
provides the necessary assurances that this trial will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and applicable national regulations and ICH guidelines. 
 
 
Site Investigator: 
 
 
 
________________________________             28 September 2023 
Principal investigator signature                            Date 
(CAPRISA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
PARTICIPATING ORGANISATIONS IN THE STUDY .......................................................... 2 
 
INVESTIGATOR SIGNATURE FORM .................................................................................. 8 
 
TABLE OF TABLES ........................................................................................................... 11 
 
TABLE OF FIGURES ......................................................................................................... 11 
 
ABBREVIATIONS AND ACRONYMS ................................................................................ 12 
 
1. 
STUDY SUMMARY ..................................................................................................... 15 
 
2. 
INTRODUCTION ......................................................................................................... 19 
2.1. 
Background and Rationale ................................................................................ 19 
2.2. 
Epidemiology of DR-TB ..................................................................................... 21 
2.3. 
Evidence for novel regimens and diagnostics proposed in this study ................. 21 
2.4. 
Potential Benefits .............................................................................................. 24 
2.5. 
Potential Harm................................................................................................... 24 
 
3. 
DEFINITIONS OF DR-TB ............................................................................................ 25 
 
4. 
STUDY DESIGN, AIMS AND OBJECTIVES ............................................................... 25 
4.1. 
Study Design ..................................................................................................... 25 
4.2. 
Study Aim .......................................................................................................... 25 
4.3. 
Primary Objectives: ........................................................................................... 26 
4.4. 
Secondary Objectives: ....................................................................................... 26 
4.5. 
Study Outcome Measures ................................................................................. 27 
 
5. 
STUDY INTERVENTION ............................................................................................. 27 
 
6. 
INVESTIGATIONAL PLAN .......................................................................................... 30 
6.1. 
Selection of study clinical research sites............................................................ 30 
6.2. 
Selection of Participants .................................................................................... 31 
6.3. 
Participant Inclusion Criteria for cohorts 1 and 2 ................................................ 31 
6.4. 
Participant Exclusion Criteria ............................................................................. 32 
6.5. 
Late Exclusion Criteria ....................................................................................... 32 
6.6. 
Screening Procedures ....................................................................................... 32 
6.7. 
Enrolment Procedures ....................................................................................... 33 
 
7. 
STUDY ASSESSMENTS AND FOLLOW-UP .............................................................. 34 
7.1. 
Schedule of evaluations .................................................................................... 34 

 
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7.2. 
General Mycobacteriology ................................................................................. 40 
7.3. 
Cost effectiveness and acceptability analysis .................................................... 41 
 
8. 
TREATMENT CONSIDERATIONS .............................................................................. 43 
8.1. 
Interruptions to treatment .................................................................................. 43 
8.2. 
Discontinuation of treatment due to toxicity or treatment failure ......................... 43 
8.3. 
Interruptions to care .......................................................................................... 44 
 
9. 
STATISTICAL CONSIDERATIONS ............................................................................. 45 
9.1. 
Power and Sample size calculations: ................................................................ 45 
9.2. 
Analysis including statistical methods: ............................................................... 46 
9.3. 
Outcome Status ................................................................................................. 47 
 
10. PROCEDURES FOR ASSESSING SAFETY AND ADVERSE EVENT REPORTING . 49 
10.1. 
Adverse Events (AEs) and Adverse Event Reporting ..................................... 49 
10.2. 
Expected Disease Related Events ................................................................. 52 
10.3. 
Serious Adverse Event Reporting .................................................................. 52 
10.4. 
Anti-TB Drug Information for new study drugs ................................................ 52 
 
11. DATA MANAGEMENT ................................................................................................ 58 
 
12. STUDY COMMITTEES ................................................................................................ 59 
12.1. 
Joint Steering Committee ............................................................................... 59 
12.2. 
Medical Monitoring Team ............................................................................... 60 
12.3. 
Data Safety Monitoring Board (DSMB)........................................................... 60 
 
13. HUMAN PARTICIPANT PROTECTION AND ETHICAL OBLIGATIONS .................... 61 
13.1. 
Ethical and Regulatory Review ...................................................................... 61 
13.2. 
Informed consent process .............................................................................. 61 
13.3. 
Participant Confidentiality .............................................................................. 62 
13.4. 
In-country Regulations of diagnostics and study drugs .................................. 62 
13.5. 
Good Clinical Practice .................................................................................... 63 
 
14. BIOHAZARD CONTAINMENT .................................................................................... 64 
 
15. REFERENCES ............................................................................................................ 65 
 
16. APPENDICES ............................................................................................................. 68 
Appendix I: General guide to safety monitoring in DR-TB therapy ................................ 68 
Appendix II: Example of TRiAD Screening Informed Consent Form ............................. 73 
Appendix III: Example of TRiAD Enrolment Informed Consent Form – Cohort 1 .......... 78 
Appendix IV: Example of TRiAD Enrolment Informed Consent Form – Cohort 2 .......... 85 

 
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TABLE OF TABLES   
 
Table 1  Overview of TRiAD Study ...................................................................................... 15 
 
Table 2: Current Drug-Resistant TB Treatment Regimen by TB resistance profile and 
proposed study approach ...................................................................................... 29 
 
Table 3: Schedule of Evaluation for Drug-Resistant Tuberculosis participants in the TRiAD 
Study Cohort 1 ...................................................................................................... 36 
 
Table 4 : Schedule of Evaluation for Drug-Resistant Tuberculosis participants in the TRiAD 
Study Cohort 2 ...................................................................................................... 39 
 
Table 5: Overview of microbiologic assessments performed after each visit ....................... 40 
 
Table 6: Reported median times (in days [IQR]) to treatment of drug-resistant TB in literature
 ........................................................................................................................................... 45 
 
Table 7: Treatment outcomes for RR-TB/MDR-TB/XDR-TB participants treated ................. 48 
 
Table 8: Grading the severity of ADR; following common guidelines and management for the 
treatment of TB used in the TRiAD study .............................................................. 50 
 
Table 9: Summary profile of drugs to be used for treatment of DR-TB in the TRiAD study .. 53 
 
TABLE OF FIGURES  
 
Figure 1 : TRiAD Study Schema ......................................................................................... 18 
 
Figure 2: Map of TRiAD Clinical Research Sites in South Africa, Nigeria and Ethiopia ........ 30 
 
Figure 3: Study screening and enrolment for the TRiAD Study ........................................... 33 

 
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ABBREVIATIONS AND ACRONYMS 
 
AE 
Adverse Events  
ADR 
Adverse Drug Reaction 
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immunodeficiency Syndrome 
AIGHD  
Amsterdam Institute For Global Health And Development 
ART 
Antiretroviral Treatment 
BDQ 
Bedaquiline 
BMI 
Body Mass Index 
BPaL 
Bedaquiline-Pretomanid-Linezolid 
BPaMz 
Bedaquiline-Pretomanid-Moxifloxacin-Pyrazinamide 
BREC 
Biomedical Research Ethics 
CAPRISA  
Centre For The AIDS Programme Of Research In South Africa  
CFZ 
Clofazimine 
Co – PI 
Co - Principal Investigator 
CRF 
Case Report Form 
CRS 
Clinical Research Site  
CT 
Cycle Threshold 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DALY 
Disability Adjusted Life Year 
DLM 
Delamanid 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-Resistant TB 
DSMB 
Data Safety Monitoring Board 
DST 
Drug Susceptibility Testing 
DS-TB 
Drug-Sensitive TB 
E 
Ethambutol 
eCFU/ml 
Estimated Colony Forming Units Per Millilitre 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture  
EDCTP 
The European And Developing Countries Clinical Trials Partnership 
EDR 
Electronic Drug Resistant Software 
EPHI 
Ethiopian Public Health Institute 
FDA 
Food And Drug Administration 
FIND  
The Foundation For Innovative New Diagnostics 
FQ 
Fluoroquinolones 
GCDMP 
Good Clinical Data Management Processes 
GCP  
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus  
HREC 
Human Research Ethics Committee 
HR-TB 
TB resistant to INH with no resistance to rifampicin 
IATA 
International Air Transport Association 

 
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ICF 
Informed Consent Form 
IHVN  
Institute Of Human Virology Nigeria 
INHhd 
High-Dose Isoniazid 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
JSC 
Joint Steering Committee 
KNCV  
KNCV Tuberculosis Foundation 
KZN 
KwaZulu – Natal 
LFX 
Levofloxacin 
LPA 
Line Probe Assay 
LTBI 
Latent TB Infection  
LTFU 
Loss To Follow-Up 
LZD 
Linezolid 
TB-MBLA 
Tuberculosis - Molecular Bacterial Load Assay 
MDR-TB 
Multi Drug-Resistant TB 
MGIT 
Mycobacteria Growth Indicator Tube 
MIC 
Minimum Inhibitory Concentration 
MMT 
Medical Monitoring Team  
M.tb 
Mycobacterium Tuberculosis 
MXF 
Moxifloxacin 
NGS 
Next-Generation Sequencing 
NHREC 
National Health Research Ethics Committee 
NIMR  
National Institute For Medical Research 
NTP 
National Tuberculosis Control Programme 
OCR 
optical character recognition  
OSR 
Ospedale San Raffaele 
pDST 
Phenotypic Drug susceptibility testing 
PTB 
Pulmonary TB 
PI 
Principal Investigator 
PID 
Participant's ID 
PLWHA 
People Living With HIV/AIDS 
PTO 
Prothionamide 
QA 
Quality Assurance 
QC 
Quality Control 
QTc 
Quantum Tunnelling Composite 
RNA 
Ribonucleic Acid 
rRNA 
Ribosomal RNA 
RR-TB 
Rifampicin-Resistant TB 
RT-qPCR 
Reverse Transcription quantitative PCR 
SA 
South Africa 
SA DoH  
South African Department Of Health  
SA GCP 
South African Good Clinical Practice 
SAE 
Serious Adverse Events  
SAPHRA 
South African Health Products Regulatory Agency 
SAS 
Statistical Analysis Software 

 
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SERO 
Scientific And Ethical Review Office 
SOC  
Standard Of Care 
SoE 
Schedule Of Events 
SOP 
Standard Operating Procedure 
STREAM 
Short Standardized Regimen For The Treatment Of Rifampicin-Resistant 
Tuberculosis: A Randomized Non-Inferiority Trial To Evaluate A Short 
Standardized Regimen For The Treatment Of Rifampicin-Resistant 
Tuberculosis 
STR 
Shorter Treatment Regimen 
TB 
Tuberculosis  
TRD 
Terizidone 
TTP 
Time to positivity  
TRiAD 
Triage Test For All Oral DR-TB Regimen 
USTA 
University Of St Andrews 
WGS 
Whole Genome Sequencing 
WHO 
World Health Organisation  
XDR-TB 
Extensively Drug-Resistant TB 
Z 
Pyrazinamide 
 

 
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1. STUDY SUMMARY  
The TRiAD study is a multi-center, multi-country Prospective Pragmatic Cohort study 
assessing the effectiveness, feasibility, acceptability, and cost-effectiveness of implementing 
the Xpert MTB/XDR (Xpert XDR; Cepheid) assay for rapid triage-and-treatment with short, all- 
oral drug resistant tuberculosis (DR-TB) treatment. The proposed study aims to screen 
approximately 4800 GeneXpert MTB/RIF or Ultra MTB-positive participants or any currently 
available Nucleic Acid Amplification Tests for drug-resistance detection changes (irrespective 
of rifampicin resistance status) from clinical research sites in South Africa, Nigeria and Ethiopia 
to enrol 880 rifampicin resistant (RR) and 400 rifampicin sensitive and isoniazid, fluroquinolone 
and or second line injectable drug (SLID) resistant participants over a period of 12-18 months. 
The Xpert XDR assay, a rapid genotypic test, will be implemented as a reflex test to detect 
resistance to isoniazid, fluoroquinolones and second-line injectable agents to provide rapid 
genotypic susceptibility testing for DR-TB detection. Participants that test positive for 
Mycobacterium tuberculosis (M.tb) with rifampicin resistance will be enrolled in Cohort 1 
(n=880). Participants that test positive for M.tb that are rifampicin susceptible with isoniazid, 
fluroquinolone and or second line injectable drug (SLID) resistant will be enrolled in Cohort 2 
(n=400). Results from the Xpert XDR assay will be used to guide selection of appropriate, 
evidence-based, all-oral DR-TB treatment regimens of shortest possible duration. The 
tuberculosis molecular bacterial load assay (TB-MBLA) will be used as an adjunct to provide 
bacillary load monitoring over the course of treatment to assess real-time treatment 
response. Operational research will provide information about the feasibility, acceptability and 
cost-effectiveness to inform policies and guidelines for programmatic implementation of the 
triage-and-treat model.  
 
Table 1  Overview of TRiAD Study  
Study Aim 
To evaluate the effectiveness, operational feasibility, acceptability, 
and cost-effectiveness of implementing the Xpert MTB/XDR assay 
for rapid triage and selection of all-oral regimens for Drug-
Resistant Tuberculosis (DR-TB) 
Study Design 
 
Prospective 
Pragmatic 
Cohort 
Study: 
non-randomized 
interventional phase 4 (clinical access protocol) implementation 
science study utilizing interventions of proven clinical efficacy 
Study Duration 
48 months: study enrolment will occur over 12 -18 months  
Sample Size 
  
A total of 1280 participants will be enrolled between 2 prospective 
study cohorts: 
Cohort 1 (newly diagnosed DR; rifampicin resistance [RR-TB] 
participants; n=880) and Cohort 2 (rifampicin sensitive and 
isoniazid, fluroquinolone and or second line injectable drug 
(SLID) resistant participants; HR-TB; n=400).  
Data from a historical cohort (Cohort 3; n=220) of RR-TB 
participants that accessed DR-TB care at each implementing site 
over the last 2 years (approximately 24 months) prior to study 
start. 

 
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Study sites  
South Africa (n=2), Nigeria (n=6) and Ethiopia (n=5) 
Study population 
 
Adult participants (18 years and over) who test positive for 
pulmonary M.tb with HR-TB or RR-TB will be approached for study 
participation  
Study intervention  
 
Xpert MTB/XDR assay as a triage test to guide early initiation of 
an appropriate all-oral DR-TB treatment regimen  
Study Objectives 
Primary Objectives:  
• 
To compare the time to initiation of resistance-pattern 
appropriate TB treatment from the date of first sputum 
collection with the standard of care compared to a 
historical cohort, stratified by geographical location 
• 
To assess the proportion of DR-TB participants with cure 
and/or DR-TB treatment completion at month 12 compared 
to a historical control group  
Secondary Objectives: 
Clinical:  
• 
To assess the safety and effectiveness of all-oral regimens 
under operational conditions 
• 
To assess all-cause mortality at month 12 and 18, rates of 
drug-related discontinuation for safety concerns and rates 
of drug-related adverse events  
Microbiological: 
• 
To assess time to culture conversion, cure, and rates of 
clinical TB relapse  
• 
To determine the prevalence of HR-TB stratified by 
geographic location 
• 
To determine the prevalence of pre-XDR and XDR-TB 
using phenotypic DST to bedaquiline, pretomanid and 
linezolid  
• 
To 
determine 
the 
proportion 
of 
participants 
with 
bedaquiline and linezolid resistance warranting a switch 
from short-course treatment  
• 
To assess the clinical utility of the TB Molecular Bacterial 
Load Assay (TB-MBLA) as a predictor of treatment 
outcome 
• 
To assess the diagnostic and clinical performance of the 
test and triage approach by geographic location using 
whole genome sequencing (WGS) and Minimum Inhibitory 
Concentration (MIC) analysis 
• 
To determine the phylogenetic structure and full drug 
resistance 
patterns 
of 
study 
samples, 
including 
bedaquiline, linezolid, levofloxacin and pretomanid 

 
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Cost-effectiveness, feasibility and acceptability compared to 
the standard of care: 
• 
To determine cost per person tested and incremental cost 
per DR-TB participant timely initiated on the resistance- 
pattern appropriate regimen 
• 
To determine the incremental cost per Disability Adjusted 
Life Year (DALY) averted and per day delay averted in 
treatment with the resistance- pattern appropriate regimen 
• 
To assess programmatic cost-effectiveness, feasibility, and 
acceptability of implementing any currently available 
Nucleic Acid Amplification Tests for drug-resistance 
detection changes with Xpert MTB/XDR testing for HR and 
second-line DR-TB drugs 
• 
To investigate participant’s, health care provider’s and 
policy-maker’s acceptability of the triage and treat 
approach 
• 
To assess the feasibility of the implementation of the triage 
and treat approach in routine care 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 1 : TRiAD Study Schema  
Currently available Nucleic Acid Amplification Tests for drug-resistance detection  
Positive Pulmonary TB Cases / Or Individual with TB symptoms1 
 
SCREENING & 
RECRUITMENT  
STUDY COHORTS 
STUDY OUTCOMES  
 
COHORT 2: Rif sensitive TB with HR, 
FQ, Ethionamide and or 
aminoglycoside resistance-TB 
N=400 
 
XPERT XDR DST for standard DS-TB short 
course + Fluoroquinolone regimen 4 
Passive follow-up until treatment outcome 
NIGERIA 
ETHIOPIA 
SOUTH AFRICA  
COHORT 1: RR-TB 
N=880 
 
XPERT XDR DST for short,  
all-oral regimen 4 
Active follow-up and AE monitoring 
as per SoE 
Primary Outcomes5: 
 
I.
Time to initiation of an appropriate all-oral treatment regimen from date of first 
sputum collected  
II.
Proportion of patients with favourable treatment outcomes at month 12 from 
diagnosis  
Secondary Outcomes: 
I.
Incidence of adverse drug reactions documented during all-oral treatment  
II.
All-cause mortality documented during treatment and follow-up 
III.
Time specific rates of culture conversion 
IV.
Prevalence of HR-TB (cohort 2) 
V.
Prevalence of XDR-TB (cohort 2)  
VI.
Proportion of patients with Bedaquiline and linezolid resistance not eligible for short-
course treatment  
VII.
Clinical utility and feasibility of the TB-MBLA for monitoring treatment response  
VIII.
Accuracy and quality of Xpert XDR testing compared to WGS 
IX.
Additional resistance to new and re-purposed drugs using WGS 
X.
Cost-effectiveness - cost per person tested and incremental cost per DR-TB patient 
timely initiated on treatment  
XI.
Feasibility and acceptability of patient triaging (Participant and health care provider 
perspective 
Xpert XDR2 
& 
Phenotypic DST3 
1 All currently available Nucleic Acid Amplification Tests for drug-resistance detection Positive 
sputum samples will be screened using Xpert XDR assay until we meet the recruitment target for 
cohort 2. Thereafter, only RR-TB patients will be screened for cohort 1. Xpert XDR detects 
resistance to INH, Fluoroquinolones and 2nd Line Injectables  
2 All eligible patients will provide an additional sputum sample for Xpert XDR testing at screening, if 
reflex testing on provided sputum sample is not feasible  
3 Phenotypic DST to BDQ, Linezolid and Clofazimine will be offered for pre-XDR TB cases as per in-
country guidelines  
4Choice of regimen will be guided by best available evidence from clinical trials using novel regimen, 
current WHO and in-country guidelines as described in Table 2  
5 Primary outcome measures for cohort 1 will be compared to a historical dataset of DR-TB patients 
diagnosed and treated at the each of the facilities over the last 2 years (approximately 24 months) 

 
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2. INTRODUCTION 
 
2.1. Background and Rationale 
 
Tuberculosis (TB) caused by the bacterium Mycobacterium tuberculosis (M.tb), remains the 
deadliest infectious disease globally. According to the World Health Organization (WHO) 
global TB report, the burden of multidrug-resistant TB (MDR-TB); i.e., resistance to at least 
rifampicin and isoniazid, has increased by an annual rate of over 20% during the period 2009-
2017(1). In 2019, the global burden of Rifampicin-Resistant TB (RR-TB) was estimated at 
465,000 cases, 78% of which was MDR-TB. Sub-Saharan Africa carries 25% of the global 
burden of drug-resistant TB (DR-TB) (2). Successful management of DR-TB is hampered by 
difficulties in both diagnosis and treatment, fuelling the ongoing transmission of DR-TB (3). In 
order to achieve the targets of the WHO End TB strategy by 2035, a 90% decrease in TB 
incidence and a 90% reduction in TB mortality is required between 2015-2035. In line with this 
ambitious target, there is an urgent need for new diagnostic and therapeutic approaches in 
order to improve the diagnostic accuracy and timely initiation of treatment for DR-TB (4). 
 
Globally, health systems have failed to effectively implement DR-TB testing and treatment 
regimens, evidenced by dismal treatment success rates. In 2019, WHO reported treatment 
success rates of approximately 57% for DR-TB (2). Historically, the treatment of DR-TB has 
been challenging due to prolonged duration of treatment (20-24 months), severe toxicities and 
sub-optimal treatment success. Given the complex nature and duration of DR-TB treatment, 
significant medication adherence issues arise thereby contributing to poor treatment 
completion rates. Until recently, the WHO guidelines for MDR-TB (including RR-TB) and  
extensively drug-resistant TB (XDR-TB) incorporated the use of injectable aminoglycosides 
and a fluoroquinolone as the backbone of treatment (5). These agents were considered 
significant contributors in obtaining a successful treatment outcome. However, the use of 
these drugs has been associated with severe discomfort and side-effects including hearing 
loss and renal impairment, which, in addition to personal suffering, affect treatment adherence 
and completion (6). Given the toxicity associated with the second-line injectable drugs, WHO 
recently modified DR-TB treatment guidelines no longer recommend the use of second-line 
injectables as part of the MDR-TB regimen. In the latest guidelines, WHO re-classified anti-
TB drugs into three main groups according to the available evidence on DR-TB drug 
effectiveness and safety. These include; Group A (bedaquiline, linezolid, moxifloxacin or 
levofloxacin), Group B (clofazimine, and cycloserine or terizidone) and Group C (ethambutol, 
delamanid, 
pyrazinamide, 
imipenem-cilastatin, 
meropenem, 
amikacin/streptomycin, 
ethionamide/prothionamide, p-aminosalicylic acid). In line with this recommendation the 
definition of XDR-TB on the basis of resistance to second-line injectables became less 
clinically relevant. Thus, leading to 2021 revised definitions for DR-TB. According to the 
update, pre-XDR is defined as RR-TB or MDR-TB with additional resistance to a 
fluoroquinolone. XDR-TB is now defined as RR-TB or MDR-TB with resistance to a 
fluoroquinolone and at least one other group A drug. The definition for MDR-TB remains the 
same.  
 
The diagnosis of DR-TB poses a further obstacle to attaining successful treatment. In high-
burden DR-TB countries, the diagnosis of MDR-TB in most settings is a proxy diagnosis made 

 
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through a multi-step testing cascade. Currently, the front-line molecular diagnostic assay for 
drug resistance is Cepheid Xpert MTB/RIF or Xpert MTB/Ultra, which detects the presence of 
M.tb bacilli and simultaneously detects RR-TB. Whilst rapidly identifying patients eligible for 
MDR-TB treatment, the test is limited to the detection of RR only (7, 8). Patients who display 
RIF resistance receive reflex testing which includes resistance to fluoroquinolones and 
second-line injectables using standard phenotypic drug susceptibility testing (pDST) and the 
Hain Line Probe Assays (LPA 1 and 2), which detect resistance to isoniazid, rifampicin, 
fluoroquinolones and second-line injectable agents (9).  Drug susceptibility testing (DST) for 
all other drugs is conducted using phenotypic testing methods. However, following a rapid 
diagnosis by Xpert MTB/RIF or Xpert MTB/Ultra, all follow-on testing is conducted at a regional 
laboratory thereby increasing the turn-around times for providing a comprehensive resistance 
profile. Furthermore, these DST methods have several limitations. Although LPA testing can 
be rapidly performed on sputum samples, LPAs require specialised laboratory facilities, longer 
turnaround time and are associated with a high indeterminate rate (~30%) in smear-negative 
patients (10). Phenotypic DST (pDST) techniques require approximately 4-6 weeks and result 
interpretation are compounded by issues with the established critical drug concentrations used 
to predict resistance and poor performance for certain drugs such as ethionamide and 
pyrazinamide. Currently, DR-TB patients are initiated on empiric treatment, which is modified 
as DST results become available, resulting in a 4-6-week delay in initiation of appropriate 
treatment. As a result of this sub-optimal testing cascade, many patients may receive a limited 
number of effective drugs in the regimen, increasing the risk of amplifying drug resistance and 
ongoing transmission of DR-TB (3). A further challenge which hinders the diagnosis and 
treatment of DR-TB is the lack of susceptibility testing for isoniazid resistance by assays 
available at the point where the patient enters the care cascade, i.e. Xpert MTB/RIF, Xpert 
MTB/RIF Ultra, or the Truenat assays. As a consequence, isoniazid mono-resistant TB 
patients (HR-TB; i.e. patients who display INH resistance in the absence of RIF resistance) 
are not appropriately diagnosed.  This sub-set of patients receive standard DS-TB treatment, 
thereby increasing the risk of amplifying drug resistance (11).  
 
In the last few years, the DR-TB treatment landscape has been transformed drastically by 
several landmark changes to DR-TB guidelines. These include: reports confirming safety and 
the survival benefit of Bedaquiline (BDQ) for MDR-TB (12); WHO endorsement of the standard 
9 month short-course regimen for MDR-TB and the Short Standardized Regimen For The 
Treatment Of Rifampicin-Resistant Tuberculosis (STREAM ; NCT02409290) study results 
demonstrating non-inferiority of shorter DR-TB regimens to longer regimens (13, 14); the 
replacement of second-line injectables with BDQ in the standard short-course DR-TB regimen, 
resulting in the first all-oral regimen for DR-TB (15); and the results of the novel 6 month BPaL 
(BDQ, pretomanid, and linezolid) regimen for XDR-TB. These changes have resulted in a 
rapid transition to all-oral treatment options for DR-TB. Thus, the current study aims to 
implement diagnostics with proven clinical efficacy to guide treatment with novel, all-oral 
regimens as efficacy data from clinical studies emerge. Furthermore, the lack of specific 
outcome data for the novel diagnostic assays represents a significant implementation 
research gap which the study will address. Given the state of access to DR-TB diagnosis and 
treatment globally, the implementation of shorter, efficacious, and more importantly, less toxic 
regimens than the conventional long regimen holds significant promise in improving dire 
treatment success rates. Notably, this approach could potentially preserve the potency of the 
new drugs included in the shorter regimens by preventing the rapid amplification of resistance. 
 

 
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2.2. Epidemiology of DR-TB 
 
South Africa, Ethiopia and Nigeria feature prominently among the 30 high-burden TB countries 
with significantly overlapping epidemics of TB, Human Immunodeficiency Virus (HIV) and 
MDR-TB. The 30 high-burden countries collectively contribute to approximately 90% of the 
global disease burden. South Africa, in particular, remains among the few countries with a TB 
incidence exceeding 500 cases per 100,000 population with approximately 360,000 cases of 
TB reported during 2019. In 2019, 13,005 and 406 cases of laboratory confirmed RR/MDR-
TB and XDR-TB were reported in South Africa, respectively. The overall treatment success 
rate was 71% for drug-susceptible TB (DS-TB), 60 % for RR-TB/ MDR-TB and XDR-TB. 
Ethiopia has a TB incidence rate of 140 cases per 100,000 population with approximately 
157,000 cases of TB reported during 2019. In 2019, 658 and 4 cases of laboratory confirmed 
RR/MDR-TB and XDR-TB were reported in Ethiopia, respectively. The overall treatment 
success rate was 88% for DS-TB, and 75% for RR-TB/ MDR-TB and XDR-TB. Nigeria records 
a TB incidence rate of 219 cases per 100,000 population with approximately 440,000 cases 
of TB reported during 2019. In 2019, 2,384 and 16 cases of laboratory confirmed RR/MDR-
TB and XDR-TB were reported in Nigeria, respectively. The overall treatment success rate 
was 87% for DS-TB, 77% for RR-TB/ MDR-TB, and no data were available for the XDR-TB 
patients (2).  
 
2.3. Evidence for novel regimens and diagnostics proposed in this study 
 
2.3.1. Novel, all-oral treatment regimens for DR-TB 
 
Historically, MDR-TB and XDR-TB patients have been treated with a multi-drug treatment 
regimen which comprises of an intensive phase of treatment of 8 months and a total duration 
of treatment of 20-24 months. For patients with RR-TB or MDR-TB who were not previously 
treated with second-line drugs and for whom resistance to fluoroquinolones and second-line 
injectable agents was excluded or is considered highly unlikely, a shorter treatment regimen 
(STR) still including an injectable, was recommended. This STR was evaluated in Stage 1 of 
the STREAM trial and is composed of high-dose later generation fluoroquinolone, clofazimine, 
pyrazinamide and ethambutol throughout, supplemented by amikacin, prothionamide, and 
high-dose isoniazid in the intensive phase. The treatment duration of the intensive phase is 
four months (extended to a maximum of six months until sputum smear conversion), and the 
duration of the continuation phase is five months. In December 2019, WHO issued a rapid 
communication encouraging countries to replace the injectable in this regimen with BDQ and 
use the all oral bedaquiline based STR as the preferred option.  
 
In addition to this newly recommended shorter all-oral MDR-TB regimen, there are other 
shorter regimens currently being evaluated in clinical trials for the same and different patient 
groups. Many of these regimens employ new or repurposed medicines, which have been 
shown to be effective in clinical trials. These regimens have common desirable features: good 
tolerability, all-oral and with shorter treatment duration. 
 
One such regimen is the BPaL regimen which consists of BDQ, pretomanid and linezolid given 
for 6 months. Currently, the BPaL regimen is the most appropriate alternative for the treatment 
of pre-XDR TB (MDR with additional fluoroquinolone resistance) and XDR-TB (pre-XDR with 
resistance to at least one additional Group A drug). The efficacy of the regimen was evaluated 

 
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in a single-arm randomized controlled trial which demonstrated that 90% of patients recorded 
a favourable treatment outcome. Treatment associated toxicity linked to the use of linezolid 
within the regimen was reported as manageable with dose reduction and interruption of 
linezolid use (16). The BPaL regimen recently received Food And Drug Administration (FDA)  
approval for use in people with DR-TB or treatment-intolerant/non-responsive MDR-TB or 
patients for whom there is no other viable as per WHO recommendations (17).  
 
Another novel, short-course regimen under evaluation is the BPaMZ regimen indicated for use 
in HR-TB, RR-TB and MDR-TB is currently in late-stage clinical development. The regimen 
incorporates the use of two novel drugs, BDQ and pretomanid, in combination with 
pyrazinamide and moxifloxacin (SimpliciTB study). Pre-clinical data in a murine model 
demonstrated potent sterilising activity (18). Phase 2B human study data indicates superior 
efficacy of the novel combination in patients with DS-TB and MDR-TB (19). A phase 3 trial of 
the BPaMZ regimen (SimpliciTB; NCT03338621) is currently evaluating the potential to both 
shorten treatment to 4 months for patients with DS-TB and also effectively treat patients with 
RR- or MDR-TB (as a 6-month regimen, because of the higher risk of associated resistance 
to pyrazinamide) (20). Modelling analysis on the projected patient outcomes using the BPaMZ 
regimens indicates that universal implementation of the regimen has the potential to increase 
the percentage of patients with RR-TB who are cured from 60% to nearly 90% and maintain 
nearly 90% cure among patients with DS-TB. Further, the regimen could reduce treatment 
duration by two months and reduce infectious person-time by 50% (RR-TB) (21).  
 
The current programmatic DR-TB treatment regimens for each country and the proposed 
novel interventions are described in Table 2. Novel DR-TB regimens under evaluation will be 
considered for inclusion by the TRiAD Joint Steering Committee (JSC) once sufficient safety 
and efficacy data becomes available. 
 
2.3.2.  The Xpert MTB/XDR Assay 
 
The GeneXpert instrument platform is an automated cartridge-based system for TB diagnosis. 
The WHO endorsed the use of the Xpert MTB/RIF assay for the GeneXpert platform in 2010 
and the assay has since been widely used in TB programs. The Xpert MTB/RIF assay was 
subsequently replaced by the Xpert Ultra assay which demonstrated improved sensitivity in 
paucibacillary disease.  However, for RR-TB patients, the Xpert MTB/RIF and Ultra assays 
provide no further information on the resistance profile of the infecting strain type.  
 
The Xpert MTB/XDR cartridge, a new diagnostic that is being evaluated in this study, intended 
for use as a reflex test.  The assay includes eight genes and promoter regions in M. tb allowing 
for the detection of resistance to isoniazid, aminoglycosides and fluoroquinolones, 
ethionamide and the second-line injectables, enabling the diagnosis of pre-XDR TB in 
combination with Xpert MTB/RIF or Ultra. This assay showed excellent analytical performance 
in a clinical study performed at two sites with 100 sputum and 214 clinical isolates.  The assay 
demonstrated a sensitivity of 94-100% and a specificity of 100% for all drugs except for 
ethionamide in comparison to sequencing. The sensitivity and specificity when compared to 
phenotypic drug-susceptibility testing (DST) were in the same range (22, 23).   
  
 

 
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The Xpert MTB/XDR assay is undergoing external assessment in the Xpert MTB/XDR clinical 
evaluation trial (NCT03728275), wherein the diagnostic accuracy of the assay and its use in 
diverse clinical settings is being evaluated amongst 600 patients in multicentre clinical 
evaluation (20). The MTB/XDR assay incorporates the same single-step specimen processing 
as the Xpert MTB/RIF and Ultra and can be implemented with minimal staff training and 
biosafety requirements. Existing GeneXpert instruments have the potential to be upgraded 
contemporaneously by upgrading software and performing a 10-colour calibration. These are 
significant features that would permit Xpert MTB/XDR to be used in peripheral sectors of the 
global health care system, where more rapid identification of expanded drug resistance may 
improve therapeutic decision-making. WHO has endorsed the use of Xpert XDR for diagnosis 
of 
TB 
drug 
resistance 
as 
of 
June 
2021 
(https://www.who.int/publications/i/item/9789240029415). 
 
The focus of this protocol is to utilise the Xpert MTB/XDR assay to triage participants by 
promptly identify varying resistance profiles in order to guide the selection of appropriate 
treatment regimens. With optimal implementation, this new test should improve the selection 
of appropriate regimens, reducing time to appropriate treatment and improving patient 
outcomes (22, 24). Given the recent updated definition, the Xpert XDR assay will diagnose 
pre-XDR-TB. Additional DST to BDQ and linezolid (LZD) is required to define XDR-TB.  
 
2.3.3. Tuberculosis-Molecular Bacterial Load Assay (TB-MBLA) 
 
The TB-MBLA is a novel, quantitative Reverse Transcription PCR (RT-qPCR) that uses 16S-
ribosomal RNA (rRNA) targets to quantify the M.tb bacillary load over the course of treatment 
in real-time (25). A major limitation of the current TB diagnostic and management algorithm is 
the lack of a sensitive and rapid assay for evaluation of treatment efficacy and predicting 
treatment response. Current therapeutic monitoring is dependent on M.tb bacterial load 
monitoring from clinical samples inferred from Mycobacteria Growth Indicator Tube (MGIT)  
time to a positive result (TTP) and smear microscopy. This poses a challenge as most settings 
where patients first enter the care cascade have limited availability of culture resources due 
to the cost of specialised laboratory infrastructure and training requirements. When resources 
are available, culture-based results are not always made available in a clinically relevant 
timeline to inform timely clinical decision making. This is compounded by factors such as 
specimen transport, type of media, and decontamination to eliminate non-mycobacterial flora 
which compromise the consistency of culture.  
 
In addition, culture time-to-result is long and depends on the patient TB bacillary burden. This 
means that patients with a lower bacillary burden wait longer for results than patients 
presenting with a higher bacillary burden. Further, sputum culture conversion is only weakly 
predictive of long-term patient outcome for regimens but not individuals, limiting its utility to 
individual and clinical trial management. Smear microscopy, an approved routine treatment 
monitoring method, is less sensitive and cannot distinguish viable and dead bacilli. The TB-
MBLA uses abundant 16S-rRNA as a target and can accurately quantify M.tb viable bacillary 
load directly from patients’ sputum over many weeks of treatment and has the potential to 
replace culture, offering a promising solution and improved precision in clinical care. The 
assay rapidly measures patient tuberculosis bacillary burden and its change in response to 
anti-TB therapy, enabling the clinician to make an informed decision on patient progress. This 

 
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ability avoids challenges related to culture (e.g. time to results and contamination) and gives 
TB-MBLA the potential to eventually replace microscopy and culture for treatment response 
monitoring (26-28).  
 
To date, the assay has been evaluated in three high TB burden, low-resource settings in Africa 
through the European and Developing Countries Clinical Trials Partnership (EDCTP) funding. 
The data showed that TB-MBLA reduces time to detection of M. tb bacillary loads from weeks 
to hours, reproducible in different laboratory settings and has the potential to inform real time 
clinical decision of patient treatment and expedite TB drug trials (29). Furthermore, bacillary 
load measured by TB-MBLA concurs with bacillary load measured by standard MGIT culture 
(30) and can accurately distinguish the bactericidal effect of different anti-TB regimens 
(31). The current study provides a unique opportunity to evaluate the role of TB-MBLA in 
monitoring treatment response in participants receiving varying DR-TB regimen.  
 
2.4. Potential Benefits 
 
There will be a direct benefit to patients who participate in this study. Participants will have 
access to novel drugs, diagnostics and improved treatment monitoring, not otherwise available 
through standard of care practice. We believe that the diagnostic methods and drugs used in 
this study could significantly improve TB treatment outcomes. Additionally, a rapid diagnosis 
coupled with initiation of appropriate treatment could potentially reduce the number of 
participants that are lost in the care cascade during this period. Generating evidence through 
implementation research on the feasibility, acceptability and cost effectiveness of novel 
diagnostics in improving DR-TB outcomes will fast-track translation of these study findings into 
policy and practice for maximum public health benefit. Given the development of the novel 
tests and the importance of the public health approach in triaging DR-TB participants to 
suitable all-oral regimens, a study evaluating the strategy is warranted. Finally, given the 
delays in DR-TB diagnosis, and appropriate treatment initiation, high toxicity of drugs in use, 
identifying strategies to improve DR-TB outcomes are important to the success of TB 
programmes globally.  
 
2.5. Potential Harm  
 
Diagnostics 
The risk benefit ratio will vary by each type of resistance pattern detected. Detection of 
resistance conferring mutations to multiple drug classes would be beneficial to those infected 
with these strain types compared to those without any detectable resistance. Use of the Xpert 
MTB/XDR diagnostic and translation of test results for treatment modification does not 
preclude access to all other available diagnostic tests for DR-TB in the study settings. Until 
this study is completed, there is no way of knowing for sure whether a novel diagnostic that 
guides use of short-course DR-TB treatment will improve treatment outcomes in DR-TB 
participants. For this reason, there is a risk that one could be receiving DR-TB drugs that may 
not be beneficial.   
 
Therapeutics 
Risk of treatment related toxicity with DR-TB medication is the same for all participants 
exposed to given DR-TB regimen. These risks include drug toxicities from DR-TB medication 

 
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and drug interactions (e.g., between DR-TB treatment and Antiretroviral Treatment). While 
this study will be using several new drugs in novel regimens, stringent safety assessments 
from human trials conducted using these regimens have been documented and will be closely 
monitored. Several strategies have been implemented within this study to ensure safety of all 
participants should we identify any safety concerns. These include; clinical observation and 
referral for clinical care should participants experience untoward adverse events, safety 
monitoring and reporting in real time to the study safety monitoring committee and external 
review of all safety reports by local ethics committees and independent Data Safety Monitoring 
Board (DSMB).  
3. DEFINITIONS OF DR-TB 
 
• 
HR-TB is defined as resistance to at least isoniazid without rifampicin resistance  
• 
RR-TB is defined as resistance to at least rifampicin without isoniazid resistance 
 
Definitions of MDR-TB, pre-XDR and XDR-TB in background sections of this protocol refer 
to old WHO definitions:  
• 
MDR-TB; resistance to at least rifampicin and isoniazid 
• 
Pre XDR-TB; strains that fulfil the definition of MDR-TB with additional resistance 
to the aminoglycosides or fluoroquinolones  
• 
XDR-TB; strains that fulfil the definition of MDR-TB with additional resistance to the 
aminoglycosides and fluoroquinolones.  
 
For the purpose of defining DR-TB categories in the current study we will utilise updated 
2021 WHO definitions to categorise pre-XDR-TB and XDR-TB (32) 
• 
Pre-XDR TB; strains that fulfil the definition of RR-TB/MDR-TB with additional 
resistance to any fluoroquinolone  
• 
XDR-TB; strains that fulfil the definition of RR-TB/MDR-TB with additional 
resistance to any fluoroquinolone and at least one additional group A drug (BDQ 
or LZD). 
4. STUDY DESIGN, AIMS AND OBJECTIVES 
 
4.1. Study Design 
The study is a Prospective Pragmatic Cohort Study with a before-and-after study design 
 
4.2. Study Aim 
 
The overarching aim of the TRiAD study is to evaluate the effectiveness, operational feasibility, 
acceptability, and cost-effectiveness of implementing the Xpert MTB/XDR for rapid triage and 
selection of all-oral regimens for DR-TB. 
 
 
 
 

 
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4.3. Primary Objectives: 
 
• 
To compare the time to initiation of resistance-pattern appropriate TB 
treatment from the date of first sputum collection with the standard of care 
compared to a historical cohort, stratified by geographical location 
• 
To assess the proportion of DR-TB participants with cure and/or DR-TB 
treatment completion at month 12 compared to a historical control group 
 
4.4. Secondary Objectives:  
 
4.4.1. Clinical 
• 
To assess the safety and effectiveness of all-oral regimens under operational 
conditions. 
• 
To assess all-cause mortality at month 12 and 18, rates of drug/regimen 
discontinuation for safety concerns, rates of drug-related adverse events 
 
4.4.2. Microbiological 
• 
To assess time to culture conversion, cure, and rates of clinical TB relapse  
• 
To determine the prevalence of HR-TB stratified by geographic location 
• 
To determine the prevalence of pre-XDR and XDR-TB using phenotypic DST 
to bedaquiline, pretomanid and linezolid 
• 
To determine the proportion of participants with bedaquiline and linezolid 
resistance warranting a switch from short-course treatment  
• 
To assess the clinical utility of the TB Molecular Bacterial Load Assay (TB-
MBLA) as a predictor of treatment outcome 
• 
To assess the diagnostic and clinical performance of the test and triage 
approach by geographic location using whole genome sequencing (WGS) and 
Minimum Inhibitory Concentration (MIC) analysis 
• 
To determine the phylogenetic structure and full drug resistance patterns of 
study samples, including bedaquiline, linezolid, levofloxacin and pretomanid 
 
4.4.3. Cost-effectiveness, feasibility and acceptability compared to the 
standard of care 
 
• 
To determine cost per person tested and incremental cost per DR-TB 
participant timely initiated on the resistance- pattern appropriate regimen 
• 
To determine the incremental cost per DALY averted and per day delay 
averted in treatment with the resistance- pattern appropriate regimen 
• 
To assess programmatic cost-effectiveness, feasibility, and acceptability of 
implementing any currently available Nucleic Acid Amplification Tests for 
drug-resistance detection changeswith Xpert MTB/XDR testing for HR and 
second-line DR-TB drugs 
• 
To investigate participant’s, health care provider’s and policy-maker’s 
acceptability of the triage and treat approach 
• 
To assess the feasibility of the implementation of the triage and treat approach 
in routine care 

 
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4.5. Study Outcome Measures  
  
Primary Outcomes: 
• 
Time to initiation of resistance-pattern appropriate TB treatment from the date of 
first sputum collection 
• 
Proportion of participants with favourable treatment outcome as defined in section 
9.3 
 
Secondary Outcomes:  
• 
Incidence of adverse drug reactions documented during all-oral treatment under 
operational conditions (cohort 1 and 2)  
• 
All-cause mortality for the duration of treatment and follow-up (cohort 1 and 2) 
• 
Time to sputum (culture) conversion (cohort 1 and 2) 
• 
Prevalence of HR-TB (cohort 1) 
• 
Prevalence of XDR-TB (cohort 2)  
• 
Proportion of participants with BDQ and LZD resistance not eligible for short-
course treatment  
• 
Clinical utility and feasibility of TB-MBLA for bacteriological follow-up in DR-TB 
treatment (assessment of viable bacterial load trajectories in response to 
treatment) (cohort 1) 
• 
Accuracy and quality of Xpert XDR testing (cohort 1 and 2) 
• 
Additional resistance to new and repurposed drugs (cohort 1 and cohort 2) 
• 
Cost effectiveness (cost per person tested and incremental cost per DR-TB 
participant timely initiated on appropriate treatment) (cohort 1 and 2) 
• 
Feasibility and acceptability of participant triaging (participant, health care 
provider and policy makers’ perspective) with enablers and barriers for 
implementing the algorithm (cohort 1 and 2) 
• 
Operational feasibility of Xpert XDR testing (infrastructure and human resource 
requirements) (cohort 1 and 2) 
5. STUDY INTERVENTION  
 
There are 3 study interventions: 
 
1. The Xpert MTB/XDR assay will be used as a diagnostic adjunct to any currently available 
Nucleic Acid Amplification Tests for drug-resistance detection changesto screen 
participants. The Xpert MTB/XDR assay will enable prompt identification of the following 
DR-TB participant categories:  
 
a. HR-TB  
b. Rif mono-resistant TB  
c. MDR-TB  
d. Additional fluoroquinolone (FQ) resistance, i.e., pre- XDR TB 
 
2. Early initiation of the most appropriate, evidence-based DR-TB regimen. This will be 
guided by the TB resistance pattern categorization from the Xpert MTB/XDR diagnostic. 

 
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Choice of DR- TB regimen will be determined by:  
 
a. Best available evidence generated from use of novel regimens as they become 
available, or 
b. Current WHO and in-country guidelines (Table 2).  
 
3. In parallel, the TB-MBLA will be used to provide real-time bacillary load monitoring over 
the course of treatment to assess response to treatment.  
 

 
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Table 2: Current Drug-Resistant TB Treatment Regimen by TB resistance profile and proposed study approach 
Current Guidelines on DR- TB treatment 
Regimen class 
Current Recommended Regimen with Duration (months) by Drug 
resistance profile per participating country 
Proposed All-oral 
regimen# 
HR-TB 
RHZE + Lfx (6) 
RHZE + Lfx (6) # 
RR-TB and MDR-TB  
Short- Course 
Regimen  
All oral regimen: 
SA:         (4-6)BDQ-Lfx (or MXF)- LZD, INHhd-CFZ-E-Z/ (5) LFX-CFZ-E-Z  
Nigeria:  (4-6)BDQ-MFX-HH-PTO-CFZ-E-Z/ (5)BDQ (2) MFX-CFZ-E-Z 
Ethiopia:(4-6)AM-MFX-CFZ-HH-PTO-E-Z/ (5)MFX-CFZ-E-Z 
or 
Injection-based regimen: 
(4)AMK-MFX-CFZ- INHhd -PTO-E-Z/(5) MFX-CFZ-E-Z 
BDQ based all-
oral regimen# 
 
RR-TB; MDR-TB; and 
PreXDR-TB (Second- 
line resistance) 
Long all-oral Regimen* :  
SA:         (6)BDQ-LFX-CFZ-LZD/(12)LFX-CFZ- LZD 
Nigeria:  (6)BDQ-MFX-CFZ-LZD/ (12) MFX- CFZ-LZD 
Ethiopia: (6) BDQ-LFX-LZD-CFZ-CS/(14) LFX- LZD-CFZ-CS 
BPaL# 
 
PreXDR-TB (FQ 
resistance) and XDR-
TB# 
Long Individualised 
Regimen*:  
SA:         (6-8)BDQ-CFZ-LZD-DLM-TRD/(12)CFZ-LZD-TRD-Z- INHhd 
Nigeria:   (6)BDQ-CFZ-LZD-CS/ (12)CFZ-LZD- CS 
Ethiopia: (BDQ)-(LFX)- (MFX)-(LZD)-(CFZ)-(CS)- (DLM)-(PTO)-(Z)-(AM)-(S)-
(PAS) 
BPaL# 
 
 
Abbreviations: HR-TB, Isoniazid Mono-Resistant TB; RR-TB, Rifampicin-Resistant TB; MDR-TB, Multi Drug-Resistant TB; XDR, Extensively Drug-resistant TB, SA, South 
Africa, LFX, levofloxacin; BDQ, Bedaquiline; MXF, moxifloxacin; LZD, linezolid, INHhd, high-dose isoniazid; CFZ, clofazimine; E, ethambutol; Z, pyrazinamide; PTO, 
protionamide; DLM, Delamanid; TRD, Terizidone, BPaMz, Bedaquiline -Pretomanid-Moxifloxacin-Pyrazinamide ; BPaL, Bedaquiline -Pretomanid-Linezolid 
* Longer regimens recommended when the construction of MDR/RR-TB regimen with 3 group A and 2 group B drugs is not possible due to intolerance to the medicines, 
acquired additional resistance etc. 
# Regimen selection based on WHO approved all-oral regimen or the best available evidence-based regimen; once results for proposed BPaMz and ZeNIX Formal 
amendments will be submitted for review upon consideration of additional regimens for the use in the study 

 
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6. INVESTIGATIONAL PLAN 
 
6.1. Selection of study clinical research sites  
 
Countries were selected based on background disease burden of DR-TB and represent a 
diverse participant population, DR-TB patterns, and laboratory capacities. Clinical research 
sites (CRS) within countries were selected to ensure sufficient numbers of DR-TB cases to 
meet recruitment targets. Participants will be enrolled in nine clinical research sites. These are 
located in South Africa (n=2), Nigeria (n=6) and Ethiopia (n=5) (Figure 2). Addition of clinical 
research sites in the study will be based on the ability to meet the enrolment targets for each 
country. All new clinical research sites will be approved by the in-country local IRB. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Map of TRiAD Clinical Research Sites in South Africa, Nigeria and Ethiopia 
South 
Africa 
(n=2) 
Ethiopia 
    (n=5) 
Nigeria 
(n=6) 
Jos University 
Teaching Hospital 
(JUTH)
1
 
Lagos- Nigerian Institute of 
Medical Research (NIMR) 
Mainland Hospital 
2 & 3
 
Wuse General Hospital
4
 
Kubwa General Hospital
5
 
Kano Infectious 
Disease Hospital
6
 

 
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6.2. Selection of Participants 
 
Approximately 4800 participants will be screened across the 13 sites (in South Africa, Nigeria 
and Ethiopia) to enrol 1280 eligible participants. All presumptive TB patients presenting for 
diagnosis at the study sites will be approached for screening. Each of the sites will also 
contribute to the historical cohort as described below.  
 
6.2.1. Selection of cohort 1 
 
880 RR-TB (n=440 in SA, n=220 in Nigeria and n=220 in Ethiopia) participants will be enrolled 
into Cohort 1. Each participant in cohort 1 will be followed up for the duration of TB treatment 
and passively thereafter to a maximum of 18 months from TB treatment initiation.  
 
6.2.2. Selection of cohort 2  
 
400 HR participants into Cohort 2 (n=200 in SA, n=100 in Nigeria and Ethiopia). Each 
participant in cohort 2 will be followed up passively for the duration of TB treatment and 
passively thereafter to a maximum of six months. 
 
6.2.3. Selection of Historical Cohorts 
 
Each CRS will build a dataset of historical RR-TB participants that were diagnosed and started 
on treatment within 12 - 18 months prior to starting enrolment of the study at each of the clinical 
research sites. Clinical and laboratory data from this retrospective cohort will be obtained from 
treatment registers, participant charts and laboratory databases at each of the clinical research 
sites. The following data variables will be extracted: date of birth, or age, sex, HIV and ART 
status, facility or clinic, year and month of treatment, type of DR-TB, certainty of diagnosis 
(confirmed by DST or presumed, i.e., contact of DR-TB source case or failing adherent first-
line TB treatment), disease classification, treatment start date and any bacteriological results 
on treatment (date, mycobacterial culture, DST and genotypic results), where relevant. Data 
on all drugs from previous DR-TB treatment regimen, DR-TB Outcomes: cure, completion, 
default, death, loss to follow up (LTFU) will be abstracted. Historical data will be collected on 
specially designed case report forms (CRF) and will be subject to routine quality 
assurance/control QA/QC of data to ensure maximum quality. Bias by time period and by other 
confounders such as HIV, gender and age, will be controlled for in the analysis. No historical 
data will be generated for cohort 2, as no routine data on HR-TB is available.  
 
6.3. Participant Inclusion Criteria for cohorts 1 and 2 
 
1. Ambulant adults ≥ 18 years of age 
2. Newly diagnosed PTB patients receiving less than 5 days of treatment since 
new diagnosis:  
a) Cohort 1: < 5 days of DR-TB treatment 
b) Cohort 2: < 5 days of INH mono-resistant TB treatment preceding study entry 
for the current TB episode, or 
3. Sputum positive (smear and or culture) TB patients classified as failing first line 
treatment 
4. Any currently available Nucleic Acid Amplification Tests for drug-resistance 
detection changes/assay positive for M.tb infection with: 
Cohort 1: at least Rifampicin resistance  

 
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Cohort 2:  Rifampicin susceptible co-occurring with INH, fluoroquinolone, 
ethionamide or aminoglycoside resistance (detected by Xpert XDR) occurring 
alone or in combination 
5. Capacity to provide informed consent 
6. HIV infected and uninfected participants are allowed in the study. Participants 
already on ART will be allowed in the study provided the ART regimen in use 
has no contraindications to the proposed TB drug regimen 
7. Willing to have samples collected, stored indefinitely, and used for research 
purposes 
8. Able to provide reasonable proof of identity (to satisfaction of study team 
member) at or prior to enrolment 
 
6.4. Participant Exclusion Criteria  
 
Study participants will be excluded if one or more of the following conditions apply: 
 
1. Has a known severe allergy to any of the BPaL component drugs 
2. Has DST showing infection with a strain resistant to any of the component drugs 
3. Has TB meningitis, other central nervous system TB, or TB osteomyelitis; or 
4. Is pregnant or breastfeeding 
5. Is unable to take oral medications 
6. Persons with any other medical condition, precluding study participation based on 
investigator judgement  
7. Any co-existing condition that in the opinion of the attending clinician renders the 
participant unsuitable for participation in the study 
8. Co-enrolment in other interventional research studies  
 
6.5. Late Exclusion Criteria  
 
1. Resistance to BPaL component drugs on pDST conducted post study enrolment  
 
6.6. Screening Procedures 
 
Two screening strategies will be adopted: 
 
a) Patients with suspected pulmonary TB or confirmed M.tb positive (< 5 days since 
treatment initiation) will be screened and consented to provide an additional sputum 
sample for Xpert MTB/XDR testing if required. This will be based on  the routine sample 
collected for any currently available Nucleic Acid Amplification Tests for drug-
resistance detection changes 
b) We will concurrently contact all patients with newly identified RR-TB during the study 
enrolment period directly for participation in this study (laboratory records) 
 
The site investigator (or designate) will assess eligibility and ensure that the participant meets 
study inclusion criteria. Xpert MTB/XDR (Cepheid) will be implemented as an additional DR-
TB screening test. All participants must test positive for M.tb and participants with RR-TB will 
be screened for additional resistance and enrolled in Cohort 1 (estimated n=880) while those 
without RR will be screened for isoniazid resistance and enrolled in Cohort 2. Participants with 
HR-TB will be enrolled in Cohort 2 (estimated n=400). As this is an operational study, accrual 

 
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into the study will be within a specified time frame. Overview of screening and enrolment 
approach is outlined in figure 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Study screening and enrolment for the TRiAD Study 
 
6.7. Enrolment Procedures 
 
Study staff will contact potential participants meeting eligibility criteria, based on the Xpert 
XDR test, for study enrolment. Participants will be re-assessed for their willingness to 
participate in the study. Participant accrual at all sites will occur over 12 -18 months from the 
date of enrolment of the first participant. 
 
Participants will be given further information about the study. Ineligible participants will be 
referred to the National Tuberculosis Programme (NTP) for further management. Eligible 
Currently available Nucleic Acid 
Amplification Tests for drug-resistance 
detection changes 
MTB Positive 
RIF Resistant 
Screening with Xpert XDR assay 
MTB Positive 
No Rif Resistance  
 Resistance to INH, 
FQ’s & 2nd Line 
Injectables 
Resistance to INH 
only 
Study Enrolment 
DS-TB  
referred to 
NTP 
Cohort 1 
6-9 months BPaL 
9-12 months all-oral 
regimen or 
Long regimen 
Cohort 2 
6-month standard 
regimen + 
Fluoroquinolone  
pDST:  
BDQ & LIN fully 
susceptible continue in 
Cohort 1 
Presumptive  
TB Cases 
Confirmed  
TB Cases 
XDR-TB referred to 
NTP for passive 
follow-up of 
treatment outcome 

 
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participants who agree to study participation will undergo study informed consent procedures 
(signature or give a thumb print in the presence of a witness if illiterate). Enrolled participants 
will be given a signed copy to take home. 
 
After obtaining study informed consent, clinical research sites will: 
• 
Obtain consent from participants for sputum sample storage and further analysis  
• 
Record participant contact information including physical address  
• 
Interview participants to obtain demographic details, medical history (including all prior 
TB diagnoses, history of previous TB drug intake  
• 
Conduct a targeted clinical examination  
7. STUDY ASSESSMENTS AND FOLLOW-UP 
 
7.1. Schedule of evaluations 
 
The sequence of study visits and procedure schedules are presented in tables 3 and 4 
schedule of evaluations for cohort 1 and 2, respectively. These tables detail visit requirements 
for each in-person follow-up visit. Each follow-up visit will include collection of a sputum 
sample, a clinical examination and assessment for adverse drug reactions. Study staff will be 
trained to conduct study procedures in a standardised manner. Study specific standard 
operating procedures (SOPs) will guide this process.  
  
Screening (Cohorts 1 and 2): 
Screening will include the provision of introductory study information, assessment of eligibility 
criteria and obtaining written informed consent for screening procedures. Participants who 
meet the eligibility criteria will provide up to two sputum samples for currently available Nucleic 
Acid Amplification Tests for drug-resistance detection and Xpert XDR testing. For potential 
participants who do not meet the study eligibility criteria, the screening process will be 
discontinued when ineligibility is determined. 
 
Evaluations for Cohort 1: 
Participants will be scheduled to undergo appropriate evaluation at baseline, during and after 
treatment.  Study visits will occur at week 2, monthly for the duration of DR-TB treatment and 
3-monthly following completion of treatment where allowable within the study’s operational 
time frame. Participants on short-regimen will be seen for a maximum of 3 post-TB treatment 
visits, 3 months apart (Table 3). Active follow-up will occur for the duration of TB treatment 
and passively thereafter, for a maximum of 18 months after study enrolment. Participants who 
receive long treatment regimens will be actively followed-up for the duration of the intensive 
phase of treatment and passively thereafter to obtain an end-of-treatment outcome. Research-
specific activities during follow-up include assessment of clinical and microbiological response 
to treatment, solicitation and reporting of adverse events and serious adverse events, 
administration of study specific questionnaires related to costs, acceptability and feasibility of 
the intervention. Passive follow-up will be conducted telephonically or through NTP registers 
to assess rates of relapse after TB treatment completion. Study related specimen collection 
will occur at baseline (enrolment) and at all follow-up visits. Baseline sputum samples will be 
collected for Xpert MTB/XDR testing, pDST, WGS, and TB-MBLA testing. Follow-up sputum 
samples will be collected for routine culture and susceptibility testing and sputum storage for 
batched TB-MBLA testing. 
 

 
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Evaluations for Cohort 2: 
Participants will be referred to the NTP and will not undergo further active follow-up within the 
study (table 4). Treatment outcomes for these participants will be monitored passively through 
monthly telephonic monitoring or through routinely collected outcome data within the national 
TB program until 15 months after enrolment. 

 
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Table 3: Schedule of Evaluation for Drug-Resistant Tuberculosis participants in the TRiAD Study Cohort 1 
 
Visit 
Screening 
Enrolment 
 
Treatment and Follow Up Period a 
Time of visit  
 
 
24h after 1st 
treatment 
dose 
Week 2 
Month 1 
Month 2 
 
Month 3 
Month 4 
Month 5 
Month 6 
Month 9 
Month 12 
Month 15 
Month 18 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Storage informed 
consent g 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sociodemographic 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/treatment 
History b  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Exam c 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TB Symptom Profile 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Peripheral Neuropathy 
Assessment  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
 
ECG monitoring  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest X-Ray d 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
Laboratory Safety 
Assessments e 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Sputum Sampling f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sampling (1x4ml 
EDTA Tube) h 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 

 
TRiAD Study Protocol  
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Spot Urine collection 
sample (approximately 
30ml) i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Self -collection urine 
sample (approximately 
5L) j 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Participant 
Questionnaire k 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Solicited Adverse 
Events (AES) /SAE l 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Notes: 
a. Treatment and follow-up: Active follow-up will occur during TB treatment only, passive follow-up visits up to 18 months post-TB 
treatment, no specimen collection during passive follow-up.  Visits for month 12 onwards applicable to participants who continue treatment 
for longer than 6 months only. Passive follow-up visits will collect AE’s, SAE’s, verification of survival and participant reported TB outcome 
information. These will be conducted telephonically 
b. Medical History: will include TB treatment history, HIV/Status and CD4 and Viral load Monitoring: If HIV status is unknown or reported 
negative in the absence of documentation, HIV test should be requested. CD4 and Viral load test to be conducted for all HIV-positive 
participants as per standard of care  
c. Clinical Exam: will include random blood glucose test, ophthalmic examination of visual acuity and colour vision assessment, pregnancy 
test will be conducted in women of child-bearing potential and peripheral neuropathy assessment  
d. Chest X-Ray: Will be conducted at screening visit, month 4 (South African standard of care) and thereafter at the request of the treating 
clinician if deemed necessary. In Nigeria, X-rays will be done at screening visit, month 4 and end of treatment  
e. Laboratory Safety Assessments: Haematology, full blood count, clinical chemistry and urinalysis - as per routine in-country standard of 
care   
f. Sputum Sampling:  1 sample will be collected at baseline/screening: for currently available Nucleic Acid Amplification Tests for drug-
resistance detection, routine culture and Xpert XDR testing, an additional sample will be requested if required, 2 samples will be collected 
at enrolment: storage for TB-MBLA and WGS/MIC testing 
g. Optional Storage Consent for additional sampling collection and storage: Subset of participants who are willing to consent to provision of 
urine and blood samples at enrolment, month 3, the end of TB treatment, and 6 months post treatment completion if still in follow up, will 
be required to provide written consent 

 
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h. Optional Blood Sampling: # Subset of participants to provide samples to be collected at enrolment, month 3, at the end of TB treatment, 
and 6 months post treatment completion if participant still in follow up 
i. Optional Spot Urine Collection Sample: Subset of participants to provide pre-treatment spot urine collection to be conducted 
during the enrolment visit  
j. Optional Self-collection of Urine Sample: Subset of participants to collect a 24-hour urine sample following first dose of TB 
treatment and another 24-hour self-collection urine sample at month 6 after treatment initiation 
k. Participant Questionnaire: assess participant associated costs and acceptability of study approach; schedule for administration to be 
finalised with sub-study protocol  
l. Reporting of adverse events: record solicited grade 3 and 4 adverse events during treatment phase only and all serious 
adverse events throughout study follow-up. 
 
 
 
 
 
 
 
 
 
 

 
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Table 4 : Schedule of Evaluation for Drug-Resistant Tuberculosis participants in the TRiAD Study Cohort 2 
Visit 
Screening 
Enrolment 
Treatment and Follow Up Period a 
Time of visit  
 
 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 9 
Month 12 
Month 15 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
Sociodemographic Information 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical/treatment History 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
TB Symptom Profile 
 
X 
 
 
 
 
 
 
 
 
 
 
ECG monitoring  
 
X 
 
 
 
 
 
 
 
 
 
 
Chest X-Ray b 
 
X 
 
 
 
 
 
 
 
 
 
 
Sputum Sampling c 
X 
X 
 
 
 
 
 
 
 
 
 
 
Telephonic Assessment  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Notes: 
a. Treatment and follow-up: Passive follow-up visits up to 6 months post-TB treatment, routine monitoring of treatment response. Passive 
follow-up visits will collect AE’s, SAE’s, verification of survival and participant reported TB outcome information. These will be conducted 
telephonically 
b. Chest X-Ray: Will be conducted at screening visit, and thereafter at the request of the treating clinician if deemed necessary. In Nigeria, 
X-rays will be done at screening visit, month 4 and end of treatment 
c. Sputum Sampling: 1 sample will be collected at baseline/screening: for  any currently available Nucleic Acid Amplification Tests for drug-
resistance detectionand Xpert XDR testing, an additional sample will be collected if required. 
     1 sample will be collected at enrolment: for culture and storage for WGS/MIC testing 
The study SoE will be followed except when procedures are clinically indicated or not in accordance with clinical judgement. 

 
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7.2. General Mycobacteriology   
 
The following bacteriological tests will be performed at the local reference laboratory as per 
standard practice: smear, culture, diagnostic LPAs and pDST to BDQ and LZD in pre-XDR TB 
participants. At each visit, one early morning sputum sample will be tested for acid-fast bacilli 
(AFB) smear and culture. Study specific procedures assays will be carried out according to 
procedures described in the study laboratory manual. Sub-cultures will be shipped to 
Tuberculosis Supranational Reference Laboratory, San Raffaele Scientific Institute (OSR) for 
specialized tests such as MIC and WGS. 
Table 5: Overview of microbiologic assessments performed after each visit 
Visit 
Sample 
Type 
Microbiologic Assessments 
Routine Testing  
Study Intervention  
Screening  
< 2x 
Sputum 
samples  
• 
Direct microscopy for AFB; 
currently available Nucleic 
Acid Amplification Tests for 
drug-resistance detection 
changes, Hain Assay 
MTBDRplus and MTBDRsl  
• 
Culture for the 
presence/absence of M.tb 
• 
Phenotypic DST to 
bedaquiline and linezolid 
• 
GeneXpert XDR test1 
Enrolment  Sputum X2 
 
• 
Culture for  
presence/absence of 
M.tb 
• 
Sub-culture for storage 
and shipment for MIC 
and WGS3 
• 
Sputum collection for TB-
MBLA processing 2 
All visits 
post 
screening  
Sputum X2 
• 
Culture for the 
presence/absence of M.tb 
• 
Sputum collection for TB-
MBLA processing 2 
• 
Any culture positive 
sample obtained during 
or after treatment will be 
stored at site level 
(optional) 
 
Notes: 
 
1Xpert XDR testing: will be conducted on sputum sample collected at the screening visit 
following initial TB diagnosis by currently available Nucleic Acid Amplification Tests for drug-
resistance detection changes. The Xpert MTB/XDR assay will be conducted in real-time to 
evaluate INH and second-line resistance and recommend the appropriate treatment regimen. 
This test will be conducted once off at the initial visit. 

 
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2TB-MBLA testing: the test will be conducted on stored sputum samples. The test will be 
conducted using LifeArc TB-MBLA test kits. This assay will be conducted to assess the clinical 
utility of the assay, not for clinical management. It is a reverse transcription quantitative 
polymerase chain reaction (RT-qPCR) assay that uses 16S-rRNA as a marker to detect and 
quantify the load of viable M.tb bacteria in a participant’s sputum sample. The process starts 
with RNA isolation from M.tb bacteria, followed by RT-qPCR to quantify the RNA, then 
conversion of the RT-qPCR output (cycle threshold [CT] values) into bacterial load values 
(estimated colony forming units per millilitre [eCFU/ml]) using a standard curve. 
 
3Culture for storage, MIC and WGS: Isolates will be cultured from sputum samples collected 
at the screening/enrolment visit using the BD BACTEC MGIT 960 culture system at National 
Reference TB Laboratory. Cultured isolates will be stored at -80 degrees Celsius for further 
processing. 70% of clinical isolates will be sent to the study reference laboratory; OSR. OSR 
will perform quality assurance assessments of the Xpert MTB/XDR cartridge to be tested. The 
drug patterns of resistant strains detected with the XDR assay will be fully characterized by 
OSR. In parallel, OSR will populate and develop a catalogue of resistance of the sites, 
complemented by MIC testing, and seek to identify resistance markers to guide future 
diagnosis and treatment decisions. WGS testing will be conducted on 70% of total samples 
from participants with RR-TB and HR-TB enrolled from all sites in cohort 1 and 2, respectively. 
MIC testing for full phenotypic DST will be prioritized on a subset of 480 samples maximum, 
including strains with unknown mutation patterns and/or from participants failing the proposed 
regimen. The accuracy of Xpert MTB/XDR test results for drug resistance prediction will be 
assessed and quality controlled by WGS analysis. One aliquot of viable isolates from study 
samples will be referred from sites to OSR, arranging one shipment in year 1 and two 
shipments per year in the years 2, 3, 4. 
 
7.3. Cost effectiveness and acceptability analysis  
 
7.3.1 Cost effectiveness 
 
Through cost-effectiveness analyses we will determine the incremental cost per DALY averted 
from combined currently available Nucleic Acid Amplification Tests for drug-resistance 
detection and Xpert/XDR implementation, followed by an all-oral, shorter treatment regimen 
compared to the conventional standard of care for both DR-TB patients. Cost data on 
diagnostic and treatment algorithms will be collected through an ingredient approach from a 
societal perspective, including both health system and patient costs. Both provider and patient 
cost data will be collected empirically from all nine sites once the optimal implementation 
scenarios have been generated. Gaps in provider costs captured in precious costing studies 
will be collected through semi-structured interviews of key informants and document review. 
Patient costs of cohorts 1 and 2 participants will be collected via questionnaire by trained data 
collectors in tandem with select parent study follow-up visits.  
 
The primary outputs will include incremental cost per DALY averted and incremental cost per 
day of treatment delay averted compared with historical controls. These outcomes are 
assessed from the societal perspective and reported from each of the societal, provider, and 
patient perspectives. The cost-effectiveness comparison between the intervention and the 
standard of care will be modelled using primary data from the parent study, primary cost data 

 
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from providers and patients from all five trial sites, secondary data concerning national 
population characteristics and standard of care outcomes, as well as expert opinion, where 
necessary. The time frame of the model-based analysis will be from initial diagnosis to end of 
life. Deterministic and probabilistic sensitivity analyses will be conducted on model parameters 
and methodological assumptions. 
 
7.3.2 Acceptability analysis 
 
In order to assess the acceptability and feasibility of implementation of the newly proposed 
triaging and treatment algorithms we will adopt a mixed methods study design. Quantitative 
data will be collected through pre-structured questionnaires, while in-depth interviews will also 
be conducted to complement and illustrate the quantitative study results. We will recruit 
participants, and health care workers (HCW’s) from each participating sites (5 in Ethiopia, 2 
in Nigeria, 2 in South Africa) as well as relevant policy makers from each country. For the 
collection of quantitative data, per site, we will interview at least 10-25 participants (50 per 
country), 7-15 HCWs depending on the number of HCW’s directly involved in the 
implementation and execution of the intervention, approximately 35 per country, and at least 
3 policy makers (one at national, one at provincial and one at district level (i.e., programmatic 
management of DR-TB [PMDT] focal persons in each country). For the qualitative data 
collection, we will continue data collection until data saturation has been reached, although 
this will not be feasible for the policy makers, as there is only one to be interviewed per level. 
We will purposively and concurrently sample interviewees to include maximum variability: men 
and women from different participating sites, participants assigned to different regimens with 
or without comorbidities, fully or partly adherent to therapy, HCWs and stakeholders with 
different job description and years of experience in the setting.  
 
We will train local interviewers (one per participating site) on the topic guide, interview 
competences, and obtaining informed consent. The trained interviewer will conduct interviews 
using the pre-structured questionnaires and semi-structured in-depth individual interviews. 
Interviewers will be supervised by a local focal person with background in qualitative research, 
who will also oversee interview activities, and data collection (including quality and data 
saturation) and storage. All communication during interviews will be in the local language. We 
will obtain a-priori written informed consent for audiotaping the in-depth interviews and 
publication of anonymized results. Following each in-depth interview, the interviewer will 
describe interview setting, including ambiance and emotions, and verbatim transcribe and 
translate audio-recorded interviews in English. Interviewees will receive a small incentive for 
the time spent on the interview. 
 
Analysis of the quantitative data will be done using statistical software (Stata or SPSS). 
Proportions and median/mean values will be calculated as appropriate. Differences between 
subgroups will be analysed. For the qualitative part, after familiarization with the data, two 
researchers will analyse data (QSR Nvivo10 software) by using an applied thematic approach, 
which allows for inductive coding and thematising. After development of a coding scheme, 
which will be refined along the coding process, two researchers and an independent reviewer 
(one from each participating site) will regularly discuss interpretation of data, coding, and 
emerging (sub)themes. Additional to overarching study results, we will stratify analysis per 
country, health care worker/participant perspective, gender, and type of regimen received. We 

 
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will present study results by themes, including relevant interviewee quotes. This exercise will 
be conducted after each interview to judge if new themes arise from the interview. If no new 
themes arose, data saturation was reached and no more in-depth interviews will be conducted 
for that specific group of participants. We define acceptability as a multi-faceted construct that 
reflects the extent to which people delivering or receiving a healthcare intervention consider it 
to be appropriate, based on anticipated or experienced cognitive and emotional responses to 
the intervention. Both persons receiving (participants) and delivering (health care workers 
(HCW) and policy makers) the intervention will be included in the assessment. Feasibility 
reflects how viable implementation of the intervention is. Both the (anticipated and 
experienced) acceptability and feasibility will affect the intervention’s uptake and 
effectiveness. 
8. TREATMENT CONSIDERATIONS  
 
8.1. Interruptions to treatment   
 
The study treatment regimen may be interrupted at the discretion of the local PI for: 
• 
A serious adverse event 
• 
The investigator decides to withhold treatment in the interest of the safety and well-
being of the participant 
• 
Lack of effectiveness 
 
If treatment is interrupted for a suspected serious drug reaction, attempts should be made to 
identify the drug concerned. After resolution of the suspected adverse reaction, treatment may 
be gradually re-introduced until the allocated regimen has been re-instituted. 
 
In the case of the BPaL regimen, if treatment is interrupted for more than 35 consecutive days, 
the participant will be referred to the assigned expert TB clinical committee to decide on further 
management including need for change to a new individual regimen, based on clinical 
assessment and reason for interruption. Any missed doses should be made up at the end of 
the treatment to complete 24 weeks of therapy. Missed doses of linezolid alone due to adverse 
reactions are not to be made up at the end of treatment. Reasons for missing treatment must 
be identified and addressed early and noted in the participant’s file for analysis for factors 
associated with (lack of) treatment success (33).   
 
In the event that the local PI considers that treatment needs to be modified or changed, he or 
she should inform the coordinating centre by submission of an SAE form and discuss 
treatment plans with a member of the study medical monitoring team (MMT).  
 
8.2. Discontinuation of treatment due to toxicity or treatment failure 
 
The study regimens will be discontinued in some participants. In such cases, participants will 
be evaluated by the MMT and switched to an individualized regimen, based on the WHO 
guidelines for regimen design. The most common situations in which the regimen may be 
discontinued include:  
 

 
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• 
Intolerable severe toxicity. One or more drugs may need to be suspended 
permanently due to severe toxicity. In such cases, the clinical committee should review 
the medical history carefully to determine how the regimen should be modified (see 
discontinuation/modification criterion below). 
• 
Treatment failure. If clinical and bacteriological responses to treatment are poor, a 
change in the treatment regimen should be considered. DST should be repeated if 
culture is still positive at month 4, whether or not the regimen is changed, in order to 
inform future management decisions.  
• 
Resistance to drugs in the regimen. For participants who submit a sputum sample 
for culture-based second-line DST at the beginning of treatment, results may not be 
available until after treatment has started. If resistance to component drugs is 
discovered after treatment is initiated, it may be necessary to modify, extend treatment 
duration or discontinue the regimen.  
• 
Pregnancy during treatment. For participants who become pregnant during 
treatment, it may be advisable to modify or discontinue novel regimens. A decision 
regarding continuation or discontinuation of the regimen should be made after a review 
by the study MMT and discussion with the participant 
 
For participants discontinued from study treatment or whose treatment is changed and 
participants referred to the NTP, every effort should be made to continue passive follow up (at 
a reduced frequency if necessary), unless the participant has specifically withdrawn consent 
for further follow-up. In this event, a final status form should be completed. Details for 
management these participants will be outlined in a study specific SOP. 
 
8.3. Interruptions to care  
 
8.3.1. Missed Visits 
 
For each participant, clinic staff will obtain or confirm contact information. In the event that a 
participant misses a scheduled appointment, staff will try within the week following the missed 
appointment to establish telephonic communication with the participant and/or treatment 
supervisor through all possible means which they have approved while protecting their 
confidentiality. Permission for this contact must be obtained in the initial consent form. All 
attempts to locate a participant following each missed appointment will be documented in the 
source document. The need to attend all scheduled follow-up visits will be emphasized to all 
study participants at every visit. Every site will develop its own method for tracing and retaining 
participants in the study.  
 
Participants who miss their scheduled appointment will be contacted and arrangements made 
for a new appointment. If participants are not successfully reached by phone/text messaging, 
a home visit will be arranged to ensure contact. Participants returning after missed 
appointments will have procedures for the visit closest to their total time in follow up performed. 
Subsequent visits will continue as scheduled. However, treatment to be prescribed should be 
determined by the actual number of days already taken and not by time in the study. 
 
A participant will be deemed to be missing if he/she does not attend the treatment centre to 
take the treatment as prescribed for a period of one week. If the participant has not resumed 

 
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treatment within seven days, i.e., the participant has missed at least two weeks of treatment; 
a note should be made in their clinic notes with details of attempts to contact the participant. 
 
8.3.2. Loss to follow-up 
 
Every effort will be made to keep participants engaged in follow-up. If the participant does not 
return to the clinic before the study is closed, the final form will be completed at the time of 
study closeout. The form should indicate that the participant was lost to follow-up. The “loss 
to follow-up” designation cannot be made for any participant until at least 3 months after the 
participant’s scheduled visit. 
9. STATISTICAL CONSIDERATIONS  
 
9.1. Power and Sample size calculations:  
 
The study will be powered based on the two primary endpoints: 
i) 
Numbers needed to detect a reduced time to resistance-pattern appropriate 
treatment initiation for all drug-resistant cases compared to the historical 
cohort; and  
ii) 
The difference in proportion of favourable treatment outcomes compared to the 
historical cohort, allowing for stratification by study site (geographical location). 
 
Current data, mainly from South Africa, show a median time to resistance-pattern appropriate 
treatment initiation for drug-resistant participants between 15 and 46 days (1-3). With an 
assumption of an anticipated time to treatment initiation of one week in our study (allowing 
time for providing repeat sputum samples and delays in Xpert testing), 220 RR-TB 
participants must be enrolled in cohort one in each country (440 in South Africa), to achieve 
90% power to show a shortening of time to treatment initiation. This sample size includes an 
allowance for an overall 15% loss to follow-up. 
 
Table 6: Reported median times (in days [IQR]) to treatment of drug-resistant TB in literature 
Patient type 
Xpert-
based 
LPA-
based 
Phenotypic 
DST-based 
Location/date 
Ref  
All 
MDR+XDR 17 [9-47] 
38 [23-54] 
81 (49-115] 
Johannesburg, 
South Africa 
2017 
(34) 
RR 
0 [0-1] 
20 [10-16] 
106 [30-124] 
Multi-site 2011 
(Boehme) 
 
MDR 
8 [5-25] 
50  
 
MSF Cape 
Town 2015 
(35) 
MDR 
17 [13-22] 
43 [40-46] 
 
Cape Town 
2014 
(36) 
MDR 
15 [1-29] 
32 [7-57] 
 
South Africa 
2017  
(37) 

 
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RR  
(only 4 pts) 
2 
21  
40 (MGIT) 
Cape Town 
South Africa 
2011 
 
MDR 
 
 
88 [29-126] 
Korea 2019 
(38) 
 
XDR 
 
 
97 [79-126] 
Korea 2019 
(38) 
Smear 
positive 
MDR + 
XDR 
15 [1-42] 
32 [7-42] 
81 [75-107] 
Johannesburg, 
South Africa 
2017 
 
Smear 
negative  
MDR + 
XDR 
- 
54 [45-62] 
Johannesburg, 
South Africa  
Johannesburg, 
South Africa 
2017 
 
 
For the proportion of favourable study outcomes, we used the most recent treatment 
completion proportions of Kwazulu-Natal province of South Africa, including one of the study 
sites (4). The average MDR-TB treatment completion proportion is 63%, varying from 57% in 
their long regimen to 74% using a bedaquiline-based short regimen. The study sample size of 
n=220 per study site as calculated above will be sufficient to detect an improvement in 
treatment outcomes with a minimum difference from 74% to 85% (80% power; larger 
differences with 90% power [from baseline success of 71% and less]), also allowing for 15% 
loss to follow-up. 
 
The estimated XDR prevalence among MDR cases is 4.3% in South Africa (2018 Global TB 
report), 0.6% and 0.7% in Nigeria and Ethiopia (2019 Global TB report). This would mean that 
N=880*4.3% = 38 XDR cases. As BPaL eligibility extends to pre-XDR patients and treatment 
intolerant MDR patients, it is expected that a higher number will be on BPaL. A total of 40 
participants (including 15% LFU) are needed to detect an improvement from 53% to 85%. This 
number should be possible for all sites together. Assuming approx. 10% HR-TB in each site, 
we aim to enrol N=400 in cohort 2 which would allow for approximately 100 HR-TB participants 
per site, which should be sufficient for studying associated secondary study outcomes. 
 
9.2. Analysis including statistical methods: 
 
Primary endpoint analysis: 
 
• 
The time to appropriate treatment initiation will be calculated as median days (with 
interquartile range) between the first sputum collection date and the date of start of the 
regimen appropriate to the drug resistance pattern (defined as drug-resistance pattern 
appropriate treatment). This will be compared to the same time in the historical cohort 
and stratified by geographical location (study site). Confounding will be addressed by 
multivariable analysis. 
• 
The proportion of favourable study outcomes [treatment cure or completion, based on 
the WHO definitions (5) will be calculated in the overall study population of cohort 1, 
and compared with the same proportion in the historical cohort, and stratified by 
geographical location (study site). In a secondary analysis, these proportions will also 
be calculated per type of DR-TB. Confounding will be addressed by multivariable 
analysis. 
 

 
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Both of these outcomes will only be calculated in the primary cohort (cohort 1), as no reliable 
historical data exist for either endpoint for HR-TB (cohort 2). 
 
 
 
Secondary endpoint analysis: 
• 
Prevalence of HR-TB stratified by geographical location. This will be calculated in 
cohort 2 and stratified by HIV status. 
• 
The incidence of adverse events will be divided into adverse events and serious 
adverse events and calculated in proportions using both cohort 1 and 2. These will 
also be stratified by type of DR-TB, treatment regimen, and HIV status. 
• 
Feasibility and acceptability (participant and health care provider perspective), 
stratified by type of DR-TB regimen (cohort 1 and 2) 
• 
Cost-effectiveness (cost per person tested and incremental cost per DR-TB participant 
timely initiated on the resistance pattern-appropriate regimen) and, following from that, 
optimal placement of Xpert XDR in diagnostic & treatment algorithm (cohort 1 and 2) 
• 
Accuracy of Xpert XDR testing (in comparison with culture + DST/LPA/Next-generation 
sequencing [NGS]), by type of DR-TB (cohort 1 and 2) 
• 
Operational feasibility of Xpert XDR testing (infrastructure requirements and HR 
needs) (cohort 1 and 2) 
• 
Quality of Xpert XDR tests (indeterminate rate, DNA contamination rate, and 
performance variation [in time and between sites]) (cohort 1 and 2) 
• 
Clinical utility and feasibility of TB-MBLA in bacteriological follow-up of DR-TB (in 
comparison with routine culture), by type of DR-TB and regimen (cohort 1) 
• 
Additional resistance to new and repurposed drugs, by type of DR-TB and regimen 
(cohort 1 and 2) 
• 
Mathematical modelling of TB-MBLA trajectories in response to treatment 
 
Timing of analysis: 
The majority of the above outcomes will be analysed after the end of follow-up, however an 
interim analysis of the primary study outcomes as well as the safety outcomes is planned for 
Month 32 (M32) or after complete Month 12 follow-up (M12FU). This will allow for timely 
informing of policy makers as these new diagnostic tools and regimens are being rolled out. 
 
9.3. Outcome Status 
 
Outcomes are based on WHO’s reporting framework for tuberculosis in 2020 (39).Treatment 
outcome definitions have recently been revised by WHO and will be updated in the 2021 
revision of WHO’s Definitions and reporting framework for tuberculosis. Once this guideline 
becomes available and the new definitions are adopted for programmatic implementation, 
the protocol will be updated (https://www.who.int/publications/i/item/9789240022195).  
  
 
 
 
 
 

 
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Table 7: Treatment outcomes for RR-TB/MDR-TB/XDR-TB participants treated  
Outcome 
Definitions per TRiAD Protocol  
2021/2022 WHO Definitions 
Cured 
Treatment completed as 
recommended by the national 
policy without 
evidence of failure AND three or 
more consecutive cultures taken at 
least 30 days apart are negative 
after the intensive phase 
A pulmonary patient with 
bacteriologically confirmed DR-TB at 
the beginning of treatment who 
completed the recommended 
treatment , with evidence of 
bacteriological response* and no 
evidence of failure  
Treatment 
completed 
Treatment completed as 
recommended by the national 
policy without evidence of failure 
BUT no record that three or more 
consecutive cultures taken at least 
30 days apart are negative after 
the intensive phase 
A patient who completed treatment 
as recommended and who does not 
meet the definition of cure or 
treatment failure  
Treatment 
failed * 
Treatment terminated or need for 
permanent regimen change of at 
least two anti-TB drugs because 
of: 
- 
lack of conversion by the 
end of the intensive phase, 
or 
- 
bacteriological reversion in 
the continuation phase after 
conversion to negative, or 
- 
evidence of additional 
acquired resistance to 
fluoroquinolones or second-
line injectable drugs, or 
- 
adverse drug reactions 
(ADRs) 
A patient whose treatment regimen 
needed to be terminated or 
permanently changed to new 
regimen or treatment strategy. 
Reasons for change include : 
- 
No clinical and or 
bacteriological response 
- 
Adverse drug reaction/s 
- 
Evidence of additional drug 
resistance to medicines in 
the regimen  
Died 
A participant who dies for any 
reason during the course of 
treatment. 
A patient who died for any reason 
during treatment  
Lost to 
follow-up 
A participant whose treatment was 
interrupted for 2 consecutive 
months or 
more. 
A patient with treatment 
interrupted for ≥2 consecutive 
months for any reason without 
medical approval  
Not 
evaluated 
A participant for whom no 
treatment outcome is assigned. 
(This includes cases “transferred 
out” to another treatment unit and 
whose treatment 
outcome is unknown) 
A patient recorded in the register 
and who does not have the 
necessary recorded data to enable 
classification of any outcome  
Treatment 
success 
The sum of cured and treatment 
completed 
Is sum of cured and treatment 
completed 

 
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Sustained 
treatment 
success  
(optional 
outcome) 
 
A patient assessed at 6 months and 
at 12 months after successful TB 
treatment, who is alive and free of 
TB.  
 
*For treatment failed, lack of conversion by the end of the intensive phase implies that 
the participant does not convert within the maximum duration of the intensive phase 
applied by the programme. If no maximum duration is defined, an 8-month cut-off is 
proposed. For regimens without a clear distinction between intensive and continuation 
phases, a cut-off 8 months after the start of treatment is suggested to determine when 
the criteria for Cured, Treatment completed and Treatment failed start to apply. 
 
The terms “conversion” and “reversion” of culture results are defined as follows:  
• 
Conversion (to negative): culture is considered to have converted to negative when 
two consecutive cultures taken at least 30 days apart are found to be negative. In such 
case, the specimen collection date of the first negative culture is used as the date of 
conversion.  
• 
Reversion (to positive): culture is considered to have reverted to positive when after 
an initial conversion, two consecutive cultures taken at least 30 days apart are found 
to be positive.  
 
“Recurrent TB” is defined as being either of the following circumstances after cure or 
completion of treatment:  
• 
Two consecutive positive cultures, or  
• 
One positive culture with clinical signs and symptoms or radiographic deterioration (an 
isolated positive smear or culture without clinical or radiographic deterioration after 
treatment completion provides insufficient evidence to define recurrent TB).  
 
If genotyping is available, recurrent TB may be further classified as relapse, reinfection, or 
undetermined as defined below:  
• 
Relapse: isolates of the recurrent episode share the same genotype pattern with 
isolates of the first episode of MDR-TB.  
• 
Reinfection: isolates of the recurrent episode and isolates of the first episode of MDR-
TB have different genotype patterns.  
• 
Undetermined: there is insufficient information to determine whether the recurrent 
episode is due to relapse or reinfection.  
10. PROCEDURES FOR ASSESSING SAFETY AND ADVERSE EVENT REPORTING 
 
10.1. 
Adverse Events (AEs) and Adverse Event Reporting  
 
An AE is defined as any untoward medical or social occurrence in a clinical research 
participant that may or may not have a causal relationship with the study drugs/interventions. 
The principles of ICH GCP require that investigators follow specific procedures when notifying 
adverse events or reactions in clinical trials.  
 

 
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Adverse drug reaction (ADR): is defined as a response to a medicine in humans that is 
noxious and unintended, including lack of efficacy, and that occurs at doses normally used in 
man and that can also result from overdose, misuse or abuse of a medicine. All adverse 
events judged by either the investigator as having a reasonable causal relationship to a 
medicinal product qualify as adverse reactions. ADRs that occur following enrolment will be 
considered AEs and will be recorded on the AE CRF.  
 
Unexpected Adverse Reaction (UAR): is a reaction in which the nature, specificity, severity 
and outcome is not consistent with the approved package insert for a registered medicine (or 
investigator’s brochure for an investigational product). When the outcome of the adverse 
reaction is not consistent with the applicable product information, this adverse reaction should 
be considered as unexpected. UARs that occur following enrolment will be considered AEs 
and will be recorded on the AE CRF. 
 
Clinical AEs grade 3-5 will be recorded via the AE recording CRF. The clinical course of each 
grade 3 and 4 event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment is not the cause. All participants reporting an AE will be 
followed clinically, until the AE resolves (returns to baseline/non-gradable range). AEs that are 
ongoing at the time of study exit will be followed up for up to 30 days after study exit and then, 
if not resolved, will be referred to a health care provider for further follow-up. 
 
The Principal Investigator (PI) or designee must determine the severity of the AE and 
document it on the appropriate CRF (AE Form). Generally if toxicity occurs on any of the drugs 
used in the study, the decision on whether to continue or stop the drug will depend on severity 
of the toxicity, duration of treatment received, whether the participant has culture converted, 
how many other active drugs are in regimen, how essential the drug is to the regimen and 
whether it can be replaced with another active drug. Each decision will be decided upon by 
the attending clinician. Severity does not have the same meaning as seriousness, since a 
participant can experience a severe event such as a skin rash that is not serious. Grading is 
subjective, based upon perspective of the attending clinician and participant. Additionally, 
especially for measurements and laboratory results, grading may differ according to age, 
gender, body mass index (BMI) and weight.  
Table 8: Grading the severity of ADR; following common guidelines and management for the 
treatment of TB used in the TRiAD study 
Grade 
Severity Rating 
Definition 
Grade 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. The participant will be 
followed carefully and the study drugs will be continued 
Grade 2 
Moderate 
Mild to moderate limitation in activity ‐ some assistance 
may be needed; no or minimal medical 
intervention/therapy required. The participant will be 
followed more closely, with additional laboratory and/or 
clinic visits as necessary; treatment should be continued 
unless in the view of the clinician/investigator this would 
be unsafe. 

 
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Grade 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
Grade 4 
Potentially life 
threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable.  
Grade 5 
Fatal 
Death 
 
An AE does not include:  
• 
Pre-existing diseases or conditions present or detected prior to start of study drug 
administration that does not increase in grade. All pre-existing conditions (grade 3 or 
higher) must be clearly documented on the enrolment CRF If the frequency, intensity, 
or the character of the condition worsens to grade >3 level during the reporting 
period, the event should be defined as an AE;  
• 
Medical or surgical procedures (e.g. Surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an adverse event;  
• 
Situations where an untoward medical occurrence has not occurred (e.g. 
Hospitalization for elective surgery, social and/or convenience admissions).  
 
The PI or designee must determine the relationship of the AE to the drugs under investigation 
and document on the appropriate CRF (AE Form). For each AE, an assessment of the 
relatedness to the study drug will be made using the WHO criteria: 
  
Probable: The event is an identifiable clinical or laboratory-linked phenomenon; the time 
elapsed between the administration of the drug and the occurrence of the event is plausible; 
the event cannot be explained by concurrent disease or any other drug or chemical; the 
participant recovered within a plausible length of time following withdrawal of the drug; re-
challenge did not occur, or the result is unknown. 
 
Possible: The time elapsed between the administration of the drug and the occurrence of the 
event is plausible; the outcome of withdrawal of the suspect medicine is not known, and/or the 
medicine might have been continued and the final outcome is not known; and/or there might 
be no information on withdrawal of the medicine; and/or the event could be explained by 
concomitant disease or use of other drugs or chemicals; and/or there might be no information 
on the presence or absence of other medicines. 
 
Unrelated (Unlikely): The event occurred with a duration to onset that makes a causal effect 
improbable with the drug being considered; and/or the event commenced before the first 
administration of the drug; and/or the drug was withdrawn and this made no difference to the 
event when, clinically, recovery would be expected; and/or it is strongly suggestive of a non-
causal relationship if the drug was continued and the event resolved. This category has also 
been referred to as doubtful. 
 
All AEs will be captured regardless of the association or otherwise to the study product and 
reported on the AE CRF in accordance with study specific procedures. All AE reports will 
contain at least the date the AE occurred, a brief description of the event, the relationship to 

 
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study drug, the study drug action taken, the outcome, date resolved, and the seriousness of 
the event. 
 
10.2. 
Expected Disease Related Events   
 
In this study population, with DR-TB and HIV, some participants may be critically ill and will 
have a complicated clinical course. Opportunistic infections and/or nosocomial infections are 
expected. Disease-related events may be frequent and include: 
• 
Death which will always be reported as an SAE  
• 
HIV-related opportunistic infections / illnesses   
• 
Common ART side-effects e.g. anaemia, sleep disturbance, diarrhoea, mild renal 
dysfunction 
• 
Hospitalisation due to respiratory symptoms or HIV related conditions  
Expected disease-related events will be recorded in study CRFs but will not require reporting 
to regulatory authorities unless the severity of the event was considered to be unexpected.  
 
10.3. 
Serious Adverse Event Reporting 
 
An SAE or Serious Adverse Reaction (SAR) or Suspected Unexpected Serious Adverse 
Reaction (SUSAR) includes an experience where any AE, AR or UAR that at any dose:  
• 
Results in death;  
• 
Is life-threatening;  
• 
Requires hospitalization or prolongation of existing hospitalization;  
• 
Results in persistent or significant disability or incapacity; or is a medically significant/ 
important event or reaction that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require intervention 
to prevent one of the other outcomes listed in the definition above.  
 
All serious ADRs will be reported.  
 
10.4. 
Anti-TB Drug Information for new study drugs 
 
There are no absolute contraindications for the use of any drug in the treatment of DR-TB, a 
disease that poses serious risk of death or debilitation to the participant if treated inadequately. 
However, relative contraindications, side-effect profiles and drug-drug interactions must be 
considered when selecting and administering the drug throughout. If the clinician judges that 
the potential benefits outweigh the potential risk (also considering alternative treatment 
options) treatment may proceed with caution. The Companion Handbook to the WHO 
guidelines for programmatic management of drug-resistant tuberculosis (40) provides relevant 
information for most anti-TB medicines, with the exception of pretomanid which was in use 
when the handbook was written. Details for key drugs in the TRiAD study are summarised in 
Table 9 below and guidelines for medical management can be found in Appendix I. Wherever 
necessary, advice may be sought from the study MMT. 
 
 
 
 

 
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Table 9: Summary profile of drugs to be used for treatment of DR-TB in the TRiAD study 
Bedaquiline 
Activity against TB, 
Mechanism of 
action, and 
metabolism  
Bactericidal: Inhibits ATP synthesis.  
The drug has a 5.5-month half-life. Cytochrome P450 3A4 
(CYP3A4) is the major CYP isoenzyme involved in the metabolism 
of bedaquiline. The metabolism leads to the formation of an M2 
metabolite which is not thought to contribute significantly to clinical 
efficacy but may contribute to QTc prolongation.  
Bedaquiline is mainly eliminated in faeces. The renal clearance of 
unchanged drug is insignificant. 
Dose  
Adults: 400 mg once daily for 2 weeks, followed by 200 mg, 3 times 
per week for 22 weeks with food. 
  
If a dose is missed during the first 2 weeks of treatment, 
participants should not make up the missed dose but should 
continue the usual dosing schedule. From week 3 onwards, if a 200 
mg dose is missed, participants should take the missed dose as 
soon as possible, and then resume the 3 times a week regimen. 
Special 
Circumstances  
Use in renal disease: No dosage adjustment is required in 
participants with mild to moderate renal impairment (dosing not 
established in severe renal impairment, use with caution). 
 
Use in hepatic disease: No dosage adjustment is required in 
participants with mild to moderate hepatic impairment. Dosing and 
toxicity not well established in severe hepatic impairment, use with 
caution and only when the benefits outweigh the risks. 
 
Use in pregnancy/breast feeding: Very limited data. Each case 
must be individually assessed.  
Adverse Reactions*  Common: Nausea, vomiting, abdominal pain, loss of appetite, joint 
pain (arthralgia), headache, chest pain, haemoptysis  
Serious: QT prolongation (more common in hypokalaemia, 
proarrhythmic conditions, of if combined with other QTc-prolonging 
drugs), hyperuricaemia, phospholipidosis (the accumulation of 
phospholipids in the body’s tissues), elevated aminotransferases. 
Possibly an increased risk of pancreatitis. 
Contraindications  
Do not use or discontinue bedaquiline if: 
• 
Clinically significant ventricular arrhythmia. 
• 
A QTcF interval of >500ms (confirmed by repeat ECG). 
• 
Severe liver disease. 
Use with caution in the following situations (with more frequent 
ECG monitoring and evaluation of risk versus benefit): 
• 
Use with other QT prolonging drugs (see drug interactions) 
• 
A history of torsade de pointes 
• 
A history of congenital long QT syndrome 
• 
A history of hypothyroidism and bradyarrhythmias 
• 
A history of uncompensated heart failure 

 
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• 
Serum calcium, magnesium or potassium levels below the 
lower limits of normal. 
Any syncopal event (e.g. fainting) should prompt immediate 
medical evaluation and ECG. 
Drug Interactions* 
Anti-arhythmic drugs, tricyclic anti-depressants, anti-psychotics, 
chloroquine & hydroxychloroquine, some other TB drugs (e.g. 
clofazimine & fluoroquinolones), and macrolide antibiotics may 
increase risk of QTc prolongation. 
CYP3A4 inducers (including rifampicin, rifabutin, rifapentine, 
phenytoin and carbamazepine) can accelerate metabolism of 
bedaquiline resulting in reduced effect.  
CYP3A4 inhibitors (including azole antifungals) slow metabolism of 
bedaquiline resulting in increased concentrations of bedaquiline. 
Some anti-retroviral drugs are CYP3A4 inducers (e.g. efavirenz) or 
inhibitors (e.g. the protease inhibitors), so combined HIV and TB 
therapy requires careful consideration.  
Guidance on 
monitoring 
ECG: before initiation of treatment, and at least 2, 4, 8, 12 and 24 
weeks after starting treatment. More frequently if heart conditions, 
hypothyroidism or electrolyte disturbances are present.  
LFT: at baseline and repeated monthly. 
Pretomanid 
Activity against TB 
 
Indicated as part of a combination regimen with bedaquiline and 
linezolid for treatment of adults with pulmonary XDR or treatment-
intolerant or nonresponsive MDR TB 
Dose  
Pretomanid 200 mg daily 26 weeks 
Special 
Circumstances  
Use in renal or hepatic disease: Effect on the safety, effectiveness, 
and pharmacokinetics unknown. 
If hepatotoxicity develops on a pretomanid-containing regimen, the 
entire regimen should be interrupted if: 
• 
Any aminotransferase elevation is accompanied by a total 
bilirubin elevation >2x ULN 
• 
Aminotransferase elevations are >8 x ULN 
• 
Aminotransferase elevations are >5x ULN and persist 
beyond 2 weeks 
 
Any concerns about hepatotoxicity should be discussed promptly 
with the Medical Monitoring team. 
 
There are no data on the use of pretomanid in pregnancy, or during 
breast feeding. 
Adverse Reactions* 
In clinical trials of the bedaquiline-pretomanid-linezolid regimen, 
reported severe adverse reactions have included:  
• 
hepatotoxicity  
• 
myelosuppression, peripheral and optic neuropathy (all 
known adverse reactions to linezolid 

 
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• 
QTc prolongation (known adverse reaction to bedaquiline)  
Pre-clinical animal studies reported testicular atrophy and fertility 
problems. Potential effects on human male fertility are still being 
evaluated. 
Contraindications  
Pretomanid should always be initiated as part of a treatment 
regimen including bedaquiline and linezolid, so it is contraindicated 
if these drugs are contra-indicated. 
 
After treatment initiation: 
If bedaquiline is discontinued, pretomanid must also be 
discontinued, and the entire regimen should be re-assessed. 
 
If linezolid is permanently discontinued during the initial four 
consecutive weeks of treatment, the bedaquiline-pretomanid-
linezolid regimen should also be discontinued and the entire 
treatment regimen should be re-assessed.  
 
If linezolid is discontinued after the initial four weeks of consecutive 
treatment, the bedaquiline-pretomanid regimen may be continued.  
 
Drug Interactions*  
CYP3A4 Inducers: Co-administration of pretomanid with rifampicin 
and efavirenz may result in a decrease in pretomanid plasma 
concentrations. Avoid co-administration of the combination 
bedaquiline-pretomanid-linezolid regimen with rifampin, efavirenz, 
or other strong or moderate CYP3A4 inducers. 
Lopinavir/ritonavir (LPV/r): Co-administration of pretomanid with 
LPV/r did not affect the plasma concentrations of pretomanid. LPV/r 
can be co-administered with the combination bedaquiline-
pretomanid-linezolid regimen. 
Guidance on 
monitoring 
ECG before initiation of treatment. 
Check serum potassium, calcium and magnesium and correct 
abnormalities before initiation of treatment. 
Assess for symptoms and signs of liver disease (such as fatigue, 
anorexia, nausea, jaundice, dark urine, liver tenderness, and 
hepatomegaly and check LFTs (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase, and 
bilirubin) before initiation of treatment. 
Monitor clinically and biochemically for hepatotoxicity during 
treatment. 
Linezolid  
Activity against TB, 
Mechanism of 
action, and 
metabolism  
Bactericidal: Inhibits protein synthesis. 

 
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Dose  
Adults: 600 mg, once daily. (Reduce to 300 mg/day if serious 
adverse effects develop). Ongoing trials may inform on revised 
dosing. 
Vitamin B6: All participants should receive vitamin B6 while 
receiving linezolid. 
Special 
Circumstances  
Use in renal disease: No dose adjustment is recommended, but 
metabolites may accumulate. 
Use in hepatic disease: Rarely associated with increased 
transaminases. 
Use in pregnancy/breastfeeding: Not recommended during 
pregnancy or breastfeeding due to limited data. 
Adverse Reactions*  Common: diarrhoea, nausea, vomiting, headache, transient 
increases in LFTs. 
 
Serious: myelosuppression (decreased level of platelets, white 
blood cells, and/or anaemia), optic and peripheral neuropathy 
(increased risk with prolonged treatment and may be irreversible) 
lactic acidosis (may present recurrent nausea or 
vomiting, unexplained acidosis, or a low bicarbonate level). 
Contraindications  
Hypersensitivity to oxazolidinones. 
Symptoms of neuropathy (pain, numbness, tingling or weakness in 
the extremities). 
Drug Interactions* 
Avoid concurrent use with serotonergic agents, such as 
monoamine oxidase inhibitors (MAOIs), selective serotonin 
reuptake inhibitors (e.g. fluoxetine, paroxetine), lithium, tricyclic 
antidepressants etc., as it may cause serious neurological reactions 
such as seizures and serotonin syndrome. 
Guidance on 
monitoring 
Monitor for peripheral neuropathy and optic neuritis (visual 
eye tests every two months or if symptoms develop, clinical 
examination for peripheral neuropathy monthly or if symptoms 
develop). Monitor a complete blood count weekly during the initial 
period, then monthly. 
Moxifloxacin 
Activity against TB, 
Mechanism of 
action, and 
metabolism  
Bactericidal: inhibits DNA gyrase 
Dose  
Adults: 400 mg daily (oral or IV) 
Special 
Circumstances  
Use in renal disease: Excretion unchanged during renal failure; no 
data on effect of dialysis. 
Use in hepatic disease: Rarely associated with hepatotoxicity; use 
with caution. No dose adjustment required for mild or moderate 
liver disease. 
Use during pregnancy/breastfeeding: Fluoroquinolones are 
generally avoided during pregnancy and breastfeeding due to 
observation of arthropathy in animal models. However, there are 

 
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case reports of fluoroquinolones being used safely during 
pregnancy. 
Adverse Reactions*  Common: Nausea, vomiting, diarrhoea, dizziness, headache, 
transient increases in LFTs. 
Serious: QTc prolongation (more common in hypokalaemia, 
predisposing cardiac conditions, or if combined with other QTc 
prolonging drugs), arthralgia, tendon inflammation and/or rupture, 
hepatotoxicity, hypo/hyperglycaemia. 
Contraindications  
Fluoroquinolone intolerance, prolonged QTc (>500ms). 
Fluoroquinolones may lower seizure threshold, so use with caution 
in participants with CNS disorders. 
Drug Interactions* 
Caution if used alongside other drugs known to prolong QTc.  
Guidance on 
monitoring 
Symptomatic monitoring. 
Some guidelines recommend ECG at baseline, 2 weeks and every 
3 months thereafter, especially if concurrent use with other 
medicines which may prolong QTc. 
Levofloxacin 
Activity against TB, 
Mechanism of 
action, and 
metabolism  
Bactericidal: inhibits DNA gyrase 
Dose  
Adults: For treatment of TB disease 10–15 mg/kg once daily.  
Renal failure/dialysis: 750–1000 mg/dose, 3 times weekly (not 
daily) for creatinine clearance <30 ml/min. 
Special 
Circumstances  
Use in renal disease: Dosage adjustment is recommended if 
creatinine clearance is <50 ml/min. The drug is not cleared by 
haemodialysis; supplemental doses after dialysis are not 
necessary. Use in hepatic disease: Drug concentrations are not 
affected by hepatic disease. Presumed to be safe in severe liver 
disease. 
 
Use during pregnancy/breastfeeding: Fluoroquinolones are 
generally avoided during pregnancy and breastfeeding due to 
observation of arthropathy in animal models. However, there are 
case reports of fluoroquinolones being used safely during 
pregnancy. 
Adverse Reactions* 
Nausea and bloating. Headache, dizziness, insomnia or 
tremulousness. Rare-tendon rupture, arthralgias (can usually be 
treated symptomatically). QTc prolongation, hypoglycaemia. 
Contraindications  
Fluoroquinolone intolerance, prolonged QTc (>500ms). 
Fluoroquinolones may lower seizure threshold, so use with caution 
in participants with CNS disorders. 
Drug Interactions* 
Caution if used alongside other drugs known to prolong QTc. 
Guidance on 
monitoring 
Symptomatic monitoring.  
Some guidelines recommend ECG at baseline, 2 weeks and every 
3 months thereafter, especially if concurrent use with other 
medicines which may prolong QTc. 

 
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* Information on adverse reactions and drug interactions is not exhaustive. Please refer to 
pharmacy formulary, or discuss with the medical monitoring team as necessary. 
11.  DATA MANAGEMENT  
 
All data management activities will be undertaken by the applicable regulatory frameworks 
and managed by CAPRISA for all sites. This includes the European Medicines Agency (EMA) 
regulations relating to data integrity, data protection and privacy and the relevant health 
products regulatory authorities of South Africa, Nigeria and Ethiopia. The TRiAD study will 
also abide by all relevant institutional review board regulations. The Data management 
systems in CAPRISA meet FDA requirements as they are Code of Federal Regulations (CFR) 
Part 11 compliant (the part of Title 21 of the CFR that establishes the U.S. FDA regulations 
on electronic records and electronic signatures). The Data Management standard processes 
are aligned with the Good Clinical Data Management Processes (GCDMP). 
 
The data collection method that will be used is Electronic Data Capture (EDC) using DFexplore 
(5.1.0, DF/Net, Seattle, USA). DFexplore is a validated clinical database management system 
which is FDA CFR Part 11 compliant. Electronic Case Report Form (eCRF) data will reside 
on the DFexplore server housed at CAPRISA Doris Duke Medical Research Institute (DDMRI) 
and is backed up at regular intervals at CAPRISA DDMRI. 
 
The electronic-CRF design will be guided by the study protocol with final approval by the study 
team. All study staff will be allocated user roles, specific to their function in the study. Database 
access will be restricted by passwords and validation levels. The study staff and statistician 
can access the database in “read-only” mode once data has been entered. All data roles will 
have write-access for data entry purposes and all data will be managed by the CAPRISA Data 
Management team manager. All external electronic lab data must be password protected and 
will be imported into DFexplore. 
 
In the event of internet downtime, power outages, or any situation that makes the system 
inaccessible, one-ply paper CRFs will be used to collect the data, which will be scanned 
through to the CAPRISA data centre once the internet is active again. DFexplore has optical 
character recognition (OCR) which will read the check boxes and numerical fields on the CRFs 
and store them in the study database. Any fields not recognized by the OCR system will be 
entered manually by data encoders. Data encoders will verify all data by cross-checking the 
scanned version to what is captured by OCR. 
 
All queries and/or reasons for data changes will be generated electronically and will form part 
of the weekly and/or monthly QC Reports that will be distributed to the appropriate study team 
members. Study staff also have the option of addressing any query at any time. Queries 
arising during validation of the data will be recorded in QC reports sent to the sites on a regular 
basis. Any queries from scanned CRFs resulting in a change to the database must be 
documented on the original CRF and rescanned. QC rates will be communicated to the site 
monthly. Scheduled monthly downloads will be sent to the study statistician in the SAS/CSV 
format. These downloads will also be made available at country level on regular interval on 
request. 
 

 
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Study staff who have access to the data on their computer systems will be trained on how to 
use the system and the importance of system security. Support will always be available from 
the data manager and IT department at CAPRISA, if any issues arise. 
 
Breaches of data integrity, data protection and privacy are defined as any serious breach of 
the European General Data Protection Regulation (GDPR), EU 2016/679, for all personal data  
processing activities applicable under this regulation. Serious breaches of the GDPR are those 
related to sensitive personal data and defined as: 
 
• 
Unauthorized or unlawful processing of sensitive personal data collected as part of the 
study is monitored by the Data Manager in accordance with the Data Management 
Plan. Accidental loss of sensitive personal data collected as part of the study is 
prevented by internal policies (included in the Data Management Plan) around access 
to sensitive personal data and use of electronic and paper carriers of sensitive personal 
data. In addition, all investigators and data collection and data management staff in 
TRIAD need to report loss of carriers that might contain sensitive personal data to their 
site-PI.   
• 
Destruction or damage of sensitive personal data collected as part of the study is 
monitored by the central Data Manager and site Data Managers in accordance with 
the Data Management Plan. 
 
In an event where breaches of data integrity, data protection and privacy occurs, potential 
breaches are reported to the Project Coordinator within 2 working days of the breach 
becoming known as outlined in the Policy for immediate reporting to EDCTP document. 
 
All CRFs and source documents are to be securely stored in the participant study file in a 
secure double-locked, fire resistant unit with restricted access in accordance with GCP 
requirements. Upon completion of the study, the close-out site monitoring visit and finalization 
of the database for analysis, any original forms will be bound and kept for long term storage. 
12. STUDY COMMITTEES   
 
12.1. 
Joint Steering Committee 
 
A consortium Joint Steering Committee (JSC) will be established in order to manage the 
overall collaboration and make decisions in accordance with the research collaboration 
agreement. 
 
 Committee accountabilities will include: 
• Oversight of the TRiAD project 
• Approve project plans, study protocol, and communication/publication plans 
• Ensure that all necessary regulatory authority and ethics committee approvals have 
been obtained 
• Take relevant decisions to enable the conduct of the project and the achievement of 
agreed deliverables 
 

 
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The JSC will consist of one member from each of the collaborating organizations. The lead 
participant of coordinating institution of the project will be the chairperson of the JSC. Other 
parties, including but not limited to project funders, may be invited to send one or more 
representatives to participate in JSC meetings. These additional parties are entitled to 
participate in the JSC meetings and contribute to discussions but may not vote on decisions 
to be taken by the JSC. In detail, a member of EDCTP will act as observer on the JSC. The 
JSC will meet routinely once a quarter though additional meetings may be scheduled by the 
chairperson, as required. 
 
A quorum for the JSC meeting will be two thirds representation of the consortium, in  addition 
to the chairperson. Since senior members from each collaborating organisation serve on the 
JSC, it is able to make decisions rapidly, if needed. The JSC will also ensure that the project 
activities are in accordance with the collaborative agreement and funders requirements.  The 
JSC will have equal representation from all institutions directly involved in the project.  The 
chairperson of the JSC may appoint an ethics advisor to participate in deliberations on any 
ethical matters that are on the JSC agenda. The main purpose of the JSC is to enhance 
sharing of information and ensure effective communication of each partner’s trial-related 
activities. Final decision-making processes will be based on a consensus approval. 
 
12.2. 
Medical Monitoring Team (MMT)   
 
A MMT will be established for the study. The overall objective of medical monitoring is to 
enhance the consistency of participant management within the context of the protocol.  This 
improves participant safety and enhances the consistency of the data emerging from the 
study. The MMT will work with the Principal Investigators, and Site Investigators to ensure: 
 
1. Adequate safety oversight of study participants 
2. Optimal consistency of clinical management across all sites in the TRiAD study 
During the study, it will the responsibility of the MMT to respond to queries on clinical 
management from Site Investigators and consult with the Principal Investigator regarding any 
concerns which arise. When requested by an investigator, a medical monitor discusses 
potential participant recruitment and outcome allocations with site investigators and helps to 
ensure that only participants who meet the protocol inclusion and exclusion criteria are 
enrolled in the study. The medical monitor also offers advice on toxicity management in 
accordance with established study protocols are followed, and reviews data, when provided, 
in order to support prompt identification of potential safety concerns. The medical monitor may 
discuss the progress of subjects in the trial and any safety concerns that are new or are being 
tracked. Communication with the MMT will be by telephone and / or electronic means as 
appropriate to the clinical situation. AEs and other non-urgent medical concerns will be 
discussed by the MMT on a regular basis with the Principal Investigator. The MMT will also 
advise PI’s/ site-clinicians on the management of interruptions to treatment and 
discontinuation of treatment due to toxicity and treatment failure. 
12.3. 
Data Safety Monitoring Board (DSMB) 
 
Safety will be monitored internally by the medical monitoring team and externally an 
independent DSMB for the study. The details of the operation and responsibilities of the DSMB 
will be defined in a DSMB Charter. The Charter will delineate the duties, responsibilities, and 

 
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procedures of the DSMB. CAPRISA will lead the development of the Charter. The DSMB will 
be comprised by a statistician, and at least two experts in TB or HIV clinical studies (infectious 
disease specialist or clinician), all independent of the study team. 
 
The DSMB will meet via teleconference annually and will review primary and key secondary 
endpoint data.  Each meeting will comprise an open session, which will be attended by the 
study team. At the end of the open session, the DSMB will have a closed session, attended 
only by DSMB members. More frequent or ad hoc reviews of safety reports may be conducted 
by the DSMB as needed. After each DSMB meeting, the Chairperson will issue a written report 
describing all recommendations. The DSMB could recommend that the study should proceed 
as designed, should proceed with design modifications, or should be discontinued. 
13. HUMAN PARTICIPANT PROTECTION AND ETHICAL OBLIGATIONS 
 
13.1. 
Ethical and Regulatory Review 
 
SOUTH AFRICA; CAPRISA/WITS Health Consortium: Ethical approval for the conduct of this 
study in South Africa will be sought from the UKZN Biomedical Research Ethics Committee 
(BREC) for ethical review for CAPRISA and the and the Human Research Ethics Committee 
(HREC) for WITS. Regulatory approval will be sought from  South African Health Products 
Regulatory Authority (SAPHRA) for both clinical research sites in South Africa. These 
institutions are registered with the South African Department of Health’s National Health 
Research Ethics Council (http://www.doh.gov.za/nhrec) (NHREC REC 200408-009), and 
the US Office for Human Research Protections (http://www.hhs.gov/ohrp/) (OHRP). 
 
NIGERIA/IHVN: Ethical approval for the conduct of this study in Nigeria will be sought from 
the Nigerian National Health and Research Ethics Committee of Nigeria (NHREC), the IRB of 
the University of Maryland, Baltimore, (UMB) (the country PI is also a Professor of Medicine 
at UMB), and the health research ethics committees of all the participating clinics sites. 
 
ETHIOPIA/EPHI: Ethical approval for the conduct of this study in Ethiopia will be sought from 
the Scientific and Ethical Review Office (SERO) which is the office of the secretariat for the 
institutional review board of Ethiopian Public Health Institute (EPHI). The protocol reviewed 
by EPHI-IRB will be submitted to National Research Ethics Review Committee (NRERC) as it 
involves human participants and new diagnostic that are not registered for use in Ethiopia. 
 
 
13.2. 
Informed consent process 
 
Written informed consent will be obtained from each study participant prior to screening and 
enrolment. Written informed consent will also be obtained for long-term specimen storage and 
possible future analyses. Participants will be provided with a copy of their informed consent 
forms if they wish to receive them.  
 
Study informed consent forms will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. The informed consent forms will also be 

 
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translated into respective languages for each country and the accuracy of the translation will 
be verified through independent back-translation. 
 
The study consent process will include an assessment of each potential participant’s 
understanding of the study and the risks and benefits of study participation, which are essential 
for an informed decision. Participants who are not able to demonstrate adequate 
understanding of key concepts will not be enrolled in the study. 
 
Only participants who give informed consent per IRB/IEC requirements will be enrolled in the 
protocol. Potential participants will have the requirements of the protocol explained to them 
and they will have the opportunity to discuss the protocol with the site investigator or designee 
before consent is obtained. They will be assured that their decision to participate is voluntary 
and made completely without prejudice to their future care and treatment. Once the study 
team member is satisfied that the participant has understood the requirements of the protocol 
and the informed consent form (ICF), the participant will be asked to sign and date the ICF. 
The originals will be retained in the clinical research unit’s research file and a copy will be 
provided to the participant. Participants may refuse to participate in this protocol. If they decide 
to participate, they may change their minds and discontinue after the study has started without 
facing penalties or loss of benefits. This will be monitored continuously throughout the study 
period. If the participant decides to leave the study, he/she can notify the PI or designee. If 
enrolled participants want to withdraw their consent for long-term storage and possible future 
research testing of their biological samples, they can simply contact the PI or designee. The 
samples remaining in storage will be destroyed and documented in the laboratory 
management system. 
 
13.3. 
Participant Confidentiality 
 
All records identifying the participant will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. All participant data 
including laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ethics committee or the sponsor’s 
designee. External monitors will also review clinical information. QA officers and Head of QA 
will not be on delegation of Authority Log as these staff serve as internal and/or external 
monitors. 
 
13.4. 
In-country Regulations of diagnostics and study drugs 
 
Each participating clinical research site: 
• 
Needs to attain the relevant Institutional Review Board/Ethics Committee approvals 
for the study 
• 
Is responsible for all necessary regulatory approvals for the study, and shall prepare, 
file and hold all applicable regulatory approvals for the study   

 
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• 
Is also solely responsible for all regulatory obligations associated with the study, 
including the collection and submission of all applicable regulatory information 
(including adverse events) to the appropriate in-country regulatory authority 
• 
Is responsible for sourcing all necessary import permits and material transfer 
agreements  
 
A study specific drug and diagnostic management SOP contains details relating to the supply 
and management of study products as well as on-site storage and accountability. 
 
13.5. 
Good Clinical Practice 
 
South Africa: The study will be carried out according to ICH-GCP and South African Good 
Clinical Practice Guidelines (SA GCP). The PI and/or designee will ensure that the study staff 
are conducting the study in accordance with current SA GCP and ICH-GCP guidelines, ensure 
appropriate human participants training for all study staff and safety of all study participants. 
The study protocol and participant informed consents and all future revisions of these latter 
documents will be reviewed and approved by UKZN BREC and SAPHRA prior to 
implementation. Quality control officers will perform daily quality checks on participant data 
and the Data manager will oversee the maintenance and completeness of the participant data.  
 
All Serious Adverse Events (SAE’s) will be reported to UKZN BREC and SAPHRA within 7 
business days of site awareness. The DSMB will meet at designated timepoints to analyse 
and discuss safety data and make recommendations for the continuation of the study and 
participant care. 
 
Nigeria: All study activities will be performed in accordance with the ICH-GCP guidelines and 
the NHREC code of conduct. Under the leadership of the Country PI, appropriate trainings on 
research ethics will be provided for the study team and clinic site personnel involved in the 
study implementation. Certificates from these trainings will be archived for reference 
purposes. 
 
In line with the WHO recommendation for new medicines and regimens, active drug safety 
management and monitoring systems will be deployed to report SAE’s and AE’s of special 
interest. This will also be in accordance with the reporting guidelines of National Agency for 
Food and Drug Administration and Control (NAFDAC), as well as NHREC. To maintain high 
quality data capture, daily quality control checks will be performed on all filled case report 
forms. 
Ethiopia: The study will be carried out according to ICH-GCP, Clinical Trial Authorization 
Guideline and National Research Ethics Review Guideline. The protocol will be approved by 
the national and institutional Ethics Committee. The Principal Investigator ensures the study 
is conducted as per the protocol. All study team will be trained on study participant enrolment, 
data management and security, safety of study participant. 
Serious Adverse effect will be reported to the national clinical review committee and study 
team. The study team will ensure the recommendation is communicated and use for 
participant care. 

 
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14. BIOHAZARD CONTAINMENT 
 
The research complies with applicable health and safety procedures and with applicable 
international and national law regarding the protection of humans, including research staff. 
 
All precautions will be employed by all personnel during the collection of  samples and all 
dangerous materials, including diagnostic specimens and infectious substances, must be 
transported using packaging mandated by CFR 42 Part 72. Please refer to instructions 
detailed in the International Air Transport Association (IATA) Dangerous Goods Regulations.  
 
Experimental assays will be conducted in a Biosafety level 3 laboratory facility. All staff and 
students will receive comprehensive safety training on handling of the hazardous organisms. 
Effective personal protective equipment will be supplied. 

 
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15. REFERENCES 
 
1. WHO. Global tuberculosis report World Health Organization; 2018. 
2. WHO. Global tuberculosis report World Health Organization; 2020. 
3. Dheda K, Gumbo T, Maartens G, Dooley KE, Murray M, Furin J, et al. The Lancet 
Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, 
transmission, diagnosis, and management of multidrug-resistant and incurable 
tuberculosis. The Lancet Respiratory Medicine. 2019;7(9):820-6. 
4. WHO. The End TB Strategy: global strategy and targets for tuberculosis prevention, care 
and control after 2015. Geneva, Switzerland: WHO, 2015. 2016. 
5. WHO. Consolidated guidelines on drug-resistant tuberculosis treatment. 2019. 
6. Zhiyi Lan M, Nafees Ahmad P, Parvaneh Baghaei M, Linda Barkane M, Andrea Benedetti 
P, Sarah K Brode M, et al. Drug-associated adverse events in the treatment of multidrug-
resistant tuberculosis: an individual patient data meta-analysis. The Lancet 2020;8(3). 
7. WHO. Largest ever roll-out of GeneXpert® rapid TB test machines, in 21 countries. World 
Health Organization. 2013. 
8. WHO. Next-generation Xpert® MTB/RIF Ultra assay recommended by WHO. World 
Health Organization; 2017. 
9. WHO. The use of molecular line probe assays for the detection of resistance to second-
line anti-tuberculosis drugs: policy guidance.: World Health Organization; 2016. Report 
No.: 9241510560. 
10. Tomasicchio M, Theron G, Pietersen E, Streicher E, Stanley-Josephs D, Van Helden P, 
et al. The diagnostic accuracy of the MTBDRplus and MTBDRsl assays for drug-resistant 
TB detection when performed on sputum and culture isolates. Scientific reports. 
2016;6:17850. 
11. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-
resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. The 
Lancet Infectious Diseases. 2017;17(2):223-34. 
12. Olayanju O, Limberis J, Esmail A, Oelofse S, Gina P, Pietersen E, et al. Long-term 
bedaquiline-related treatment outcomes in patients with extensively drug-resistant 
tuberculosis from South Africa. European Respiratory Journal. 2018;51(5):1800544. 
13. WHO. Treatment guidelines for drug-resistant tuberculosis: World Health Organization; 
2016. 
14. Nunn AJ, Phillips PP, Meredith SK, Chiang C-Y, Conradie F, Dalai D, et al. A trial of a 
shorter regimen for rifampin-resistant tuberculosis. New England Journal of Medicine. 
2019;380(13):1201-13. 
15. Zhao Y, Fox T, Manning K, Stewart A, Tiffin N, Khomo N, et al. Improved treatment 
outcomes with bedaquiline when substituted for second-line injectable agents in 
multidrug-resistant tuberculosis: a retrospective cohort study. Clinical Infectious Diseases. 
2018;68(9):1522-9. 
16. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of 
highly drug-resistant pulmonary tuberculosis. New England Journal of Medicine. 
2020;382(10):893-902. 
17. WHO. Rapid Communication: Key changes to the treatment of drug-resistant tuberculosis. 
2019. 
18. Li S-Y, Tasneen R, Tyagi S, Soni H, Converse PJ, Mdluli K, et al. Bactericidal and 
sterilizing activity of a novel regimen with bedaquiline, pretomanid, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrobial agents and chemotherapy. 
2017;61(9):e00913-17. 
19. Dawson R, Harris K, Conradie A, Burger D, Murray S, Mendel C, et al., editors. Efficacy 
of bedaquiline, pretomanid, moxifloxacin & PZA (BPAMZ) against DS-& MDR-TB. 

 
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Conference on Retroviruses and Opportunistic Infections (CROI), CROI Foundation in 
partnership with the International Antiviral Society-USA, Seattle, WA; 2017. 
20. ClinicalTrials. Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-
Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients. National 
Library of Medicine (US). 2017:Identifier NCT03338621. 
21. Kendall EA, Malhotra S, Cook-Scalise S, Denkinger CM, Dowdy DW. Estimating the 
impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of 
projected patient outcomes and epidemiological considerations. BMC infectious diseases. 
2019;19(1):794. 
22. Xie YL, Chakravorty S, Armstrong DT, Hall SL, Via LE, Song T, et al. Evaluation of a rapid 
molecular drug-susceptibility test for tuberculosis. New England Journal of Medicine. 
2017;377(11):1043-54. 
23. Cao Y, Parmar H, Gaur RL, Lieu D, Raghunath S, Via N, et al. Xpert MTB/XDR: a 10-
Color Reflex Assay Suitable for Point-of-Care Settings To Detect Isoniazid, 
Fluoroquinolone, 
and 
Second-Line-Injectable-Drug 
Resistance 
Directly 
from 
Mycobacterium tuberculosis-Positive Sputum. Journal of Clinical Microbiology. 
2021;59(3). 
24. Dorman SE, Schumacher SG, Alland D, Nabeta P, Armstrong DT, King B, et al. Xpert 
MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a 
prospective multicentre diagnostic accuracy study. The Lancet Infectious Diseases. 
2018;18(1):76-84. 
25. Gillespie SH, Sabiiti W, Oravcova K. Mycobacterial load assay.  Diagnostic Bacteriology: 
Springer; 2017. p. 89-105. 
26. Hai HT, Vinh DN, Thu DD, Hanh NT, Phu NH, Srinivasan V, et al. Comparison of the 
Mycobacterium tuberculosis molecular bacterial load assay, microscopy and GeneXpert 
versus liquid culture for viable bacterial load quantification before and after starting 
pulmonary tuberculosis treatment. Tuberculosis. 2019;119:101864. 
27. Honeyborne I, McHugh TD, Phillips PP, Bannoo S, Bateson A, Carroll N, et al. Molecular 
bacterial load assay, a culture-free biomarker for rapid and accurate quantification of 
sputum Mycobacterium tuberculosis bacillary load during treatment. Journal of clinical 
microbiology. 2011;49(11):3905-11. 
28. Honeyborne I, Mtafya B, Phillips PP, Hoelscher M, Ntinginya EN, Kohlenberg A, et al. The 
molecular bacterial load assay replaces solid culture for measuring early bactericidal 
response to antituberculosis treatment. Journal of clinical microbiology. 2014;52(8):3064-
7. 
29. Sabiiti W, Azam K, Farmer ECW, Kuchaka D, Mtafya B, Bowness R, et al. Tuberculosis 
bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular 
Bacterial Load Assay. Thorax. 2020;75(7):606-8. 
30. Mtafya B, Sabiiti W, Sabi I, Msuya Y, Ntinginya N. Clinical evaluation of the novel 
molecular bacterial load assay for real-time monitoring of tuberculosis treatment 
response. Access Microbiology. 2019;1(1A):284. 
31. Mbelele PM, Mpolya EA, Sauli E, Mtafya B, Ntinginya NE, Addo KK, et al. 
Mycobactericidal effect of different regimens measured by molecular bacterial load assay 
among people treated for multidrug-resistant tuberculosis in Tanzania. Journal of clinical 
microbiology. 2021. 
32. WHO. Updated definitions of extensively drug-resistant tuberculosis. 2021 27 January 
2021. 
33. Conradie F. NiX-TB trial experience: safety reporting and recommendations for 
programmatic implementation of the regimen. The 50th Union World Conference on Lung 
Health. 2019;Hyderabad India. 
34. Evans D, Schnippel K, Govathson C, Sineke T, Black A, Long L, et al. Treatment initiation 
among persons diagnosed with drug resistant tuberculosis in Johannesburg, South Africa. 
PloS one. 2017;12(7):e0181238. 
35. Cox HS, Daniels JF, Muller O, Nicol MP, Cox V, van Cutsem G, et al., editors. Impact of 
decentralized care and the Xpert MTB/RIF test on rifampicin-resistant tuberculosis 

 
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treatment initiation in Khayelitsha, South Africa. Open forum infectious diseases; 2015: 
Oxford University Press. 
36. Naidoo P, Du Toit E, Dunbar R, Lombard C, Caldwell J, Detjen A, et al. A comparison of 
multidrug-resistant tuberculosis treatment commencement times in MDRTBPlus line 
probe assay and Xpert® MTB/RIF-based algorithms in a routine operational setting in 
Cape Town. PLoS One. 2014;9(7):e103328. 
37. Cox H, Dickson-Hall L, Ndjeka N, van’t Hoog A, Grant A, Cobelens F, et al. Delays and 
loss to follow-up before treatment of drug-resistant tuberculosis following implementation 
of Xpert MTB/RIF in South Africa: a retrospective cohort study. PLoS medicine. 
2017;14(2):e1002238. 
38. Jo E-J, Park S, Lee KM, Kim I, Eom JS, Kim M-H, et al. Time to appropriate treatment in 
patients with multidrug-resistant tuberculosis in South Korea: Are we still in 2010? PloS 
one. 2019;14(4):e0216084. 
39. Definitions W. Definitions and reporting framework for tuberculosis. Geneva: World Health 
Organization. 2020. 
40. WHO. Companion handbook to the WHO guidelines for the programmatic management 
of drug-resistant tuberculosis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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16. APPENDICES 
 
Appendix I: General guide to safety monitoring in DR-TB therapy 
 
This information, based on WHO guidance, represents a general guide for clinicians managing 
participants during the TRiAD study. Information contained herein is intended to supplement 
Section 10.4 of the TRiAD study protocol. Specific practice at each site may vary, in 
accordance with National Tuberculosis Programme protocols in participating countries. The 
Medical Monitoring Team should be consulted as necessary to address concerns when they 
arise.  
 
1. Baseline safety tests during regimen selection / before initiation of therapy 
 
The TRiAD study protocol requires baseline data collection encompassing: medical history 
(including HIV status and CD4 count), clinical examination (including random blood glucose, 
ophthalmological examination of visual acuity and colour vision assessment, pregnancy test 
and peripheral neuropathy assessment), chest X-ray and laboratory safety assessments 
(according to in country standard of care).   
 
The table, below, provides additional information and recommendations 
 
Assessment / measurement 
Rationale and possible actions* 
Treatment management with routine Laboratory measurement abnormalities 
Baseline renal function (esp. 
serum potassium and 
creatinine) 
Preferably avoid second line TB drugs (e.g. 
aminoglycosides or capreomycin) if there is baseline 
renal dysfunction 
Baseline full blood count 
Caution and close monitoring of linezolid use if anaemia, 
leukopaenia or thrombocytopenia at baseline 
Baseline liver function (esp. 
bilirubin, ALT) 
Caution with rifampicin, isoniazid, pyrazinamide, 
bedaquiline and pretomanid 
Thyroid function test (e.g. 
TSH) 
Caution with use of ethionamide / prothionamide and 
PAS 
Additional considerations 
Problem of visual acuity / 
colour vision 
Consider omitting ethambutol from treatment regimen if 
abnormal; caution with use of linezolid 
Neurological abnormality (esp. 
peripheral neuropathy)  
Caution with use of isoniazid, linezolid, cycloserine or 
terizidone 
Co-prescribe Vitamin B6 as preventive therapy 
Psychological illness 
Preferably avoid cycloserine or terizidone 
ECG 
Caution with use of QTc prolonging drugs (esp. 
bedaquiline, fluoroquinolones, clofazimine, delamanid) if 
baseline QTc >450ms 
Preferably avoid these drugs if QTc <500ms 
Audiometry 
Perform wherever possible if planning to initiation 
injectable second line TB drugs (aminoglycosides or 
capreomycin); however, preferably avoid these drugs, 
esp. if there is any baseline abnormality 
 
*Discuss points of concern with Medical Monitoring Team.

 
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2. Safety monitoring during DR-TB treatment 
 
Monitoring evaluation 
Recommended frequency* 
Routine Laboratory measurements as per in-country guideline 
Renal function (esp. serum 
potassium and creatinine) 
At baseline, then monthly if possible while receiving an 
injectable agent 
Consider more frequently in higher risk groups (e.g. HIV-
infected participants, diabetics, known underlying renal 
disease) 
Serum magnesium and 
calcium  
Check, if possible, when hypokalaemia is diagnosed 
Repeat check potassium, magnesium, calcium if QTc 
prolongation or cardiac arrhythmias 
Liver function (bilirubin, ALT) 
Check monthly on rifampicin, isoniazid, pyrazinamide, 
bedaquiline and pretomanid containing regimens 
Frequency may be gradually reduced if stable, or may 
be more frequent in high-risk groups (e.g. underlying 
liver disease, viral hepatitis)  
Full blood count 
If on linezolid, check weekly at first then monthly (may 
reduce frequency in longer-term use if stable) 
TSH 
Check every 3 months if receiving both 
ethionamide/prothionamide and PAS 
Check every six months if receiving one of 
ethionamide/prothionamide or PAS 
Also monitor for clinical signs of hypothyroidism if using 
those drugs 
Lactic acid 
Check if concern of lactic acidosis on linezolid and / or 
antiretroviral therapy 
Additional considerations 
Visual, neurological and 
psychological evaluations 
Perform according to clinical concern at each 
consultation 
ECG 
Repeat during treatment; frequency dependent on 
specific QTc prolonging drugs in treatment regimen, and 
other cardiac risk factors 
Audiometry 
Repeat monthly, if possible, whilst on second-line 
injectable drugs 
 
*Discuss emergent abnormalities with Medical Monitoring Team (consider: is there a 
need for symptomatic therapy, dose change, treatment interruption, or change of 
regimen?).

 
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3. Initial management of common adverse events 
 
Adverse events should be reported according to Sections 10.1 – 10.3 of the protocol. The table 
below provides additional information but is not exhaustive. Support should be sought from the 
Medical Monitoring Team as necessary. 
 
Adverse event 
Likely drug 
Initial management 
Comment 
Rash / allergy / 
anaphylaxis 
Any drug 
If serious reaction, stop 
therapy and manage 
according to emergency 
protocols 
 
Eliminate other potential 
allergens 
 
Minor dermatological 
reactions may be treated 
with antihistamines and 
topical/systemic 
corticosteroids 
 
 
Dry skin and chronic skin 
discolouration are 
common, sometimes 
problematic, side-effects of 
with clofazimine 
 
Re-introduction of drugs 
should be discussed with 
the PI and Medical 
Monitoring Team; any drug 
causing anaphylaxis or 
Stevens-Johnson-
Syndrome should never be 
reintroduced 
 
All allergies should be 
noted on the CRF and in 
the participant’s medical 
record 
Nausea / vomiting 
/ diarrhoea / 
abdominal pain 
Any drug, esp. 
Ethionamide / 
Prothionamide, 
PAS 
Symptomatic therapy 
including hydration and anti-
emetics 
 
Investigate potential causes 
including the risk of 
underlying systemic toxicity 
(e.g. lactic acidosis, liver 
dysfunction) 
 
Check electrolytes, 
especially if using QTc 
prolonging medications 
 
Consider adjusting timings / 
doses of suspected drugs 
Temporarily suspending 
suspect drugs may be 
necessary 
 
Some anti-emetic drugs 
(e.g. ondansetron) can also 
prolong the QTc; be 
cautious monitor closely if 
concurrently using QTc 
prolonging anti-TB 
medications 
 
Antacids may interfere with 
absorption of 
fluoroquinolones; avoid 
concurrent use 
 
Adverse event 
Likely drug 
Initial management 
Comment 
Hepatotoxicity 
Rifampicin, 
isoniazid, 
pyrazinamide, 
bedaquiline, 
pretomanid 
Stop treatment if 
• 
Any ALT elevation is 
accompanied by a 
bilirubin elevation >2x 
ULN 
• 
ALT is >8 x ULN 
• 
ALT is >5x ULN and 
persist beyond 2 
weeks 
 
Eliminate other potential 
causes of liver toxicity 
(e.g. viral hepatitis, 
alcohol, concurrent 
medications) 
 
Re-introduction of drugs, 
after interruption, should 
be discussed with the PI 
and Medical Monitoring 
Team 

 
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Continue to monitor liver 
function until it returns to 
normal; seek specialist 
support for progressive 
disease 
Hypothyroidism 
Ethionamide / 
prothionamide, 
PAS 
Can be treated with 
levothyroxine and TSH 
monitoring 
 
Usually completely 
reversible on completion 
of therapy. 
Arthralgia 
Pyrazinamide / 
fluoroquinolones, 
bedaquiline 
Check urate, treat with 
non-steroidal anti-
inflammatory drugs if 
possible 
 
Consider dose reduction 
or interruption of suspect 
drug, if symptoms are 
severe 
Rarely, severe tendonitis 
and tendon rupture can 
occur with 
fluoroquinolones; should 
significant tendon 
inflammation be 
suspected consider 
stopping the 
fluoroquinolone 
Nephrotoxicity 
Injectable second 
line drugs 
Monitor renal function and 
serum electrolytes closely 
 
Consider reducing to 
thrice weekly dosing or 
changing to an all-oral 
treatment regimen if 
possible 
First-line 
recommendations for DR-
TB now avoid nephrotoxic 
injectable drugs whenever 
possible 
Deafness / 
vestibular toxicity 
(dizziness and 
tinnitus 
Injectable second 
line drugs 
Consider reducing to 
thrice weekly dosing or 
changing to an all-oral 
treatment regimen if 
possible 
 
Hearing loss from 
injectable drugs can be 
permanent: first-line 
recommendations for DR-
TB now avoid nephrotoxic 
injectable drugs whenever 
possible 
 
 
 
Adverse event 
Likely drug 
Initial management 
Comment 
Peripheral 
neuropathy 
Cycloserine / 
terizidone, 
linezolid, 
isoniazid 
 
Correct any vitamin or 
nutritional deficiencies. 
Increase pyridoxine to the 
maximum daily dose 
(200mg /day) 
 
Simple and neuropathic 
analgesia 
 
Consider whether drug 
doses can be reduced 
without compromising the 
regimen. Switching 
potential culprit drugs to 
alternatives may be 
necessary 
Be mindful of other 
potential contributors to 
multi-factorial 
neuropathy (e.g. HIV, 
ART, diabetes, 
hypothyroidism, alcohol) 
Psychological upset 
(depression / 
psychosis) 
Cycloserine / 
terizidone 
Dose reduction or stopping 
the drug may be 
necessary. 
Consider all potential 
contributors to 
psychological problems 

 
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– seek specialist support 
as appropriate 
Visual disturbance / 
optic neuritis 
Ethambutol / 
linezolid 
Stop suspect drug 
 
Seek ophthalmology 
support 
Ethambutol is typically 
associated with colour 
blindness 
Lactic acidosis 
Linezolid 
Stop linezolid 
Consider other potential 
causes of lactic acidosis 
(e.g. ART, sepsis) 
QTc prolongation 
Bedaquiline, 
delamanid, 
fluoroquinolones, 
clofazimine  
Check that potassium, 
calcium and magnesium 
levels are in the normal 
range 
 
Avoid other drugs which 
increase the QTc 
 
Consider suspension / 
discontinuation of QTc 
prolonging drugs if the 
cardiac risk outweighs the 
potential benefit 
Intensified ECG 
monitoring is indicated if 
QTc >450ms 
 
Consideration of 
suspending possible 
culprit drugs if QTc 
>500ms 
 
Greater caution required 
in participants with 
underlying cardiac 
disease 
Haematological 
abnormalities 
Linezolid 
Consider dose reduction or 
suspension of linezolid if 
progressive anaemia 
myelosuppression 
Remember that blood 
dyscrasias can 
occasionally occur with 
other anti-TB drugs 
 
 

 
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Appendix II: Example of TRiAD Screening Informed Consent Form  
 
 
 
TRiAD INFORMED CONSENT FORM: SCREENING 
(ENGLISH) 
 
TITLE: A Phase 4 Operational Study to Assess the Effectiveness, Feasibility, Acceptability, and 
Cost-Effectiveness of Implementing the GeneXpert MTB/XDR (Xpert XDR; Cepheid) Assay 
for Rapid Triage-and-Treatment of DR-TB 
 
 
INFORMATION FOR PARTICIPANTS  
 
SHORT TITLE:                                              Triage Test for All Oral DR-TB Regimen (TRiAD Study) 
 
PRINCIPAL INVESTIGATOR: 
 
Prof Kogieleum Naidoo 
 
ADDRESS: 
 
 
 
 
719 Umbilo Road 
 
 
 
 
 
 
Doris Duke Medical Research Institute (2nd floor) 
 
 
 
 
 
 
Nelson R Mandela School of Medicine 
 
 
 
 
 
 
University of Kwa-Zulu Natal 
 
 
 
 
 
 
Durban, 4013 
 
 
TELEPHONE: 
 
 
           +27 31 260 4687 
 
ETHICS COMMITTEE: 
 
 
University of KwaZulu Natal Biomedical Research  
 
 
 
 
 
 
Ethics Committee (UKZN BREC) 
 
 
 
 
 

 
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Information Sheet and Consent to Participate in Research 
 
Instructions: 
1. Please read and understand the information below 
2. If you have any questions or need any explanations, please feel to discuss with the 
person handing you the Informed Consent Form at any time. 
3. Once you have agreed to participate in the study and you will be asked to sign below.  
We will give a copy (if you wish to have one) and a copy will be placed in your file.  The 
original will be kept in a secure room by the study co-ordinator 
 
 
Date:           ____________________________ 
 
Dear patient, 
 
We are performing a research study across 9 study sites in South Africa (2), Nigeria (2) and Ethiopia 
(5). The Principal Investigator for this site is Prof Kogieleum Naidoo, telephone number is +27 31 260 
4687 and email is kogie.naidoo@caprisa.org. 
 
1. Why am I being asked to volunteer? 
 
This is a screening consent form.  You are being asked to volunteer for screening tests to find out 
if you are eligible for a research study called the TRiAD study. We approached you to participate 
in this study as you have symptoms suggestive of tuberculosis (TB) in the lung or have been 
recently diagnosed with lung TB based on your sputum test. We wish to collect an additional 
sputum sample to undertake further testing for TB drug resistance on your sputum. Before you 
decide to participate, it is important that you understand why the research is being done and what 
it will involve. Please take time to consider the following information explained below before 
deciding whether you wish to participate in this study.  We will explain this carefully but please feel 
free to ask questions or discuss with others.   
 
Joining this study is voluntary and will not affect the care you receive at this site or elsewhere. 
 
2. What is the purpose the study? 
 
TB, caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a serious infectious 
disease throughout the world. Some people have a form of TB that does not respond to standard 
drug therapy, this is called drug-resistant tuberculosis (DR-TB). Early diagnosis of drug-resistant 
TB will enable your health care worker to give you the most effective TB treatment.  
 
Researchers have been searching for better ways to diagnose and treat drug resistant TB infection. 
Sputum samples taken from people with TB symptoms undergo routine GeneXpert testing in the 
laboratory. This test finds TB and also finds resistance to the TB drug rifampicin (RIF). In this study 
we propose using an updated version of the routine GeneXpert MTB/RIF or Ultra test called the  
Xpert XDR test. The Xpert XDR test will screen your sputum for presence of resistance to additional 
TB drugs. This test will be done before your treatment regimen is selected.  Should the Xpert XDR 
test confirm TB and show presence of resistance to additional TB drugs, you will be contacted to 
enrol into our study.  
 
3. Is it necessary for me to take part in the study? 
 
It is important that you know the following: 

 
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• 
You are only being asked to provide an additional sputum for Xpert XDR testing at this time.  
Even if you agree to have the screening test, you do not have to join this study 
• 
Your participation is voluntary; you do not have to have the screening Xpert XDR test if you 
do not want to participate in this study 
• 
Your decision to not participate in this study will not result in losing your regular medical 
care 
• 
You will receive the results of the screening test is positive and you are being considered 
for participation in this study 
 
4. What do I have to do if I decide to take part in the screening tests? 
 
If you agree to have screening sputum test, this will be done in addition to the routine TB test 
performed on your sputum.   
 
Screening Visit: 
The procedures done at this visit today will take 15 – 30 minutes   
 
• 
You will be asked to provide the following information, in order for us to contact you, should 
you have a positive Xpert XDR test: 
o Contact telephone number 
o Any alternate telephone numbers  
o Where you live  
 
• 
Study staff will take a sputum sample, to test your drug resistance to different TB drugs (if 
any)  
o You will be told your TB test result as soon as it is available.  You will talk with the 
study staff about the meaning of your results, how you feel about them, and ways to 
prevent the spread of TB. Only those with a recent valid TB test result will be 
considered for inclusion in this study.   
o Participants suffering clinically significant medical conditions or have previous 
exposure to TB drugs; Bedaquiline and/or linezolid, cannot join this study.  We will tell 
you where you can get care and other services you may need.  The study staff will tell 
you about other studies you may be eligible for, if any. 
 
If the sputum GeneXpert MTB/RIF or Ultra test results show that you can join the TRiAD study, 
you may be contacted for enrollment into the study. Participants will be enrolled in this study for 12 
-18 months; however this period could be shorter or longer than anticipated.  If you decide to be in 
this study, you will be asked to sign another consent form. 
 
5. What are the risks and disadvantages of taking part? 
 
There are no disadvantages of taking part in this study  
 
6. What are the possible benefits of taking part? 
 
The primary benefit of screening for this study is having access to the new Xpert XDR diagnostic.  
 
7. Reasons why you may be withdrawn from the screening tests without your consent 
 
• 
Sputum sample submitted is inadequate for the Xpert XDR test 
• 
You are found not to be eligible for this study 
• 
Other reasons identified by study staff 
 

 
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8. Will I receive payment? 
 
There is no re-imbursement for the screening test.   
 
9. Will my taking part in the study be kept confidential? 
 
Yes.  All information collected about you during the course of the research will be kept strictly 
confidential.   
 
10. What happens if I am injured or have concerns?  
 
It is unlikely that you will be injured as a result of screening for this study. If you are injured as a 
result of screening for this study, you will be given immediate necessary treatment for your injuries 
at the study site, or referred to the nearest health facility for treatment. There will be no 
compensation provided for research related injuries. You do not give up any legal rights by signing 
this consent form.  If you have any concerns about any aspect of this study, you should ask to 
speak to the study staff who will be able to better answer your questions.   
 
11. What will happen to any samples I give? 
 
All sputum samples collected will be used to determine your TB diagnosis and for detection of TB 
drug resistance using the routine GeneXpert MTB/RIF or Ultra, and the XPERT XDR test. 
 
12. Contacts and Questions 
If you ever have any questions about the screening tests, or if you have a research-related injury, 
you should contact: 
BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
Research Office, Westville Campus 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2604769 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
 
You will be given a copy of the information sheet and a signed consent form to keep if you 
wish to do so. Thank you for taking the time to read this information sheet.  
 

 
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SIGNATURE FOR SCREENING STUDY INFORMED CONSENT 
 
If you have read this screening consent form (or had it explained to you), all your questions 
have answered, and you agree to provide a sputum sample for Xpert XDR testing and take 
part in this study, please sign your name below: 
 
 
__________________________________      _____________________               _________ 
Participants Name (Print) 
 
 
       Participants Signature  
                  Date 
 
 
 
 
__________________________________     ______________________              _________ 
Study Staff Conducting the Consent  
       Study Staff Signature  
                  Date 
(Print) 
 
 
 
__________________________________     _______________________            _________ 
Witness’s Name (Print)  
 
 
       Witness’s Signature 
 
      Date 
(If Applicable) 
 
 
 

 
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Appendix III: Example of TRiAD Enrolment Informed Consent Form – Cohort 1
 
TRiAD INFORMED CONSENT FORM:  
STUDY ENROLMENT IN COHORT 1 
(ENGLISH) 
 
TITLE: A Phase 4 Operational Study to Assess the Effectiveness, Feasibility, Acceptability, and 
Cost-Effectiveness of Implementing the GeneXpert MTB/XDR (Xpert XDR; Cepheid) Assay 
for Rapid Triage-and-Treatment of DR-TB 
 
 
INFORMATION FOR PARTICIPANTS  
 
SHORT TITLE:                                             Triage Test for All Oral DR-TB Regimen (TRiAD) 
PRINCIPAL INVESTIGATOR: 
 
Prof  Kogieleum Naidoo 
ADDRESS: 
 
 
 
 
719 Umbilo Road 
 
 
 
 
 
 
Doris Duke Medical Research Institute (2nd floor) 
 
 
 
 
 
 
Nelson R Mandela School of Medicine 
 
 
 
 
 
 
University of Kwa-Zulu Natal 
 
 
 
 
 
 
Durban, 4013 
 
TELEPHONE: 
 
 
           +27 31 260 4687 
ETHICS COMMITTEE: 
 
 
University of KwaZulu Natal Biomedical Research  
 
 
 
 
 
 
Ethics Committee (UKZN BREC) 

 
TRiAD Study Protocol  
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Information Sheet and Consent to Participate in Research 
Instructions: 
1.  Please read and understand the information given below 
2.  If you have any questions or need any explanations, then please feel to discuss with the 
person handing you the Informed Consent Form at any time. 
3. Once you have agreed to participate in the study and you will be asked to sign the 
enrollment informed consent form.  We will give a copy (if you wish to have one) and a 
copy will be placed in your file.  The original will be kept in a secure room by the study 
coordinator 
 
 
Date:           ____________________________ 
You are being invited to take part in this research study because you have recently been diagnosed 
with drug resistant TB based on your sputum test results and are therefore eligible for a short oral 
drug resistant tuberculosis treatment regimen.  The doctor in charge of this study is Dr Kogieleum 
Naidoo. Before you decide if you want to enroll in this study, we want you to know more about the 
study. 
This consent form gives you information about this study, which will be done at King DinuZulu Hospital 
Complex in Durban.  Please ask questions and discuss any concerns you may have with the research 
staff. If you agree to take part in this study, you will be asked to sign this consent form. You will be 
given a copy of this consent form to keep.  
Please note that: 
• 
Your participation in this study is entirely voluntary. You may decide not to participate in the 
study, but you will still receive the same medical care as determined by your doctor.   
• 
You may stop taking part in the study at any time and this will not affect the care you receive 
at the hospital. 
• 
You may contact the Biomedical Research Ethics Committee (BREC) on 031-260 4769 or 
031-260 1074 (business hours) if you have questions about your rights as a research subject. 
 
1. What is the purpose the study? 
 
The purpose of this study is to help doctors to rapidly identify and treat drug-resistant TB with the 
best available drugs. By allowing us to ask questions, collect information, and collect monthly 
sputum samples from you we will be able to assess the relationship between better diagnosis and 
treatment of drug resistant tuberculosis on treatment outcomes for drug-resistant tuberculosis. 
 
2. How many people will take part in this study? 
 
Approximately 320 participants will take part in this study. 
 
 
 

 
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3. What is involved in this study? 
 
If you would like to participate in this study, you will be asked questions about your medical history 
and any medicines that you have taken. If you agree to participate in the study, we will collect 
medical information including results of blood tests, X- rays and sputum tests from your medical 
records.  During your enrollment and follow-up visits, we will ask you to produce sputum samples 
which will be collected, processed and stored for future analysis  
 
You will be requested to visit the clinic for study visits in two weeks, and monthly thereafter for 
about 6 months (while you receive the entire short-course TB treatment regimen, or during the 
intensive phase of TB treatment if you are receiving a longer regimen). Thereafter, we will see you 
at the clinic three-monthly until 12 months since your TB diagnosis. We will still maintain telephonic 
contact with you every three months until about 18 months since TB diagnosis, irrespective of 
whether or not you are still receiving TB treatment.   
 
Use of Data/Specimens  
For this study we will share your sputum, samples with other researchers at another institution  
(collaborators at San Raffaele Scientific Institute in Italy) so that other research studies can be 
done. If your sputum sample is shared with the other institution, your identifying information will not 
be included. If you agree to let us keep your samples for future research, your sputum will be stored 
at the CAPRISA Research Laboratory for 10 years.  If we are required to perform any additional 
tests on your sputum, CAPRISA will contact the Biomedical Research Ethics Committee for 
approval. There will be no additional medications given to you, other than the standard medications 
your doctors prescribe for you. 
 
4. How long will I be in the study? 
 
You will be followed-up actively through the course of your drug-resistant tuberculosis treatment 
and through telephonic calls afterwards to a maximum of 18 months. 
 
5. Are there benefits to taking part in this study? 
 
If you participate in this study, you will likely receive a faster and more comprehensive diagnosis 
of drugs that you are resistant. You will possibly be cured sooner with a shorter duration of only 
6-12 months treatment. However, should you have severe disease as determined by your doctor, 
the regimen selected maybe longer i.e. up to 18 months 
 
6. What are the potential risks associated with this study? 
 
There is a possibility of failure of the short regimens to provide intended therapeutic effect. In such 
cases you will be given treatment as per the sputum drug susceptibility results. There is a potential 
risk for psychological distress from attending study related visits. Please note that you can withdraw 
from the study at any time. 
 
 
 
 

 
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7. What about confidentiality and sharing information? 
 
We are collecting information on enrolled patients as the tests and drugs used in this study are 
new to the TB program.  The information we get from this study may help us to treat future patients 
with drug-resistant TB better. The results of clinical tests performed as part of this study will in your 
confidential medical record. The information that we collect from you will be kept confidential, using 
an anonymous identifier. Clinical staff, sponsor and/or its representatives, and regulatory agencies 
may access your clinical records.  The information and results from this study, if published in 
scientific journals or presented at scientific meetings, will be unlinked to your name (made 
anonymous). 
 
8. What other choices do I have besides this study? 
 
If you choose not to participate in this study, you can still receive medical treatment at King 
DinuZulu referral hospital. 
 
9. Will I receive payment? 
 
You will be compensated R300 for each study visit for your time and effort provided in participating 
in the research. For the follow-up visits you will also be compensated R300. 
 
10. What are the costs to me? 
 
Taking part in this study will not involve additional costs to you. Treatment for drug resistant TB 
and HIV is provided at no cost according to the practices and policies of King DinuZulu referral 
hospital and the KwaZulu-Natal Department of Health. 
 
11. What happens if I am injured or have concerns?  
 
It is unlikely that you will be injured as a result of enrollment for this study. If you are injured as a 
result of enrolling for this study, you will be given immediate necessary treatment for your injuries 
at the study site, or referred to the nearest health facility for treatment. There will be no 
compensation provided for research related injuries. You do not give up any legal rights by signing 
this consent form.  If you have any concerns about any aspect of this study, you should ask to 
speak to the study staff who will be able to better answer your questions.   
 
12. What if I decide not to participate in the study? 
Taking part in this study is your choice.  You may choose to either take part or not take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care. 
13. Contacts and Questions 
 
• 
If you have any questions while taking part in this research study, you should contact the 
Principal Investigator:  Dr. Kogie Naidoo 
Telephone: +27 31 566 0500 
Email: Kogie.naidoo@caprisa.org 

 
TRiAD Study Protocol  
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• 
For questions about your rights as a research participant, or any problems related to the 
study you may contact: Biomedical Research Ethics Committee (BREC)  
Research Office, Westville Campus 
Govan Mbeki Building 
Private Bag X 54001  
Durban 4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2604769 (business hours) - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za 
 
• 
If you have any questions regarding the study that was not answered to your satisfaction 
by your doctor and the Ethics Committee, you should write to The South African Health 
Products Regulatory Authority (SAHPRA) at: 
The Registrar  
SAHPRA 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Your participation in this research is voluntary, and you will not be penalized or lose benefits if you 
refuse to participate or decide to stop. 
 
If you agree to participate you will be given a copy of the information sheet and a signed 
consent form to keep if you wish to do so. Thank you for taking the time to read this 
information sheet.  
 

 
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INFORMED CONSENT SIGNATURE FOR STUDY ENROLMENT  
 
The research study, including the above information, has been described to me orally. I 
understand what my involvement in the study means and I voluntarily agree to participate.  
 
1. I give my permission to participate in the study  
 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
2. I give my permission for my samples to be collected and stored for future research 
use 
 
Samples will be collected and stored for future research use. For this study we may share 
your sputum samples with other researchers at other institutions so that other research studies 
can be done now or in the future. If your sputum samples are shared with other institutions, 
your identifying information will not be included. The research team may use these samples 
to confirm test results or to do additional new tests if required. Your samples will not be sold 
or used in other products that make money for researchers. To protect your identity your 
sample container will not have your name or any information that may identify you. Only your 
participant number will be used on sample containers.  
 
Any studies that use your samples will be reviewed by the Biomedical Research Ethics 
Committee of the University of KwaZulu Natal. 
 
The researchers do not plan to contact you or your regular doctor with any results that are 
done on the stored samples after the study has been completed. This is because research 
tests are often done with experimental procedures so the results from one study are generally 
not useful for making decisions on managing your health. Should a rare situation come up 
where the researchers decide that a specific test result would provide important information 
for your health, the researchers will notify the study doctor who will try to contact you or your 
regular doctor. If you wish to be notified of this type of test result, you need to make sure that 
you contact the study nurse or doctor with any changes to your phone number or address. If 
you want your regular doctor to be told about this kind of test result, you need to provide the 
study team with the contact details of your regular doctor. 
 
 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
 

 
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3. I give my permission for any collected samples to be shipped to collaborators 
outside of South Africa. 
 
 
_______________________________      _____________________       ______________ 
Participants Name (Print) 
                    Participants Signature             Date (dd/mm/yr) 
 
4. I give my permission for Telephonic Contact 
 
If you cannot come to the CAPRISA offices at KDH for your study visit, study staff will 
contact you on your cell phone or home phone to complete study questionnaires. Study staff 
will ask you to go to a quiet place where you cannot be disturbed so you may answer 
confidential questions. 
 
                   YES, I agree to be contacted telephonically by CAPRISA staff to complete study  
                   questionnaires 
 
                   NO, I do not agree to be contacted telephonically by CAPRISA staff to complete 
study questionnaires 
 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
 
 
 
 
 

 
TRiAD Study Protocol  
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Appendix IV: Example of TRiAD Enrolment Informed Consent Form – Cohort 2 
 
 
TRiAD INFORMED CONSENT FORM:  
STUDY ENROLMENT IN COHORT 2 
(ENGLISH) 
 
TITLE: A Phase 4 Operational Study to Assess the Effectiveness, Feasibility, Acceptability, and 
Cost-Effectiveness of Implementing the GeneXpert MTB/XDR (Xpert XDR; Cepheid) Assay 
for Rapid Triage-and-Treatment of DR-TB 
 
 
INFORMATION FOR PARTICIPANTS  
 
SHORT TITLE:                                             Triage Test for All Oral DR-TB Regimen (TRiAD) 
PRINCIPAL INVESTIGATOR: 
 
Prof  Kogieleum Naidoo 
ADDRESS: 
 
 
 
 
719 Umbilo Road 
 
 
 
 
 
 
Doris Duke Medical Research Institute (2nd floor) 
 
 
 
 
 
 
Nelson R Mandela School of Medicine 
 
 
 
 
 
 
University of Kwa-Zulu Natal 
 
 
 
 
 
 
Durban, 4013 
 
TELEPHONE: 
 
 
           +27 31 260 4687 
ETHICS COMMITTEE: 
 
 
University of KwaZulu Natal Biomedical Research  
 
 
 
 
 
 
Ethics Committee (UKZN BREC) 

 
TRiAD Study Protocol  
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Information Sheet and Consent to Participate in Research 
Instructions: 
1.  Please read and understand the information given below 
2.  If you have any questions or need any explanations, then please feel to discuss with the 
person handing you the Informed Consent Form at any time. 
3. Once you have agreed to participate in the study and you will be asked to sign the 
enrollment informed consent form.  We will give a copy (if you wish to have one) and a 
copy will be placed in your file.  The original will be kept in a secure room by the study 
coordinator 
 
 
Date:           ____________________________ 
You are being invited to take part in this research study because you have been diagnosed with 
resistance to one TB drug based on your recent sputum test results. You are therefore eligible for 
an alternate standard TB treatment regimen.  The doctor in charge of this study is Dr Kogieleum 
Naidoo. Before you decide if you want to enroll in this study, we want you to know more about the 
study. 
 
This consent form gives you information about this study, which will be done at King DinuZulu Hospital 
Complex in Durban.  Please ask questions and discuss any concerns you may have with the research 
staff. If you agree to take part in this study, you will be asked to sign this consent form. You will be 
given a copy of this consent form to keep.  
 
Please note that: 
• 
Your participation in this study is entirely voluntary. You may decide not to participate in the 
study, but you will still receive the same medical care as determined by your doctor.   
• 
You may stop taking part in the study at any time and this will not affect the care you receive 
at the hospital. 
• 
You may contact the Biomedical Research Ethics Committee (BREC) on 031-260 4769 or 
031-260 1074 (business hours) if you have questions about your rights as a research subject. 
 
1. What is the purpose the study? 
 
The purpose of this study is to help doctors to rapidly identify and treat drug-resistant TB with the 
best available drugs. By allowing us to ask questions, collect information from the DR TB program 
on your progress with treatment and results of sputum samples we will be able to assess the 
relationship between better diagnosis and treatment of drug resistant tuberculosis, on drug-
resistant tuberculosis treatment outcomes. 
 
2. How many people will take part in this study? 
 
Approximately 100 participants will take part in this study. 
 
 
 

 
TRiAD Study Protocol  
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3. What is involved in this study? 
 
If you would like to participate in this study, you will be asked questions about your medical history 
and any medicines that you have taken. If you agree to participate in the study, we will see you at 
our clinic for an enrollment visit only where we will collect medical information including results of 
blood tests, X- rays and sputum tests from interviewing you and from your medical records. At this 
visit a sputum sample will be collected from you. This sample will be processed and stored for 
future analysis. Although we do not require you to attend any further research visits, we will collect 
all clinical and laboratory information for this episode of TB from your clinical records.   
 
We will maintain telephonic contact, monthly for six months and 3-monthly thereafter, until 6 
months after the end of your TB treatment.  
 
Use of Data/Specimens  
For this study we will share your sputum samples with other researchers at another institution  
(collaborators at San Raffaele Scientific Institute in Italy) so that other research studies can be 
done. If your sputum sample is shared with the other institution, your identifying information will not 
be included. If you agree to let us keep your samples for future research, your sputum will be stored 
at the CAPRISA Research Laboratory for 10 years.  If we are required to perform any additional 
tests on your sputum, CAPRISA will contact the Biomedical Research Ethics Committee for 
approval. There will be no additional medications given to you, other than the standard medications 
your doctors prescribe for you. 
 
4. How long will I be in the study? 
 
You will be followed up telephonically after this visit for 6 months after TB treatment . 
 
5. Are there benefits to taking part in this study? 
 
If you participate in this study, there may be a direct benefit to you. you will likely receive a more 
comprehensive diagnosis of drugs that you are resistant to faster.  We believe that the diagnostic 
and drugs used in this study may significantly improve your TB treatment outcomes, but no 
guarantee can be made. It is important to note that there are no significant risks or benefits for you 
to produce a sputum sample.   
 
6. What are the potential risks associated with this study? 
 
There is a possibility of failure of the short/new regimens to provide intended therapeutic effect. In 
such cases you will be given treatment as per the sputum drug susceptibility results. There is a 
potential risk for psychological distress from attending study related visits. Please note that you 
can withdraw from the study at any time. 
 
7. What about confidentiality and sharing information? 
 
We are collecting information on enrolled patients as the tests and drugs used in this study are 
new to the TB program.  The information we get from this study may help us to treat future patients 
with drug-resistant TB better. The results of clinical tests performed as part of this study will in your 
confidential medical record. The information that we collect from you will be kept confidential, using 
an anonymous identifier. Clinical staff, sponsor and/or its representatives, and regulatory agencies 
may access your clinical records.  The information and results from this study, if published in 
scientific journals or presented at scientific meetings, will be unlinked to your name (made 
anonymous). 
 
 

 
TRiAD Study Protocol  
Page 88 of 91 
 Version 6.0, 12 September 2023 
 
8. What other choices do I have besides this study? 
 
If you choose not to participate in this study, you can still receive medical treatment at King 
DinuZulu referral hospital. 
 
9. Will I receive payment? 
 
You will be compensated R300 for the enrolment visit only 
 
10. What are the costs to me? 
 
Taking part in this study will not involve additional costs to you. Treatment for drug resistant TB 
and HIV is provided at no cost according to the practices and policies of King DinuZulu referral 
hospital and the KwaZulu-Natal Department of Health. 
 
11. What happens if I am injured or have concerns?  
 
It is unlikely that you will be injured as a result of enrollment for this study. If you are injured as a 
result of enrolling for this study, you will be given immediate necessary treatment for your injuries 
at the study site, or referred to the nearest health facility for treatment. There will be no 
compensation provided for research related injuries. You do not give up any legal rights by signing 
this consent form.  If you have any concerns about any aspect of this study, you should ask to 
speak to the study staff who will be able to better answer your questions.   
 
12. What if I decide not to participate in the study? 
Taking part in this study is your choice.  You may choose to either take part or not take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care. 
13. Contacts and Questions 
• 
If you have any questions while taking part in this research study, you should contact the 
Principal Investigator:  Dr. Kogie Naidoo 
Telephone: +27 31 566 0500 
Email: Kogie.naidoo@caprisa.org 
 
• 
For questions about your rights as a research participant, or any problems related to the 
study you may contact: Biomedical Research Ethics Committee (BREC)  
Research Office, Westville Campus 
Govan Mbeki Building 
Private Bag X 54001  
Durban 4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2604769 (business hours) - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za 
 
• 
If you have any questions regarding the study that was not answered to your satisfaction 
by your doctor and the Ethics Committee, you should write to The South African Health 
Products Regulatory Authority (SAHPRA) at: 
The Registrar  

 
TRiAD Study Protocol  
Page 89 of 91 
 Version 6.0, 12 September 2023 
 
SAHPRA 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Your participation in this research is voluntary, and you will not be penalized or lose benefits if you 
refuse to participate or decide to stop. 
 
If you agree to participate you will be given a copy of the information sheet and a signed 
consent form to keep if you wish to do so. Thank you for taking the time to read this 
information sheet.  
 

 
TRiAD Study Protocol  
Page 90 of 91 
 Version 6.0, 12 September 2023 
 
INFORMED CONSENT SIGNATURE FOR STUDY ENROLMENT  
 
The research study, including the above information, has been described to me orally. I 
understand what my involvement in the study means and I voluntarily agree to participate.  
 
1. I give my permission to participate in the study  
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
2. I give my permission for my samples to be collected and stored for future research 
use 
 
Samples will be collected and stored for future research use. For this study we may share 
your sputum samples with other researchers at other institutions so that other research studies 
can be done now or in the future. If your sputum samples are shared with other institutions, 
your identifying information will not be included. The research team may use these samples 
to confirm test results or to do additional new tests if required. Your samples will not be sold 
or used in other products that make money for researchers. To protect your identity your 
sample container will not have your name or any information that may identify you. Only your 
participant number will be used on sample containers.   
 
Any studies that use your samples will be reviewed by the Biomedical Research Ethics 
Committee of the University of KwaZulu Natal. 
 
The researchers do not plan to contact you or your regular doctor with any results that are 
done on the stored samples after the study has been completed. This is because research 
tests are often done with experimental procedures so the results from one study are generally 
not useful for making decisions on managing your health. Should a rare situation come up 
where the researchers decide that a specific test result would provide important information 
for your health, the researchers will notify the study doctor who will try to contact you or your 
regular doctor. If you wish to be notified of this type of test result, you need to make sure that 
you contact the study nurse or doctor with any changes to your phone number or address. If 
you want your regular doctor to be told about this kind of test result, you need to provide the 
study team with the contact details of your regular doctor. 
 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
 
 
 

 
TRiAD Study Protocol  
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3. I give my permission for any collected samples to be shipped to collaborators 
outside of South Africa. 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr) 
 
 
4. I give my permission for Telephonic Contact 
 
Study staff will contact you on your cell phone or home phone to complete study 
questionnaires. Study staff will ask you to go to a quiet place where you cannot be disturbed 
so you may answer confidential questions. 
 
                   YES, I agree to be contacted telephonically by CAPRISA staff to complete study  
                   questionnaires 
 
                   NO, I do not agree to be contacted telephonically by CAPRISA staff to complete   
study questionnaires 
 
 
______________________________      _____________________         ______________ 
Participants Name (Print) 
 
        Participants Signature             Date (dd/mm/yr)